Stricker, B.H.Ch.

The effect of thiazide and loop diuretics on urinary levels of free deoxypyridinoline: An osteoclastic bone-resorption marker (Article)

2013-06-01T00:00:00Z

What is known and Objective Diuretics can cause changes in calcium levels due to renal effects. Moreover, calcium levels can also vary as a result of changes in intestinal absorption and in the activity of osteoclastic cells. A marker of osteoclastic bone-resorption activity is the level of urinary free deoxypyridinoline (FDP). Deoxypyridinoline (DP) acts as a cross-link between adjacent collagen chains to provide structural rigidity. Our aim was to investigate the association between use of thiazides and loop diuretics and urinary levels FDP. Methods In this follow-up study, data were obtained from the Rotterdam Study, a large population-based prospective cohort study. For a subset of 658 participants, urinary levels of FDP were measured at baseline. Linear regression analysis was performed to assess the association between the use of thiazides and loop diuretics and the urinary levels of FDP. Results In women, current use of loop diuretics for less than 42 days was associated with an increased level of urinary FDP (+3·43 nmol deoxypyridinoline per mmol urinary creatinine; 95% CI 1·85; 5·02) compared with no use. However, use for a period of more than 42 days was not associated with an increased level of FDP, nor was past use of loop diuretics. For thiazide diuretics, no statistically significant associations were found. What is new and Conclusion In women, short-term use of loop diuretics is associated with an increased level of FDP, reflecting increased bone resorption by osteoclasts. As the difference disappears with longer term use, the clinical significance is unclear and the value of FDP as a biomarker in this setting is not established. The molecular mechanism for the observed differences in bone fracture rates with use of diuretics remains unclear.

External Validation of the Fatty Liver Index for Identifying Nonalcoholic Fatty Liver Disease in a Population-based Study (Article)

2013-04-09T00:00:00Z

Background & Aims: We aimed to validate the fatty liver index (FLI), an algorithm that is based on waist circumference, body mass index, and levels of triglyceride and γ-glutamyltransferase. We calculated its ability to identify fatty liver disease from any cause or nonalcoholic fatty liver disease (NAFLD) in a large population of white elderly persons. Methods: We collected ultrasonography and FLI data from participants of the Rotterdam Study from February 2009 to February 2012; 2652 subjects (mean age, 76.3 ± 6.0 years) were interviewed and received a clinical examination that included abdominal ultrasound, analysis of blood samples during fasting, and anthropometric assessment. The ability of the FLI to detect (nonalcoholic) fatty liver was assessed by using area under the receiver operator characteristic (AUROC) curve analysis. Results: FLI score was associated with NAFLD in multivariable analysis (odds ratio, 1.05; 95% confidence interval [CI], 1.04-1.05; P < .001). FLI identified patients with NAFLD with an AUROC curve of 0.813 (95% CI, 0.797-0.830) and those with fatty liver from any cause with an AUROC curve of 0.807 (95% CI, 0.792-0.823). Conclusions: The FLI (an algorithm that is based on waist circumference, body mass index, and levels of triglyceride and γ-glutamyltransferase) accurately identifies NAFLD, confirmed via ultrasonography, in a large, white, elderly population.

Statin use is associated with reduced incidence and progression of knee osteoarthritis in the Rotterdam study (Article)

2012-05-01T00:00:00Z

Background: Osteoarthritis is the most frequent chronic joint disease causing pain and disability. Besides biomechanical mechanisms, the pathogenesis of osteoarthritis may involve inflammation, vascular alterations and dysregulation of lipid metabolism. As statins are able to modulate many of these processes, this study examines whether statin use is associated with a decreased incidence and/or progression of osteoarthritis. Methods: Participants in a prospective population-based cohort study aged 55 years and older (n=2921) were included. x-Rays of the knee/hip were obtained at baseline and after on average 6.5 years, and scored using the Kellgren and Lawrence score for osteoarthritis. Any increase in score was defined as overall progression (incidence and progression). Data on covariables were collected at baseline. Information on statin use during follow-up was obtained from computerised pharmacy databases. The overall progression of osteoarthritis was compared between users and non-users of statins. Using a multivariate logistic regression model with generalised estimating equation, OR and 95% CI were calculated after adjusting for confounding variables. Results: Overall progression of knee and hip osteoarthritis occurred in 6.9% and 4.7% of cases, respectively. The adjusted OR for overall progression of knee osteoarthritis in statin users was 0.43 (95% CI 0.25 to 0.77, p=0.01). The use of statins was not associated with overall progression of hip osteoarthritis. Conclusions: Statin use is associated with more than a 50% reduction in overall progression of osteoarthritis of the knee, but not of the hip.

Generalizing lung-cancer screening results (Article)

2012-01-12T00:00:00Z

Cholesterol-lowering drugs and incident open-angle glaucoma: A population-based cohort study (Article)

2012-01-04T00:00:00Z

Background: Open-angle glaucoma (OAG) is a progressive neurodegenerative disease that may lead to blindness. An elevated intraocular pressure (IOP) is its major risk factor. OAG treatment is currently exclusively directed towards the lowering of the IOP. IOP lowering does not prevent disease progression in all patients and thus other treatment modalities are needed. Earlier studies reported cholesterol-lowering drugs to have neuroprotective properties. The aim of this study was to determine the associations between the use of cholesterol-lowering drugs and incident OAG. Methodology/Principal Findings: Participants in a prospective population-based cohort study underwent ophthalmic examinations, including IOP measurements and perimetry, at baseline and follow-up. The use of statins and non-statin cholesterol-lowering drugs was monitored continuously during the study. Associations between the use of cholesterol-lowering drugs and incident OAG were analyzed with Cox regression; associations between cholesterol-lowering drugs and IOP at follow-up were analyzed with multiple linear regression. During a mean follow-up of 9.8 years, 108 of 3939 eligible participants (2.7%) developed OAG. The hazard ratio for statin use was 0.54 (95% confidence interval 0.31-0.96; P = 0.034) and for non-statin cholesterol-lowering drugs 2.07 (0.81-5.33; P = 0.13). The effect of statins was more pronounced with prolonged use (hazard ratio 0.89 [0.41-1.94; P = 0.77] for use two years or less; 0.46 [0.23-0.94; P = 0.033] for use more than two years; P-value for trend 0.10). The analyzes were adjusted for age and gender, baseline IOP and IOP-lowering treatment, the family history of glaucoma, and myopia. There was no effect of statins on the IOP. Conclusions/Significance: Long-term use of statins appears to be associated with a reduced risk of OAG. The observed effect was independent of the IOP. These findings are in line with the idea that statins have neuroprotective properties and may open a way to a new OAG treatment modality.

Research highlights (Article)

2012-01-01T00:00:00Z

Risk of cancer in patients on insulin glargine and other insulin analogues in comparison with those on human insulin: Results from a large population-based follow-up study (Article)

2012-01-01T00:00:00Z

Aims/hypothesis Several publications suggest an association between certain types of insulin and cancer, but with conflicting results. We investigated whether insulin glargine (A21Gly,B31Arg,B32Arg human insulin) is associated with an increased risk of cancer in a large population-based cohort study. Methods Data for this study were obtained from dispensing records from community pharmacies individually linked to hospital discharge records from 2.5 million individuals in the Netherlands. In a cohort of incident users of insulin, the association between insulin glargine and other insulin analogues, respectively, and cancer was analysed in comparison with human insulin using Cox proportional hazard models with cumulative duration of drug use as a time-varying determinant. The first hospital admission with a primary diagnosis of cancer was considered as the main outcome; secondary analyses were performed with specific cancers as outcomes. Results Of the 19,337 incident insulin users enrolled, 878 developed cancer. Use of insulin glargine was associated with a lower risk of malignancies in general in comparison with human insulin (HR 0.75, 95% CI 0.71, 0.80). In contrast, an increased risk was found for breast cancer (HR 1.58, 95% CI 1.22, 2.05). Dose-response relationships could not be identified. Conclusion/interpretation Users of insulin glargine and users of other insulin analogues had a lower risk of cancer in general than those using human insulin. Both associations might be a consequence of residual confounding, lack of adherence or competing risk. However, as in previous studies, we demonstrated an increased risk of breast cancer in users of insulin glargine in comparison with users of human insulin.

Novel CYP3A4 intron 6 single nucleotide polymorphism is associated with simvastatin-mediated cholesterol reduction in the Rotterdam Study (Article)

2011-12-01T00:00:00Z

Objectives: CYP3A4 is involved in the oxidative metabolism of many drugs and xenobiotics including the HMG-CoA reductase inhibitor simvastatin. The objective of this study was to investigate whether a new CYP3A4 functional single nucleotide polymorphism (SNP) in intron 6 (CYP3A4*22) modifies the effect of simvastatin on total cholesterol (TOTc) or LDL cholesterol (LDLc) reduction in a population-based cohort study. Methods: In a total of 80 incident simvastatin users, the association between the CYP3A4 intron 6 C>T SNP (rs35599367) and reduction in cholesterol levels was analyzed using linear regression analysis and adjusting for potential confounding factors. Results: The CYP3A4*22 allele was associated with a trend towards a stronger simvastatin lipid-lowering response, as reflected by the greater reduction in both TOTc and LDLc levels when compared with homozygous wild type. We observed that the CYP3A4*22 allele carriers had an increased reduction in TOTc and LDLc:-0.25 mmol/l (95% confidence interval [CI95%]=[-0.52; 0.01], P=0.058) and-0.29 mmol/l (CI95%=[-0.58; 0.01], P=0.054) when compared with homozygous CC. When we adjusted the model for potential confounding factors, the corresponding reduction in TOTc was-0.31 mmol/l (CI95%=[-0.59;-0.04], P=0.028) and for LDLc-0.34 mmol/l (CI95%=[-0.66;-0.02], P=0.034) greater for CYP3A4*22 allele carriers when compared with homozygotes wild type. Conclusion: The CYP3A4*22 intron 6 SNP T-variant allele was associated with reduced CYP3A4 activity, resulting in a better lipid lowering response to simvastatin, when data were adjusted for confounding factors. This observation is a step towards the clarification of the reasons of interindividual variability in statins response and may potentially lead to improved tailoring of simvastatin therapy.

Selective serotonin re-uptake inhibiting antidepressants and the risk of overanticoagulation during acenocoumarol maintenance treatment (Article)

2011-11-01T00:00:00Z

AIM The aim of this study was to investigate the effects of co-medication with selective serotonin re-uptake inhibitors (SSRIs) on overanticoagulation during acenocoumarol maintenance treatment. METHODS All subjects from The Rotterdam Study who received acenocoumarol maintenance treatment between April 1 1991 and September 9 2009 were followed for the event of an international normalized ratio (INR) ≥6, until death, end of treatment or end of the study period. With the Andersen-Gill extension of the Cox proportional hazards model, risks for repeated events of overanticoagulation in relation to concomitant SSRI use were calculated. RESULTS The risk for overanticoagulation during acenocoumarol maintenance treatment was increased in combination with fluvoxamine (HR 2.63, 95% CI 1.49, 4.66) and venlafaxine (HR 2.19, 95% CI 1.21, 3.99). There was no increase in risk for the other SSRIs, but numbers of exposed cases were low for all SSRIs except paroxetine. CONCLUSION Fluvoxamine and venlafaxine were associated with a more than double risk of INR values ≥6 in acenocoumarol treated subjects. © 2011 The Authors. British Journal of Clinical Pharmacology

Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function (Article)

2011-11-01T00:00:00Z

Pulmonary function measures reflect respiratory health and are used in the diagnosis of chronic obstructive pulmonary disease. We tested genome-wide association with forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced vital capacity in 48,201 individuals of European ancestry with follow up of the top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P < 5 ×-10-8) with pulmonary function in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (also known as EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1 and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function.

Complications after hip arthroplasty and the association with hospital procedure volume: A nationwide retrospective cohort study on 50,080 total hip replacements with a follow-up of 3 months after surgery (Article)

2011-10-01T00:00:00Z

Background and purpose: It has been suggested that a higher procedure volume is associated with less complications after hip arthroplasty. In order to investigate the incidence of serious negative outcomes and a possible association with procedure volume, we performed a retrospective nationwide cohort study on total hip replacements in all Dutch hospitals. Methods: All total hip replacements (n = 50,080) that were identified as primary intervention in all general and university medical centers between January 1, 2002 and October 1, 2004 were included. Primary endpoints of follow-up were mortality and complications during admission, and re-admission within 3 months due to complications. Variables that were assessed as potential risk factor were age, sex, duration of (preoperative) admission, specific diagnosis, acute/non-planned admission, co-morbidity, and hospital procedure volume. Results: Age, sex, and comorbidity were associated with complications and mortality. Additionally, acute admission was a risk factor for mortality but not for complications. There was no linear trend indicating that decreasing volume led to an increasing number of complications, and no statistically sginificant effect for mortality was found. Interpretation: After adjustment for several risk factors, we found that the hospitals performing most hip procedures every year had fewer complications during index admission, but that they did not have a lower mortality than groups performing fewer procedures. The lack of a linear trend may be explained by the fact that almost all Dutch hospitals perform a high number of hip arthroplasties each year.

Genetic variation in the renin-angiotensin system, use of renin-angiotensin system inhibitors and the risk of myocardial infarction (Article)

2011-09-01T00:00:00Z

Introduction. This study investigated whether variation in the genes encoding for ACE, AGT and AGTR1 modifies the risk of myocardial infarction (MI) related to ACE inhibitors and AT II antagonists. Methods. A nested case-control study among users of antihypertensive drugs, in whom the polymorphisms ACE-G4656C, ACE-T3892C, AGT-C235T and AGTR1-A1166C were genotyped. Results. Among 613 cases and 3630 controls, the risk of MI was significantly lower among users of ACE inhibitors compared with that in users of other antihypertensives (adjusted OR, 0.78; 95% CI, 0.63-0.97). In patients using ACE inhibitors the largest risk reduction was found in patients carrying the ACE-4656-G allele (GC and GG genotypes) compared with patients carrying the CC genotype (OR, 0.68; 95% CI, 0.53-0.86 and OR, 1.26, 95% CI, 0.78-2.02, respectively). The synergy index for this interaction was statistically significant (SI, 0.58; 95% CI, 0.35-0.95). The risk of MI was reduced in those who were current users of ACE inhibitors those who had been prescribed dosages lower than the equivalent of 1 defined daily dose (DDD) and those having the AGTR1-1166AC or AA genotype compared with that in users of ACE inhibitors with the AGTR1-1166CC genotype (SI, 3.67; 95% CI,1.18-11.4). None of the polymorphisms modified the effectiveness of AT II antagonists regarding the risk of MI. Conclusion. This study shows an interaction between the use of ACE inhibitors and ACE-G4656C polymorphism, and in low doses also with AGTR1-A1166C polymorphism, in the prevention of MI.

The Rotterdam Study: 2012 objectives and design update (Article)

2011-08-31T00:00:00Z

Abstract The Rotterdam Study is a prospective cohort study ongoing since 1990 in the city of Rotterdam in The Netherlands. The study targets cardiovascular, endocrine, hepatic, neurological, ophthalmic, psychiatric, dermatological, oncological, and respiratory diseases. As of 2008, 14,926 subjects aged 45 years or over comprise the Rotterdam Study cohort. The findings of the Rotterdam Study have been presented in over a 1,000 research articles and reports (see www.erasmus-epidemiology.nl/rotterdamstudy). This article gives the rationale of the study and its design. It also presents a summary of the major findings and an update of the objectives and methods.

Invited commentary: Sex-steroid hormones and qt-interval duration (Article)

2011-08-15T00:00:00Z

In this issue of the Journal, Zhang et al. (Am J Epidemiol. 2011;174(4):403-411) make a substantial contribution to research in the area of hormonal influences on cardiac repolarization by demonstrating an inverse association between testosterone levels and the Bazett's adjusted QT interval (QTc) and RR-adjusted QT interval in men but not in postmenopausal women. They suggest that testosterone levels might explain the difference in QTc-interval duration between men and women and could contribute to population variability in QTc-interval duration among men. In this commentary, the gender difference and the role of testosterone in human cardiac repolarization are addressed. In addition, the gender differences in the congenital long-QT syndrome, drug-induced ventricular arrhythmias, and sudden cardiac death are discussed.

Genetic variability within the cholesterol lowering pathway and the effectiveness of statins in reducing the risk of MI (Article)

2011-08-01T00:00:00Z

Genetic variability has been shown to affect statin responsiveness. Participants from the Utrecht Cardiovascular Pharmacogenetics (UCP) studies were enrolled from a population-based registry of pharmacy records linked to hospital discharge records (PHARMO) to investigate tagging SNPs within candidate genes involved in the cholesterol lowering pathway for modification of the effectiveness of statins in reducing the risk of myocardial infarction (MI). Patients who received a prescription for an antihypertensive drug and/or had hypercholesterolemia were selected from the PHARMO database. We designed a nested case-control study in which cases were hospitalized for MI and controls were not. Patients were contacted through their community pharmacies. For this study, only hypercholesterolemic participants were selected. Logistic regression analysis was used to investigate pharmacogenetic interactions. The Heart and Vascular Health Study (HVH) was used to replicate findings from UCP. The study population included 668 cases and 1217 controls. We selected 231 SNPs of which 209 SNPs in 27 genes passed quality control. Ten SNPs in eight genes were found to influence the effectiveness of statins in UCP, of which the most significant interaction was found with SCARB1 rs4765615. Other genes that reached statistical significance (p< 0.05) included two SNPs in PCSK9 (rs10888896 and rs505151 (E670G)), two SNPs in ABCG5 (rs4245786 and rs1864815), LIPC rs16940379, ABCA1 rs4149264, PPARG rs2972164, LRP1 rs715948, and SOAT1 rs2493121. None of the total of 5 SNPs that were available for replication in HVH reached statistical significance. In conclusion, ten SNPs were found to modify the effectiveness of statins in reducing the risk of MI in the UCP study. Five were also tested in the HVH study, but no interactions reached statistical significance.

Mild hyponatremia as a risk factor for fractures: The rotterdam study (Article)

2011-08-01T00:00:00Z

Recent studies suggest that mild hyponatremia is associated with fractures, but prospective studies are lacking. We studied whether hyponatremia is associated with fractures, falls, and/or bone mineral density (BMD). A total of 5208 elderly subjects with serum sodium assessed at baseline were included from the prospective population-based Rotterdam Study. The following data were analyzed: BMD, vertebral fractures (mean follow-up 6.4 years), nonvertebral fractures (7.4 years), recent falls, comorbidity, medication, and mortality. Hyponatremia was detected in 399 subjects (7.7%, 133.4±2.0mmol/L). Subjects with hyponatremia were older (73.5±10.3 years versus 70.0±9.0 years, p<.001), had more recent falls (23.8% versus16.4%, p<.01), higher type 2 diabetes mellitus prevalence (22.2% versus 10.3%, p<.001), and more often used diuretics (31.1% versus 15.0%, p<.001). Hyponatremia was not associated with lower BMD but was associated with increased risk of incident nonvertebral fractures [hazard ratio (HR) =1.39, 95% confidence interval (CI) 1.11-1.73, p=.004] after adjustment for age, sex, and body mass index. Further adjustments for disability index, use of diuretics, use of psycholeptics, recent falls, and diabetes did not modify results. In the fully adjusted model, subjects with hyponatremia also had increased risk of vertebral fractures at baseline [odds ratio (OR)=1.78, 95% CI 1.04-3.06, p=.037] but not at follow-up. Finally, all-cause mortality was higher in subjects with hyponatremia (HR=1.21, 95% CI 1.03-1.43, p=.022). It is concluded that mild hyponatremia in the elderly is associated with an increased risk of vertebral fractures and incident nonvertebral fractures but not with BMD. Increased fracture risk in hyponatremia also was independent of recent falls, pointing toward a possible effect on bone quality. Copyright

Incidence, treatment, and case-fatality of non-traumatic subarachnoid haemorrhage in the Netherlands (Article)

2011-07-01T00:00:00Z

Background: Non-traumatic subarachnoid haemorrhage (SAH) is a devastating disorder and in the majority of cases it is caused by rupture of an intracranial aneurysm. No actual data are available on the incidence of non-traumatic SAH and aneursymal SAH (aSAH) in the Netherlands and little is known about treatment patterns of aSAH. Our purpose was therefore to assess the incidence, treatment patterns, and case-fatality of non-traumatic (a)SAH within the Dutch general population. Methods: Two population based data sources were used for this retrospective cohort study. One was the nationwide hospital discharge registry (National Medical Registration, LMR). Cases were patients hospitalized for SAH (ICD-9-code 430) in 2001-2005. The second source was the Integrated Primary Care Information (IPCI) database, a medical record database allowing for case validation. Cases were patients with validated non-traumatic (a)SAH in 1996-2006. Incidence, treatment, and case-fatality were assessed. Results: The incidence rate (IR) of non-traumatic SAH was 7.12 per 100,000 PY (95%CI: 6.94-7.31) and increased with age. The IR of aSAH was 3.78 (95%CI: 2.98-4.72). Women had a twofold increased risk of non-traumatic SAH; this difference appeared after the fourth decade. Non-traumatic SAH fatality was 30% (95%CI: 29-31%). Of aSAH patients 64% (95%CI: 53-74%) were treated with a clipping procedure, and 26% (95%CI: 17-37%) with coiling. Conclusion: Non-traumatic SAH is a rare disease with substantial case-fatality; rates in the Netherlands are similar to other countries. Case-fatality is also similar as well as age and sex patterns in incidence.

Susceptibility to amoxicillin-clavulanate-induced liver injury is influenced by multiple HLA class i and II alleles (Article)

2011-07-01T00:00:00Z

Background & Aims: Drug-induced liver injury (DILI), especially from antimicrobial agents, is an important cause of serious liver disease. Amoxicillin-clavulanate (AC) is a leading cause of idiosyncratic DILI, but little is understood about genetic susceptibility to this adverse reaction. Methods: We performed a genome-wide association study using 822,927 single nucleotide polymorphism (SNP) markers from 201 White European and US cases of DILI following AC administration (AC-DILI) and 532 population controls, matched for genetic background. Results: AC-DILI was associated with many loci in the major histocompatibility complex. The strongest effect was with an HLA class II SNP (rs9274407, P = 4.8 × 10-14), which correlated with rs3135388, a tag SNP of HLA-DRB1 (*)1501-DQB1 (*)0602 that was previously associated with AC-DILI. Conditioned on rs3135388, rs9274407 is still significant (P = 1.1 × 10-4). An independent association was observed in the class I region (rs2523822, P = 1.8 × 10-10), related to HLA-A (*)0201. The most significant class I and II SNPs showed statistical interaction (P =.0015). High-resolution HLA genotyping (177 cases and 219 controls) confirmed associations of HLA-A (*)0201 (P = 2 × 10-6) and HLA-DQB1 (*)0602 (P = 5 × 10-10) and their interaction (P =.005). Additional, population-dependent effects were observed in HLA alleles with nominal significance. In an analysis of autoimmune-related genes, rs2476601 in the gene PTPN22 was associated (P = 1.3 × 10-4). Conclusions: Class I and II HLA genotypes affect susceptibility to AC-DILI, indicating the importance of the adaptive immune response in pathogenesis. The HLA genotypes identified will be useful in studies of the pathogenesis of AC-DILI but have limited utility as predictive or diagnostic biomarkers because of the low positive predictive values.

Transient ischemic attack and incident depression (Article)

2011-07-01T00:00:00Z

Background and Purpose- Depression after stroke is common. Like stroke, transient ischemic attack (TIA) is a manifestation of long-term atherosclerotic damage to the brain. However, the risk of depression developing after a TIA is uncertain. We studied whether TIA increases the risk of incident late-life depression. Methods- A cohort study of 5095 inhabitants of Rotterdam, the Netherlands, was performed between 1993 and 2005. Participants were aged 56 years or older and free of depression at baseline. TIA and depression were identified through regular standardized examinations and continuous monitoring of medical records. We estimated hazard ratios (HR) with time-varying Cox regression analyses, adjusting for sociodemographic and health-related factors. Results- During follow-up, 407 depressive syndromes occurred, of which 103 met criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM) for depressive disorders. TIA was significantly associated with the risk of incident depressive syndromes (HR, 1.68; 95% CI, 1.12-2.51) and DSM-defined depressive disorders (HR, 2.42; 95% CI, 1.26-4.67). The risk of depressive syndromes increased with the number of TIA a person had experienced (HR, 1.45; 95% CI, 1.17-1.81), as did the risk of depressive disorders (HR, 1.63; 95% CI, 1.18-2.24). In persons without a history of depression at baseline, we found an almost 3-fold increased risk of DSM-defined depressive disorders (HR, 2.91; 95% CI, 0.96-8.81). Conclusions- TIA was independently associated with an increased risk of incident depression. Our finding suggests that symptomatic cerebrovascular disease increases the vulnerability to late-life depression. Copyright

Identification of a sudden cardiac death susceptibility locus at 2q24.2 through genome-wide association in european ancestry individuals (Article)

2011-06-01T00:00:00Z

Sudden cardiac death (SCD) continues to be one of the leading causes of mortality worldwide, with an annual incidence estimated at 250,000-300,000 in the United States and with the vast majority occurring in the setting of coronary disease. We performed a genome-wide association meta-analysis in 1,283 SCD cases and >20,000 control individuals of European ancestry from 5 studies, with follow-up genotyping in up to 3,119 SCD cases and 11,146 controls from 11 European ancestry studies, and identify the BAZ2B locus as associated with SCD (P = 1.8×10-10). The risk allele, while ancestral, has a frequency of ~1.4%, suggesting strong negative selection and increases risk for SCD by 1.92-fold per allele (95% CI 1.57-2.34). We also tested the role of 49 SNPs previously implicated in modulating electrocardiographic traits (QRS, QT, and RR intervals). Consistent with epidemiological studies showing increased risk of SCD with prolonged QRS/QT intervals, the interval-prolonging alleles are in aggregate associated with increased risk for SCD (P = 0.006).

Proton pump inhibitors and the risk of overanticoagulation during acenocoumarol maintenance treatment (Article)

2011-05-01T00:00:00Z

In the Netherlands, several reports have described a potentiation of acenocoumarol-induced anticoagulation by co-medication of omeprazole or esomeprazole and competitive inhibition of CYP2C19 has been suggested as a possible mechanism for this interaction. We conducted an observational cohort study to investigate the effects of various proton pump inhibitors (PPIs) on acenocoumarol effectiveness. All 2755 subjects from the Rotterdam Study who received acenocoumarol maintenance treatment between April 1st, 1991 and September 9th, 2009 were followed for events of an international normalized ratio (INR)≥6, until death, end of treatment, or end of the study period. The Andersen-Gill extension of the Cox proportional hazards model was used to calculate risks for repeated events of overanticoagulation in relation to concomitant PPI use. The risk for overanticoagulation was most pronounced for esomeprazole (HR 1·99, 95% CI 1·55-2·55) and lansoprazole (HR 1·49, 95% CI 1·05-2·10). There was also a lower and non-significant risk increase for the other PPIs. We did not detect a modification of these results by CYP2C19*2 genotype. Caution should be paid to co-medication with esomeprazole and lansoprazole during acenocoumarol treatment and possibly also with other PPIs.

Inhaled anticholinergic drugs and risk of acute urinary retention (Article)

2011-04-01T00:00:00Z

OBJECTIVE To investigate the association between the use of inhaled anticholinergic drugs and the risk of acute urinary retention (AUR) under real-life circumstances. PATIENTS AND METHODS We conducted a nested case-control study within a cohort of patients with chronic obstructive pulmonary disease (COPD; as AUR has been associated with the use of inhaled anticholinergic drugs, which are used as first-line treatment for COPD) from the Integrated Primary Care Information (IPCI) database. The cohort consisted of all patients with COPD aged ≥45 years, registered between 1996 and 2006, with ≥12 months of valid history. Cases were patients with a first diagnosis of AUR. To each case, controls were selected matched for age, gender and index date. Multivariate conditional logistic regression analysis was used to calculate adjusted odds ratios (ORadj) with 95% confidence intervals (95% CI). RESULTS Within the cohort of 22 579 patients with COPD, 209 cases were identified. Current use of inhaled anticholinergic drugs was associated with a 40% increase in risk for AUR (ORadj1.40; 95% CI 0.99-1.98) compared with non-users. Among current users, the risk was highest for the recent starters (ORadj3.11; 95% CI 1.21-7.98). The risk of long-acting anticholinergic drug tiotropium was not substantially different from that of the short-acting anticholinergic ipratropium. The association was not dose-dependent, but changed by mode of administration, with nebulizers having the highest risk (ORadj2.92; 95% CI 1.17-7.31). In men with COPD and benign prostatic hyperplasia (BPH) the association was strongest (ORadj4.67; 95% CI 1.56-14.0). CONCLUSION Current use of inhaled anticholinergic drugs increases the risk of AUR, especially in patients with BPH or if administered via a nebulizer.

Effect of short-term NSAID use on echocardiographic parameters in elderly people: A population-based cohort study (Article)

2011-04-01T00:00:00Z

Background: Non-steroidal anti-inflammatory drugs (NSAIDs) are associated with an increased risk of heart failure. NSAIDs inhibit the synthesis of renal prostaglandin, which results in a higher total blood volume, cardiac output and preload. The association between recent start of NSAIDs in elderly people and echocardiographic parameters was investigated. Methods: In the Rotterdam Study, a population-based cohort study, the effect of NSAIDs on left ventricular end-systolic dimension, left ventricular end-diastolic dimension, fractional shortening and left ventricular systolic function was studied in all participants for whom an echocardiogram was available (n=5307). NSAID use was categorised as current NSAID use on the date of echocardiography, past use and never used before echocardiography during the study period. Current use was divided into short-term NSAID use (≤14 days) and long-term NSAID use (>14 days). Associations between drug exposure and echocardiographic measurements were assessed using linear and logistic regression analyses. Results: Current NSAID use for <14 days was associated with a significantly higher left ventricular endsystolic dimension (+1.74 mm, 95% CI 0.20 to 3.28), left ventricular end-diastolic dimension (+3.69 mm, 95% CI 1.08 to 6.31) and significantly lower fractional shortening (-6.03%, 95% CI -9.81% to -2.26%) compared with non-users. Current NSAID use for >14 days was associated with a higher left end-diastolic dimension (+1.96 mm, 95% CI 0.82 to 3.11) but there was no change in the other echocardiographic parameters. Conclusion: This study is the first to investigate the association between NSAIDs and echocardiographic parameters and suggests that there is a transient effect of short-term use of NSAIDs on the left ventricular dimension and function of the heart.

A nationwide study of three invasive treatments for trigeminal neuralgia (Article)

2011-03-01T00:00:00Z

Invasive procedures for treatment of trigeminal neuralgia (TGN) include percutaneous radiofrequency thermocoagulation (PRT), partial sensory rhizotomy (PSR), and microvascular decompression (MVD). Using a nationwide discharge registry from The Netherlands, we assessed the frequency of use and patient characteristics, and evaluated treatment failure for each patient undergoing PRT, PSR, or MVD from January 2002 through December 2004. Only patients without a procedure in the year prior were included. Primary outcome was readmission for repeat procedures for TGN or known complications within 1 year. Comparability of patient populations was assessed through propensity scores based on hospital, age, sex, and comorbidity. Conditional logistic regression matched on propensity score was used to calculate relative risks (RR) with 95% confidence intervals (CIs) for repeat procedures or complications. During the study period, 672 patients with TGN underwent PRT, 39 underwent PSR, and 87 underwent MVD. Hospital type was the predominant determinant of procedure type; age, sex, and comorbidity were weak predictors. The RR for repeat procedures for PSR was 0.21 (95% CI: 0.07 to 0.65) and for MVD was 0.13 (95% CI: 0.05 to 0.35) compared with PRT (RR 1). For complications, the RR of PSR was 5.36 (95% CI: 1.46 to 19.64) and of MVD was 4.40 (95% CI: 1.44 to 13.42). Sex, urbanization, and comorbidity did not influence prognosis, but hospital and surgical volume did. In conclusion, although PSR and MVD are associated with a lower risk of repeat procedure than PRT, they seem to be more prone to complications requiring hospital readmission. Microvascular decompression and partial sensory rhizotomy are associated with a lower risk of undergoing a repeat procedure compared with percutaneous radiofrequency thermocoagulation but are more prone to complications requiring readmission to hospital.

OCT1 polymorphism is associated with response and survival time in anti-Parkinsonian drug users (Article)

2011-02-01T00:00:00Z

Substrates for the Organic Cation Transporter 1, encoded by the SLC22A1 gene, are metformin, amantadine, pramipexole, and, possibly, levodopa. Recently, we identified that the rs622342 A > C polymorphism is associated with the HbA1c lowering effect in metformin users. In the Rotterdam Study, we associated this polymorphism with higher prescribed doses of all anti-Parkinsonian drugs. Between the first and fifth prescriptions for levodopa, for each minor rs622342 C allele, the prescribed doses were 0.34 defined daily dose higher (95% CI 0.064, 0.62; p∈=∈0.017). The mortality ratio after start of levodopa therapy was 1.47 times higher (95% CI 1.01, 2.13; p∈=∈0.045).

β-Blockers and the risk of incident depression in the elderly (Article)

2011-02-01T00:00:00Z

The hypothesis that β-blockers cause depression has been both confirmed and refuted in previous studies. However, in hardly any of these studies, depression was systematically and adequately assessed. The aim of this cohort study was to examine whether β-blockers, in general, highly lipid-soluble, nonselective, or serotonergic receptor-binding β-blockers, are associated with incident depression. Between 1993 and 2005, 5104 elderly persons were followed for incident depressions. Depressions were identified by regular interview and continuous monitoring of medical records. Cases were categorized as clinically relevant depressive symptoms or as depressive syndromes, the latter including Diagnostic and Statistical Manual of Mental Disorders-IV-defined depressive disorders. Pharmacies provided information on filled β-blockers. We used Cox regression with drug use as a time-dependent variable to analyze the data, adjusted for potential demographic covariates, activity of daily living, and (contra)indications for β-blockers. We found that use of β-blockers in general did not convey an increased risk of depressive symptoms (hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.37-1.59) or depressive syndromes (HR, 0.99; 95% CI, 0.53-1.84). Highly lipid-soluble β-blockers, mostly propranolol in our study, were associated with depressive symptoms during the first 3 months of use (HR, 3.31; 95% CI, 1.03-10.6), but not with depressive syndromes. Nonselective or serotonergic receptor affinity was not associated with an increased risk of depressive symptoms or syndromes independent of high lipid solubility. We conclude that β-blockers in general do not convey an increased risk of depression. Lipophilic β-blockers are associated with an increased risk of depressive symptoms. Copyright

Non-cardiovascular drugs that inhibit hERG-encoded potassium channels and risk of sudden cardiac death (Article)

2011-02-01T00:00:00Z

Background: Virtually all QTc-prolonging drugs act by blocking the human ether a go-go-related gene (hERG)-encoded potassium channels (hERG channels), whereas not all QTc-prolonging drugs are associated with an increased risk of serious cardiac arrhythmias. This study assessed whether non-cardiovascular hERG channel blockers are associated with an increased risk of sudden cardiac death (SCD) and whether hERG-channel-inhibiting capacity is an indicator of the risk of SCD. Methods and results: The risk of SCD was studied in the Integrated Primary Care Information database, a longitudinal general practice research database. A case-control study was performed, matched for age, gender and calendar time. Odds ratios were calculated with conditional logistic regression, multivariably adjusted. In addition, the hERG-channel-inhibiting capacity of the different drugs was compared, defined as the effective free therapeutic plasma concentration (ETCPunbound) divided by the concentration that inhibits 50% of the potassium channels (IC50), with the risk of SCD. 1424 cases of SCD and 14 443 controls were identified. Current use of hERG channel blockers was associated with an increased risk of SCD. The risk of SCD was significantly increased in users of antipsychotic drugs. Patients using hERG channel blockers with a high ETCPunbound/IC50 ratio (≥0.033) had a higher risk of SCD than patients using drugs with a low ETCPunbound/IC50 ratio (<0.033). Conclusions: The current use of hERG channel blockers was associated with an increased risk of SCD in the general population. In addition, drugs with a high hERG-channel-inhibiting capacity had a higher risk of SCD than drugs with a low hERG-channel-inhibiting capacity.

A nationwide study of three invasive treatments for trigeminal neuralgia (Article)

2011-01-01T00:00:00Z

Dependency of phenprocoumon dosage on polymorphisms in the VKORC1, CYP2C9, and CYP4F2 genes (Article)

2011-01-01T00:00:00Z

Background: Genome-wide association studies (GWAS) on warfarin and acenocoumarol showed that interindividual dosage variation is mainly associated with single nucleotide polymorphisms (SNPs) in VKORC1 and to a lesser extent in CYP2C9 and CYP4F2. For phenprocoumon dosage, the genes encoding CYP3A4 and ApoE might play a role. OBJECTIVE: To assess the association between common genetic variants within VKORC1, CYP2C9, CYP4F2, CYP3A4, and ApoE and phenprocoumon maintenance dosage, and to identify novel signals using GWAS. METHODS: We selected all participants from the Rotterdam study who were treated with phenprocoumon. For each SNP, we tested the association between the above-mentioned genotypes and age, sex, body mass index, and target INR adjusted-phenprocoumon maintenance dosage. Results: Within our study population (N=244), VKORC1, CYP2C9, CYP4F2 genotypes together explained 46% of phenprocoumon maintenance dosage variation. Each additional VKORC1 variant allele reduced phenprocoumon maintenance dosage by 4.8 mg/week (P<0.0001) and each additional CYP2C9 variant allele by 2.2 mg/week (P=0.002). Each additional variant allele of CYP4F2 increased phenprocoumon dosage by 1.5 mg/week (P=0.022). Variant alleles of CYP3A41*B and ApoE showed no association with phenprocoumon dosage. Genome-wide significant SNPs were all related to VKORC1 activity. Best associated were two SNPs in complete linkage disequilibrium with each other and with SNPs within VKORC1: rs10871454 [Syntaxin 4A (STX4A)] and rs11150604 (ZNF646), each with a P value of 2.1×10- 22. Each reduced phenprocoumon maintenance dosage weekly by 4.9 mg per variant allele. Conclusion: Similar to earlier findings with warfarin and acenocoumarol, phenprocoumon maintenance dosage depended on polymorphisms in the VKORC1 gene.

Sex-related differences in hospital admissions attributed to adverse drug reactions in the Netherlands (Article)

2011-01-01T00:00:00Z

AIM Adverse drug reactions (ADRs) are a major burden in health care, regularly leading to hospital admission, morbidity or death. Women tend to have a higher risk of adverse drug reactions with a 1.5 to 1.7-fold greater risk than men. Our primary aim was to study differences in ADR-related hospitalizations between the sexes.METHODS We conducted a nationwide study of all ADR-related hospitalizations in the period between 2000 and 2005 in the Netherlands, which were selected from all 9 287 162 hospital admissions in this period. ADR-drug group combinations with at least 50 admissions in one of the sexes were selected. Relative risks and confidence intervals were calculated with respect to total admissions and total prescriptions with men as reference.RESULTS In total, 0.41% of the 4 236 368 admissions in men (95% CI 0.40, 0.42%) and 0.47% of the 5 050 794 admissions in women (95% CI 0.46, 0.48%) were attributed to an ADR by medical specialists (57% of all ADR-related admissions were in women). Differences between the sexes in risk for ADR-related hospitalization were found for antineoplastic and immunosuppressive drugs, antirheumatics, anticoagulants and salicylates, cardiovascular and neurological drugs, steroids and antibiotics. In certain drug categories, risks for hospitalization changed after taking into account total drug prescriptions.CONCLUSION In all different drug classes, significant differences exist between the sexes in ADR-related hospital admissions. Cardiovascular drugs account for the most pronounced differences between men and women. More research is needed to explain the clear sex differences in ADR-related hospital admissions. © 2010 The Authors. British Journal of Clinical Pharmacology

Cytochrome P450 3A gene variation, steroid hormone serum levels and prostate cancer - The Rotterdam Study (Article)

2010-12-01T00:00:00Z

Purpose: To study if polymorphisms in genes encoding for CYP3A enzymes, that play a role in steroid hormone metabolism, affect steroid hormone serum levels and prostate cancer incidence or mortality. Methods: 3048 male participants of The Rotterdam Study were included. Prostate cancer cases and non-cases were studied for differences in baseline hormone levels with Student's t-test. General linear models were performed on different random subsets of hormone levels to study associations with genotype. Cox' proportional hazard models were used to study prostate cancer incidence and mortality among genotypes. Results: Both DHEAS sulphate as free-testosterone were significantly increased at baseline in males who developed a prostate cancer within the study period. CYP3A4 G-allele carriage was associated with lower levels of estrone sulphate (p = 0.005) and higher levels of estradiol (p = 0.04) compared to non-carriers. CYP3A5 A-allele carriage was associated with increased levels of estrone sulphate (p = 0.02). CYP3A7 G-allele carriage was associated with the highest number of significant differences in steroid hormone levels. Carriers of the allele resulting in continued enzyme expression during adulthood had decreased levels of dehydroepiandrosterone (DHEA) sulphate (p = 0.05), androstenedione (p = 0.006), estrone (p = 0.0001) and estrone sulphate (p = 0.003) compared to mean levels of these hormones in homozygous wild type carriers. CYP3A43 genotype was not associated with any of the studied hormone levels. However, carriers of the CYP3A43 G-allele showed a significant 5-fold increase in mortality among early onset diagnosed prostate cancers. Conclusion: Increased levels of free testosterone and DHEA sulphate were associated with prostate cancer incidence along the study period. Primarily the amount of CYP3A7 expression seemed to affect steroid hormone levels. Nevertheless, testosterone, a precursor of the prostate growth and differentiation stimulating dehydrotestosterone, was not influenced by CYP3A genotype. In line with this, no significant associations were observed for CYP3A genotypes and prostate cancer incidence.

Predicting survival and morbidity-free survival to very old age (Article)

2010-12-01T00:00:00Z

As life expectancy continually increases, it is imperative to identify determinants of survival to the extreme end of the lifespan and more importantly to identify factors that increase the chance of survival free of major morbidities. As such, the current study assessed 45 common disease factors as predictors of survival and morbidity-free survival to age 85 years. Within the Rotterdam Study, a population-based cohort, we evaluated morbidity-free participants who were able to attain age 85 within the study duration (n∈=∈2,008). Risk factors were assessed at baseline (1990-1993), and mortality and morbidities were then collected continuously until mortality or the occurrence of their 85th birthday (average time of 7.9 years). Risk factors included demographic and lifestyle variables, health and morbidity indicators and physiological makers. Major morbidities examined included dementia, cancer, cerebrovascular accident, heart failure and myocardial infarction. Logistic regression analyses demonstrated that many of the variables were independently predictive for survival and for morbidity-free ageing to 85 years. These included being female, absence of left ventricular abnormalities, stable body weight, unimpaired instrumental activities of daily living, lower C-RP levels and higher levels of femoral neck bone mineral density and albumin. Relative to non-survival, predictors were stronger for morbidity-free survival than for total survival or survival with morbidity. This suggests that lifespan and healthy survival to older age can be relatively well predicted. Understanding predictors of a long and healthy lifespan is vital for developing primary and secondary preventions to help improve the quality of life of older adults and for reducing the financial burden of the rapidly escalating ageing population.

Vitamin D-binding protein polymorphisms are not associated with development of (multiple) basal cell carcinomas (Letter To Editor)

2010-12-01T00:00:00Z

Vitamin D-binding protein (VDBP) single nucleotide polymorphisms (SNP) may affect skin carcinogenesis. The objective was to test the association between two functional VDBP SNPs and the susceptibility to (multiple) basal cell carcinomas (BCCs). Of the 7983 participants, 5790 (72.5%) and 5823 (72.9%) participants were genotyped for rs7041 and rs4588, respectively, and three haplotypes (Gc1s, Gc2 and Gc1f) were analysed. Two hundred and thirty-three persons developed a BCC of whom 122 (52.4%) developed multiple BCCs during a mean follow-up of 11.6 years. The VDBP genotype was not associated with (multiple) BCC development using Cox proportional hazards and Andersen-Gill analyses, respectively. Stratifying age groups demonstrated that in the youngest age-group, the A/T variant of rs7041 was associated with BCC development [adjusted hazard ratio (HR) = 1.88 (95%CI 1.10-3.20)], while homozygote Gc1s carriers had a significantly lower BCC risk [adjusted HR = 0.53 (95%CI 0.31-0.91)]. In conclusion, the VDBP polymorphisms were not associated with susceptibility to (multiple) BCCs, but age-gene interactions were observed.

Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction (Article)

2010-12-01T00:00:00Z

The QRS interval, from the beginning of the Q wave to the end of the S wave on an electrocardiogram, reflects ventricular depolarization and conduction time and is a risk factor for mortality, sudden death and heart failure. We performed a genome-wide association meta-analysis in 40,407 individuals of European descent from 14 studies, with further genotyping in 7,170 additional Europeans, and we identified 22 loci associated with QRS duration (P < 5 × 10 -8). These loci map in or near genes in pathways with established roles in ventricular conduction such as sodium channels, transcription factors and calcium-handling proteins, but also point to previously unidentified biologic processes, such as kinase inhibitors and genes related to tumorigenesis. We demonstrate that SCN10A, a candidate gene at the most significantly associated locus in this study, is expressed in the mouse ventricular conduction system, and treatment with a selective SCN10A blocker prolongs QRS duration. These findings extend our current knowledge of ventricular depolarization and conduction.

Multiple genetic loci influence serum urate levels and their relationship with gout and cardiovascular disease risk factors (Article)

2010-12-01T00:00:00Z

Background - Elevated serum urate levels can lead to gout and are associated with cardiovascular risk factors. We performed a genome-wide association study to search for genetic susceptibility loci for serum urate and gout and investigated the causal nature of the associations of serum urate with gout and selected cardiovascular risk factors and coronary heart disease (CHD). Methods and Results - Meta-analyses of genome-wide association studies (GWAS) were performed in 5 population-based cohorts of the Cohorts for Heart and Aging Research in Genome Epidemiology consortium for serum urate and gout in 28 283 white participants. The effect of the most significant single-nucleotide polymorphism at all genome-wide significant loci on serum urate was added to create a genetic urate score. Findings were replicated in the Women's Genome Health Study (n=22 054). Single-nucleotide polymorphisms at 8 genetic loci achieved genome-wide significance with serum urate levels (P=4×10-8to 2×10-242in SLC22A11, GCKR, R3HDM2-INHBC region, RREB1, PDZK1, SLC2A9, ABCG2, and SLC17A1). Only 2 loci (SLC2A9, ABCG2) showed genome-wide significant association with gout. The genetic urate score was strongly associated with serum urate and gout (odds ratio, 12.4 per 100 μmol/L; P=3×10-39) but not with blood pressure, glucose, estimated glomerular filtration rate, chronic kidney disease, or CHD. The lack of association between the genetic score and the latter phenotypes also was observed in the Women's Genome Health Study. Conclusions-The genetic urate score analysis suggested a causal relationship between serum urate and gout but did not provide evidence for one between serum urate and cardiovascular risk factors and CHD.

Heart failure and the risk of stroke: the Rotterdam Study (Article)

2010-11-01T00:00:00Z

Patients with heart failure used to have an increased risk of stroke, but this may have changed with current treatment regimens. We assessed the association between heart failure and the risk of stroke in a population-based cohort that was followed since 1990. The study uses the cohort of the Rotterdam Study and is based on 7,546 participants who at baseline (1990-1993) were aged 55 years or over and free from stroke. The associations between heart failure and risk of stroke were assessed using time-dependent Cox proportional hazards models, adjusted for cardiovascular risk factors (smoking, diabetes mellitus, BMI, ankle brachial index, blood pressure, atrial fibrillation, myocardial infarction and relevant medication). At baseline, 233 participants had heart failure. During an average follow-up time of 9.7 years, 1,014 persons developed heart failure, and 827 strokes (470 ischemic, 75 hemorrhagic, 282 unclassified) occurred. The risk of ischemic stroke was more than five-fold increased in the first month after diagnosis of heart failure (age and sex adjusted HR 5.79, 95% CI 2.15-15.62), but attenuated over time (age and sex adjusted HR 3.50 [95% CI 1.96-6.25] after 1-6 months and 0.83 [95% CI 0.53-1.29] after 0.5-6 years). Additional adjustment for cardiovascular risk factors only marginally attenuated these risks. In conclusion, the risk of ischemic stroke is strongly increased shortly after the diagnosis of heart failure but returns to normal within 6 months after onset of heart failure.

Drug-induced hepatic injury in children: A case/non-case study of suspected adverse drug reactions in VigiBase (Article)

2010-11-01T00:00:00Z

Aim: To identify which drugs are associated with reports of suspected hepatic injury in children and adolescents. Methods: Using a worldwide pharmacovigilance database, VigiBase, we conducted a case/non-case study on suspected adverse drug reactions (ADRs) occurring in the population <18 years old. Cases were all the records with hepatic ADRs and non-cases were all the other ADR records. Records regarding topically administered drugs were excluded from both groups. The association between drug and suspected hepatic ADRs was calculated using the reporting odds ratio (ROR) as a measure of disproportionality while adjusting for gender, country, reporter and calendar year. Sub-analyses were performed within therapeutic class and by excluding vaccination-related reports to reduce confounding. Results: Overall, 6595 (1%) out of 624 673 ADR records in children and adolescents concerned hepatic injury. Most of the reported hepatic injuries concerned children 12-17 years of age. Drugs that were most frequently reported as suspected cause and were associated with hepatic injury comprised paracetamol, valproic acid, carbamazepine, methotrexate, minocycline, zidovudine, pemoline, ceftriaxone, bosentan, ciclosporin, atomoxetine, olanzapine, basiliximab, erythromycin and voriconazole. The association between hepatotoxicity and all these drugs, except for basiliximab, is already known. Conclusions: Drug-induced hepatic injury is infrequently reported (only 1% of total) as a suspected ADR in children and adolescents. The drugs associated with reported hepatotoxicity (paracetamol, antiepileptic and anti-tuberculosis agents) are known to be hepatotoxic in adults as well, but age related changes in associations were observed. VigiBase is useful as a start to plan further drug safety studies in children.

CYP2C19*2 polymorphism is associated with increased survival in breast cancer patients using tamoxifen (Article)

2010-10-01T00:00:00Z

Abstract AIMS: Variant alleles of the CYP2C19 gene were recently associated with survival in breast cancer patients on tamoxifen therapy. CYP2C19 is one of the enzymes involved in the metabolism of tamoxifen into active metabolites. We investigated the hypothesis that CYP2C19*2 and *3 variants, known for their lack of enzyme activity, are associated with an increased breast cancer mortality rate in patients using tamoxifen. MATERIALS & METHODS: In the prospective population based Rotterdam study, the association between CYP2C19*2 carriers and breast cancer mortality was studied among 80 incident users of tamoxifen. Survival was analyzed with life tables and Cox regression analysis, with drug exposure as a time-dependent variable. Adjustments were made for calendar time, average tamoxifen dose, age, the indication for tamoxifen, CYP2D6 genotype and concomitant use of CYP2C19 inhibitors or inducers. RESULTS: In patients on tamoxifen, CYP2C19*2 carriers were associated with a significantly longer breast cancer survival rate than patients with the wild-type (hazard ratio 0.26, 95%CI: 0.08-0.87). CONCLUSION: This study suggests that CYP2C19 genotype may possibly be a predictive factor for survival in breast cancer patients using tamoxifen.

High-ceiling diuretics are associated with an increased risk of basal cell carcinoma in a population-based follow-up study (Article)

2010-09-01T00:00:00Z

Introduction: In Caucasians, basal cell carcinoma (BCC) is among the most frequently diagnosed cancers and its incidence is increasing. Known risk factors for the development of BCC are age, sun exposure, and certain skin characteristics. Despite photosensitizing abilities of diuretic agents, little is known about a possible association with BCC. Methods: Data were obtained from the Rotterdam Study; a large prospective population-based follow-up study with coverage of prescription-only drugs from pharmacies. The diagnoses of BCC were obtained through general practitioners, and by linkage with a registry of histo- and cytopathology. Cumulative use of diuretics at the date of diagnosis was categorized into quartiles for users of high-ceiling diuretics, potassium sparing agents and thiazides. The association between these drugs and BCC was assessed by Cox proportional hazard modeling with adjustment for age, gender and potential confounders. Effect modification was tested with interaction terms. Results: Use of high-ceiling diuretics in the highest quartile (>3.7 years cumulative exposure) was associated with an increased hazard of BCC of 62% compared to no use (HR 1.6; 95% CI 1.1-2.4). Patients who used high-ceiling diuretics and had a high tendency of getting sunburned had a higher risk of diagnosis than non-users who do not easily get sunburned. Neither the use of potassium sparing agents, nor the use of thiazides was associated with BCC. Conclusion: In our study, cumulative use of high-ceiling diuretics was associated with an increased risk of diagnosis of BCC. This effect is stronger in patients who easily get sunburned.

Unrecognised myocardial infarction and long-term risk of heart failure in the elderly: The Rotterdam study (Article)

2010-09-01T00:00:00Z

Objective: To examine the association between unrecognised myocardial infarction (MI) as detected by electrocardiography and the long-term risk of heart failure. Design: The Rotterdam Study is a prospective population-based cohort study of the general population of a suburb of the city of Rotterdam, The Netherlands. Participants: At baseline 2581 men and 3724 women aged ≥55 years were classified on the basis of electrocardiography, interview and clinical data into those with recognised MI, those with ECG-based unrecognised MI and those without MI. The participants were followed-up for incident heart failure, death or end of the study period on 12 October 2006. Results: During a median follow-up time of 13.2 years, 823 cases of heart failure occurred, of which 403 in men. Independently of cardiovascular risk factors, recognised and unrecognised MIs yielded HRs of developing heart failure in men of 2.6 (95% CI 2.0 to 3.3) and 2.1 (95% CI 1.5 to 2.9), respectively. In women, recognised MI was associated with heart failure (HR=2.8; 95% CI 1.9 to 4.1), whereas unrecognised MI was not significantly related to the risk of heart failure (HR=1.1; 95% CI 0.7 to 1.7). Conclusion: Unrecognised MI detected by electrocardiography yields a long-term risk of heart failure equivalent to recognised MI in men, but is not significantly related to heart failure in women. In the light of the high incidence of both unrecognised MI and heart failure in the elderly, it may be worthwhile for both doctors and patients to improve responsiveness to typical and atypical symptoms of MI.

Pharmacogenetic interactions between ABCB1 and SLCO1B1 tagging SNPs and the effectiveness of statins in the prevention of myocardial infarction (Article)

2010-08-01T00:00:00Z

Aims: Genetic variability within the SLCO1B1 and ABCB1 transporter genes has been associated with modification of statin effectiveness in cholesterol management. Materials & methods: We conducted a case-control study using a population-based registry of pharmacy records linked to the hospital discharge records. Within a hypercholesterolemic cohort, we included 668 myocardial infarction cases and 1217 controls. Results: We tested 24 tagging SNPs and found two SNPs within ABCB1 (rs3789244, p = 0.01; rs1922242, p = 0.01) to interact with statin treatment. In addition, we found a nonsignificant haplotype-treatment interaction (p = 0.054). The odds ratio for subjects homozygous for SLCO1B1*1A was 0.49 (95% CI: 0.34-0.71) compared with 0.31 (95% CI: 0.24-0.41) for heterozygous or noncarriers of the *1A allele. Conclusion: This is the first study to demonstrate that common genetic variability within the SLCO1B1 and ABCB1 genes is associated with the modification of the effectiveness of statins in the prevention of the clinical outcome, myocardial infarction.

Risk factors for single and multiple basal cell carcinomas (Article)

2010-08-01T00:00:00Z

Objective: To investigate the incidence of single and multiple basal cell carcinoma (BCC) lesions and associated risk factors. Design: A prospective, population-based cohort study (from January 1, 1990, through December 31, 2007). Setting: Two cohorts of 10 994 Dutch people, 55 years or older, were studied in 1990 (first cohort) and 1999 (second cohort). Patients: Patients with BCC lesions were identified from the Dutch national pathology laboratories network, hospitals, and general practices. Main Outcome Measures: The associations between determinants and single and multiple BCC lesions were studied by estimating odds ratios (ORs) and hazards ratios, using multivariate logistic regression and Andersen-Gill models, respectively. Results: Of the eligible 10 820 cohortmembers, 524 (4.8%) had BCC, of whom 361 had single and 163 (31.1%) had multiple lesions. Age and red hair were significant risk factors for a first BCC lesion in a multivariate model. In the Andersen-Gill model, people who developed a first BCC lesion after 75.0 years of age were significantly less likely to develop multiple lesions (≥75.0 years adjustedOR,0.58; 95%confidenceinterval [CI], 0.47-0.71). Redhair (adjusted OR,1.43;95%CI, 1.05-1.94), high educational level (1.42; 1.12-1.81), and a first BCC lesion located on the upper extremities (1.49; 1.02-2.15) were associated with a significantly increased risk of developing multiple lesions. Conclusion: Patients who are relatively young at their first BCC diagnosis, those with red hair, those with higher socioeconomic status, and/or those with a BCC lesion on their upper extremities have a higher risk of developing multiple lesions and require closer follow-up over time.

Heart failure and incident late-life depression (Article)

2010-08-01T00:00:00Z

Objectives: To assess whether heart failure (HF) increases the risk of developing depression and whether the use of loop diuretics in persons with HF alters this risk. Design: Population-based cohort study between 1993 and 2005. Setting: Ommoord, a district of Rotterdam, the Netherlands. Participants: Five thousand ninety-five older adults free of depression at baseline. Measurements: Detailed information on HF and depression was collected during examination rounds and through continuous monitoring of medical and pharmaceutical records. HF was defined according to the criteria of the European Society of Cardiology. Depressive episodes were categorized as clinically relevant depressive symptoms and depressive syndromes, including major depressive disorders defined according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria. Hazard ratios (HRs) were calculated using multivariate Cox proportional hazard regression. Results: HF was associated with greater risk of depressive symptoms and syndromes (HR=1.41, 95% CI=1.03-1.94) and depressive syndromes only (HR=1.66, 95% CI=1.09-2.52). In participants with HF, the use of loop diuretics was associated with a lower risk of depressive symptoms and syndromes (HR=0.46, 95% CI=0.22-0.96) and depressive syndromes only (HR=0.41, 95% CI=0.16-1.00). Conclusion: HF is an independent risk factor for incident depression in elderly persons. Patient with HF require careful follow-up to monitor and prevent the onset of depression. Effective treatment of the debilitating symptoms of HF may prevent depression.

Genome-wide association analysis identifies multiple loci related to resting heart rate (Article)

2010-07-16T00:00:00Z

Higher resting heart rate is associated with increased cardiovascular disease and mortality risk. Though heritable factors play a substantial role in population variation, little is known about specific genetic determinants. This knowledge can impact clinical care by identifying novel factors that influence pathologic heart rate states, modulate heart rate through cardiac structure and function or by improving our understanding of the physiology of heart rate regulation. To identify common genetic variants associated with heart rate, we performed a meta-analysis of 15 genome-wide association studies (GWAS), including 38 991 subjects of European ancestry, estimating the association between age-, sex-and body mass-adjusted RR interval (inverse heart rate) and ~2.5 million markers. Results with P < 5 × 10-8were considered genome-wide significant. We constructed regression models with multiple markers to assess whether results at less stringent thresholds were likely to be truly associated with RR interval. We identified six novel associations with resting heart rate at six loci: 6q22 near GJA1; 14q12 near MYH7; 12p12 near SOX5, c12orf67, BCAT1, LRMP and CASC1; 6q22 near SLC35F1, PLN and c6orf204; 7q22 near SLC12A9 and UfSp1; and 11q12 near FADS1. Associations at 6q22 400 kb away from GJA1, at 14q12 MYH6 and at 1q32 near CD34 identified in previously published GWAS were confirmed. In aggregate, these variants explain ~0.7% of RR interval variance. A multivariant regression model including 20 variants with P < 10-5increased the explained variance to 1.6%, suggesting that some loci falling short of genome-wide significance are likely truly associated. Future research is warranted to elucidate underlying mechanisms that may impact clinical care.

Hedgehog-interacting protein is a COPD susceptibility gene: The Rotterdam study (Article)

2010-07-01T00:00:00Z

The Hedgehog signalling pathway plays an important role in lung morphogenesis and cellular responses to lung injury. A genome-wide association study has demonstrated that two single nucleotide polymorphisms (SNPs) near the Hedgehog-interacting protein (Hip) gene, SNP identifiers rs1828591 and rs13118928, are associated with risk of chronic obstructive pulmonary disease (COPD). The aim of the present study was to validate the observed association between genetic variation near the Hip gene and COPD, and to investigate whether risk estimates were modified by smoking behaviour. The association between the Hip gene SNPs and COPD was investigated in the Rotterdam Study by logistic regression analyses, adjusted for several covariates. In addition, an association meta-analysis was performed that included data from the genome-wide association study on COPD. Both SNPs were significantly associated with risk of COPD (OR 0.80; 95% CI 0.72-0.91). Homozygosity for the minor G allele resulted in a decreased risk of COPD of ∼40% (95% CI 0.47-0.78). There was a significant interaction with the number of pack-years of smoking (p=0.004). The meta-analysis yielded an odds ratio for COPD of 0.80 per additional G allele (p=3.4×10-9). Genetic variation near the Hip gene was significantly associated with risk of COPD, depending on the number of pack-years of smoking.

Distribution of echocardiographic parameters and their associations with cardiovascular risk factors in the Rotterdam Study (Article)

2010-07-01T00:00:00Z

Insight into echocardiographic parameters in the general population may facilitate early recognition of ventricular dysfunction, reducing the population morbidity and mortality of heart failure. We examined the distribution of structural, systolic and diastolic echocardiographic parameters and their associations with cardiovascular risk factors in the Rotterdam Study, a population-based cohort study in men and women aged ≥55 years. Participants with prevalent heart failure, myocardial infarction and atrial fibrillation and flutter were excluded. Echocardiographic parameters were assessed using two-dimensional, M-mode and Doppler echocardiography. Echocardiograms were available in 4,425 participants. Structural parameters were generally larger in men, and most consistently associated with age, body mass index and blood pressure in both sexes. Prevalence of moderate or poor left ventricular systolic function was 3.9% in men and 2.1% in women. Age, body mass index and blood pressure were most consistently associated with systolic function. E/A ratio was lower in women than in men. Age and diastolic blood pressure were most consistently associated with E/A ratio in both sexes. In conclusion, ventricular systolic and diastolic dysfunction is present in asymptomatic individuals. Selected established cardiovascular risk factors are associated with structural, systolic and diastolic parameters.

Drug- and non-drug-associated QT interval prolongation (Article)

2010-07-01T00:00:00Z

Sudden cardiac death is among the most common causes of cardiovascular death in developed countries. The majority of sudden cardiac deaths are caused by acute ventricular arrhythmia following repolarization disturbances. An important risk factor for repolarization disturbances is use of QT prolonging drugs, probably partly explained by gene-drug interactions. In this review, we will summarize QT interval physiology, known risk factors for QT prolongation, including drugs and the contribution of pharmacogenetics. The long QT syndrome can be congenital or acquired. The congenital long QT syndrome is caused by mutations in ion channel subunits or regulatory protein coding genes and is a rare monogenic disorder with a mendelian pattern of inheritance. Apart from that, several common genetic variants that are associated with QT interval duration have been identified. Acquired QT prolongation is more prevalent than the congenital form. Several risk factors have been identified with use of QT prolonging drugs as the most frequent cause. Most drugs that prolong the QT interval act by blocking hERG-encoded potassium channels, although some drugs mainly modify sodium channels. Both pharmacodynamic as well as pharmacokinetic mechanisms may be responsible for QT prolongation. Pharmacokinetic interactions often involve drugs that are metabolized by cytochrome P450 enzymes. Pharmacodynamic gene-drug interactions are due to genetic variants that potentiate the QT prolonging effect of drugs. QT prolongation, often due to use of QT prolonging drugs, is a major public health issue. Recently, common genetic variants associated with QT prolongation have been identified. Few pharmacogenetic studies have been performed to establish the genetic background of acquired QT prolongation but additional studies in this newly developing field are warranted.

Association between calcium channel blockers and gingival hyperplasia (Article)

2010-07-01T00:00:00Z

Aim: To study the effect of the dose and type of calcium channel blockers (CCBs) on the risk of gingival hyperplasia and to quantify this association. Methods: The study was conducted within the Integrated Primary Care Information Project in The Netherlands. A nested case-control study was designed within a cohort of all patients who were new users of either CCBs or drugs interacting with the renin-angiotensin system (RAS). Cases were all individuals with a validated diagnosis of gingival hyperplasia. Controls were matched on age, gender and index date. Results: Within the study population, 103 cases of gingival hyperplasia were identified and matched to 7677 controls. The risk of gingival hyperplasia was higher in current users of CCBs [adjusted odds ratio (ORadj) 2.2, 95% confidence intervals (95% CI): 1.4-3.4], especially in dihydropyridines (ORadj2.1, 95% CI: 1.3-3.5) and benzothiazepine derivatives (ORadj2.9, 95% CI: 1.3-6.5) than in RAS drug users. The risk increased in patients using more than the recommended daily dose (ORadj3.0, 95% CI: 1.6-5.5) and when the duration of current use was <1 month (ORadj5.2, 95% CI: 2.1-12.6). Conclusion: This study shows that the risk of gingival hyperplasia is twofold higher in current users of CCBs than in users of RAS drugs. The association was dose dependent and the highest for dihydropyridines or benzothiazepine derivates.

Association of genome-wide variation with the risk of incident heart failure in adults of European and African ancestry : A prospective meta-analysis from the cohorts for heart and aging research in genomic epidemiology (CHARGE) consortium (Article)

2010-06-01T00:00:00Z

Background-Although genetic factors contribute to the onset of heart failure (HF), no large-scale genome-wide investigation of HF risk has been published to date. We have investigated the association of 2 478 304 single-nucleotide polymorphisms with incident HF by meta-analyzing data from 4 community-based prospective cohorts: the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study. Methods and Results-Eligible participants for these analyses were of European or African ancestry and free of clinical HF at baseline. Each study independently conducted genome-wide scans and imputed data to the ≈2.5 million single-nucleotide polymorphisms in HapMap. Within each study, Cox proportional hazards regression models provided age- and sex-adjusted estimates of the association between each variant and time to incident HF. Fixed-effect meta-analyses combined results for each single-nucleotide polymorphism from the 4 cohorts to produce an overall association estimate and P value. A genome-wide significance P value threshold was set a priori at 5.0×10-7. During a mean follow-up of 11.5 years, 2526 incident HF events (12%) occurred in 20 926 European-ancestry participants. The meta-analysis identified a genome-wide significant locus at chromosomal position 15q22 (1.4×10-8), which was 58.8 kb from USP3. Among 2895 African-ancestry participants, 466 incident HF events (16%) occurred during a mean follow-up of 13.7 years. One genome-wide significant locus was identified at 12q14 (6.7×10-8), which was 6.3 kb from LRIG3. Conclusions-We identified 2 loci that were associated with incident HF and exceeded genome-wide significance. The findings merit replication in other community-based settings of incident HF.

Genomic variation associated with mortality among adults of European and African ancestry with heart failure: The cohorts for heart and aging research in genomic epidemiology consortium (Article)

2010-06-01T00:00:00Z

Background-Prognosis and survival are significant concerns for individuals with heart failure (HF). To better understand the pathophysiology of HF prognosis, the association between 2 366 858 single-nucleotide polymorphisms (SNPs) and all-cause mortality was evaluated among individuals with incident HF from 4 community-based prospective cohorts: the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study. Methods and Results-Participants were 2526 individuals of European ancestry and 466 individuals of African ancestry who experienced an incident HF event during follow-up in the respective cohorts. Within each study, the association between genetic variants and time to mortality among individuals with HF was assessed by Cox proportional hazards models that included adjustment for sex and age at the time of the HF event. Prospective fixed-effect meta-analyses were conducted for the 4 study populations of European ancestry (N=1645 deaths) and for the 2 populations of African ancestry (N=281 deaths). Genome-wide significance was set at P=5.0×10-7.Meta-analytic findings among individuals of European ancestry revealed 1 genome-wide significant locus on chromosome 3p22 in an intron of CKLF-like MARVEL transmembrane domain containing 7 (CMTM7, P=3.20×10-7). Eight additional loci in individuals of European ancestry and 4 loci in individuals of African ancestry were identified by high-signal SNPs (P<1.0×10-5) but did not meet genome-wide significance. Conclusions-This study identified a novel locus associated with all-cause mortality among individuals of European ancestry with HF. This finding warrants additional investigation, including replication, in other studies of HF.

Analysis of individual drug use as a time-varying determinant of exposure in prospective population-based cohort studies (Article)

2010-04-01T00:00:00Z

In pharmaco-epidemiology, the use of drugs is the determinant of interest when studying exposure-outcome associations. The increased availability of computerized information about drug use on an individual basis has greatly facilitated analyses of drug effects on a population-based scale. It seems likely that many negative findings in the early days of pharmaco-epidemiology can be explained by non-differential misclassification because of too simple (yes/no) exposure measures. In this paper, the authors discuss the importance of an adequate definition of drug exposure in pharmaco-epidemiological research and how this time-varying determinant can be analyzed in cohort studies. To reduce the risk of non-differential misclassification, a precise definition of exposure is mandatory and it is important to distinguish the complete follow-up period of a population into mutually exclusive episodes of non-use, past use and current use for each individual. By analyzing exposure to drugs as a time-dependent variable in a Cox regression model, cohort studies with complete coverage of all filled prescriptions can provide us with valid and precise risk estimates of drug-outcome associations. However, such estimates may be biased in the presence of time-dependent confounders which are themselves affected by prior exposure.

Common variants in KCNN3 are associated with lone atrial fibrillation (Article)

2010-03-01T00:00:00Z

Atrial fibrillation (AF) is the most common sustained arrhythmia. Previous studies have identified several genetic loci associated with typical AF. We sought to identify common genetic variants underlying lone AF. This condition affects a subset of individuals without overt heart disease and with an increased heritability of AF. We report a meta-analysis of genome-wide association studies conducted using 1,335 individuals with lone AF (cases) and 12,844 unaffected individuals (referents). Cases were obtained from the German AF Network, Heart and Vascular Health Study, the Atherosclerosis Risk in Communities Study, the Cleveland Clinic and Massachusetts General Hospital. We identified an association on chromosome 1q21 to lone AF (rs13376333, adjusted odds ratio = 1.56; P = 6.3 × 10 12), and we replicated this association in two independent cohorts with lone AF (overall combined odds ratio = 1.52, 95% CI 1.40-1.64; P = 1.83 × 10 21). rs13376333 is intronic to KCNN3, which encodes a potassium channel protein involved in atrial repolarization.

Serum glucose and insulin are associated with QTc and RR intervals in nondiabetic elderly (Article)

2010-02-01T00:00:00Z

Aims: To study whether nondiabetic persons with impaired fasting serum glucose and hyperinsulinemia have QTc/QT interval prolongation and RR interval shortening in the electrocardiogram (ECG), and whether these were associated with an increased risk of sudden cardiac death. Methods: This study consisted of two analyses. First, a cross-sectional analysis was used as part of the population-based Rotterdam Study including 1050 men and 1520 women (≥55 years) without diabetes mellitus. Participants in round 3 of the Rotterdam Study for whom an ECG and fasting serum glucose and fasting insulin measurements were available were eligible for the study. Participants using digoxin or QTc-prolonging drugs and participants with left ventricular hypertrophy and left and right bundle branch block were excluded. The endpoints of the study were the lengths of the QTc, QT, and RR intervals. The associations were examined by means of linear regression analysis. Secondly, in all 6020 participants of the Rotterdam Study with an ECG, the associations between the QTc, QT, and RR intervals and sudden cardiac death were examined by means of Cox regression analysis. Results: Overall, there was a significant association between impaired fasting serum glucose and the QTc interval with an increase of 2.6 ms (95% confidence interval (CI): 0.3; 5.0) in those with fasting glucose >6 mmol/l. Hyperinsulinemia was also associated with QTc prolongation (3.0 ms (0.8; 5.3)) in those with fasting insulin ≥100 pmol/l. Impaired fasting glucose (IFG) and hyperinsulinemia were significantly associated with a decrease of the RR interval (-33.7 ms (-48.8;-18.6) and -44.4 ms (-58.7; -30.0) respectively). Participants in the fourth quartile of the QTc and QT intervals had a significantly increased risk of sudden cardiac death compared to participants in the first quartile (hazard ratio (HR) 2.87 (95% CI: 2.02-4.06); HR 3.05 (1.99-4.67) respectively). Furthermore, there was a significant inverse association between the fourth quartile of the RR interval compared to the first quartile and the risk of sudden cardiac death (HR 0.49 (0.34-0.80)). Conclusion: In this population-based study, we demonstrated that IFG and hyperinsulinemia are associated with a significantly increased QTc interval and with significant shortening of the RR interval, the latter probably due to an increased sympathetic activity. In addition, we demonstrated that both a prolonged QTc interval and a shortened RR interval are associated with an increased risk of sudden cardiac death.

Genome-wide association study of PR interval (Article)

2010-02-01T00:00:00Z

The electrocardiographic PR interval (or PQ interval) reflects atrial and atrioventricular nodal conduction, disturbances of which increase risk of atrial fibrillation. We report a meta-analysis of genome-wide association studies for PR interval from seven population-based European studies in the CHARGE Consortium: AGES, ARIC, CHS, FHS, KORA, Rotterdam Study, and SardiNIA (N = 28,517). We identified nine loci associated with PR interval at P 5 × 10 8. At the 3p22.2 locus, we observed two independent associations in voltage-gated sodium channel genes, SCN10A and SCN5A. Six of the loci were near cardiac developmental genes, including CAV1-CAV2, NKX2-5 (CSX1), SOX5, WNT11, MEIS1, and TBX5-TBX3, providing pathophysiologically interesting candidate genes. Five of the loci, SCN5A, SCN10A, NKX2-5, CAV1-CAV2, and SOX5, were also associated with atrial fibrillation (N = 5,741 cases, P 0.0056). This suggests a role for common variation in ion channel and developmental genes in atrial and atrioventricular conduction as well as in susceptibility to atrial fibrillation.

Single nucleotide polymorphisms in genes that are associated with a modified response to statin therapy: the Rotterdam Study (Article)

2010-01-01T00:00:00Z

The objective of this study was to investigate whether common variation in genes involved in lipid metabolism modify the effect of statins on serum total cholesterol concentration. Statin users were identified in the Rotterdam Study, a prospective population-based cohort study of subjects >55 years of age. We studied the association between single nucleotide polymorphisms (SNPs) in genes involved in lipid metabolism and total cholesterol response to statin therapy, using linear regression analysis and adjusting for potential confounders. Replication was performed in an independent extended cohort of the Rotterdam Study. Genotype data and total cholesterol concentrations after start of statin therapy were available for 554 newly started statin users. Two SNPs were associated with a significantly higher cholesterol concentration under statin therapy: SNP rs1532624 in the CETP gene (β: 0.141 mmol l-1, P=0.004 per additional allele) and SNP rs533556 in the APOA1 gene (β: 0.138 mmol l-1, P=0.005 per additional allele). In the replication sample, only the CETP rs1532624 SNP again showed a significant association. The SNPs were not related to baseline total cholesterol in non-statin users. In conclusion, we found that the CETP rs1532624 polymorphism is associated with cholesterol response to statin therapy in a cohort of elderly subjects in the general population.The Pharmacogenomics Journal advance online publication, 2 March 2010; doi:10.1038/tpj.2010.11.

The association of serum testosterone levels and ventricular repolarization (Article)

2010-01-01T00:00:00Z

It is assumed that testosterone is an important regulator of gender-related differences in ventricular repolarization. Therefore, our aim was to study whether serum levels of testosterone are associated with QTc, QT and RR interval variation. Setting: two independent population-based cohort studies. Participants: 445 male participants (≥ 55 years) from the Rotterdam study cohort and 1,428 male participants from the study of health in Pomerania (SHIP) with an electrocardiogram who were randomly sampled for assessment of serum testosterone at baseline, after exclusion of participants with testosterone altering drugs, QTc prolonging drugs or dig(it)oxin, left ventricular hypertrophy and left and right bundle branch block. Endpoints: length of the QTc, QT and RR intervals. Analysis: linear regression model, adjusted for the two individual studies and a pooled analysis of both studies. The pooled analysis of the Rotterdam study and SHIP showed that the QTc interval gradually decreased among the tertiles (P value for trend 0.024). The third tertile of serum testosterone was associated with a lower QTc interval compared to the first tertile [-3.4 ms (-6.5; -0.3)]. However, the third tertile of serum testosterone was not associated with a lower QT interval compared to the first tertile [-0.7 ms (-3.1; 1.8)]. The RR interval gradually increased among the tertiles (P value for trend 0.002) and the third tertile of serum testosterone showed an increased RR interval compared to the first tertile [33.5 ms (12.2; 54.8)]. In the pooled analysis of two population-based studies, serum testosterone levels were not associated with the QT interval, which could be due to a lack of power. Lower QTc intervals in men with higher serum testosterone levels could be due to the association of serum testosterone with prolongation of the RR interval.

Influence of genetic variation in CYP3A4 and ABCB1 on dose decrease or switching during simvastatin and atorvastatin therapy (Article)

2010-01-01T00:00:00Z

Purpose: Simvastatin and atorvastatin are metabolized by the CYP3A4 enzyme and transported by the ABCB1 transporter. We studied whether the polymorphism CYP3A4*1B and the polymorphisms C1236T, G2677A/T and C3435T in the ABCB1 gene were associated with a decrease of the prescribed dose or a switch to another cholesterol lowering drug during simvastatin and atorvastatin therapy. These events may indicate that statin plasma levels were too high and resulted in an adverse drug reaction or a too strong reduction in cholesterol level. Methods: We identified 1239 incident simvastatin and atorvastatin users in the Rotterdam Study, a population-based cohort study. Associations between the polymorphisms in the CYP3A4 and ABCB1 gene and the time to a decrease in dose or a switch to another cholesterol lowering drug were studied using Cox proportional hazards. Results: Simvastatin and atorvastatin users with the CYP3A4*1B variant G allele had a lower risk (HR 0.46; 95%CI 0.24-0.90) for these events than users with the wild-type AA genotype. No significant associations were found for the ABCB1 polymorphisms. The association with the CYP3A4*1B polymorphism was found in women (HR 0.33; 95%CI 0.12-0.89) and was non-significant in men (HR 0.69 95%CI 0.28-1.70). This association was stronger in patients with the ABCB1 3435T variant allele versus the G allele. Conclusion: In simvastatin and atorvastatin users, the CYP3A4*1B G allele is associated with a lower risk of elevated statin plasma levels, particularly in women and in users with the ABCB1 3435T variant allele. Copyright

Interaction between polymorphisms in the OCT1 and MATE1 transporter and metformin response (Article)

2010-01-01T00:00:00Z

OBJECTIVE: Metformin is transported into the hepatocyte by organic cation transporter 1 (OCT1) and out of the hepatocyte by multidrug and toxin extrusion 1 (MATE1). Recently, we discovered that polymorphisms rs622342 A>C in the SLC22A1 gene, coding for OCT1, and rs2289669 G>A in the SLC47A1 gene, coding for MATE1, are associated with the degree of glucose lowering by metformin. In this study, we assessed whether there exists an interaction between these two polymorphisms. METHODS: We identified all incident metformin users in the Rotterdam Study, a population-based cohort study. Multiplicative interaction between the polymorphisms and change in HbA1c levels was analyzed in 98 incident metformin users. RESULTS: In incident metformin users with the OCT1 rs622342 AA genotype, genetic variation at the MATE1 rs2289669 polymorphism was not associated with change in HbA1c levels [-0.10; 95% confidence interval (CI):-0.35 to 0.14; P=0.39]. In users with the OCT1 rs622342 AC genotype, there was a tendency between rs2289669 polymorphisms and change in HbA1c (-0.31; 95% CI:-0.65 to 0.03; P=0.070) and in users with the OCT1 rs622342 CC genotype there was a significant association with change in HbA1c levels (-0.68; 95% CI:-1.06 to-0.30; P=0.005). The multiplicative interaction between these two genotypes was statistically significant (-0.52; 95% CI:-0.94 to-0.11; P=0.015). CONCLUSION: The effect of the MATE1 rs2289669 polymorphism on the glucose lowering effect of metformin is larger in incident users with the OCT1 rs622342 CC genotype than in incident users with the AA genotype. The effect in incident users with the OCT1 rs622342 AC genotype is in between.

Meta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function (Article)

2010-01-01T00:00:00Z

Spirometric measures of lung function are heritable traits that reflect respiratory health and predict morbidity and mortality. We meta-analyzed genome-wide association studies for two clinically important lung-function measures: forced expiratory volume in the first second (FEV1) and its ratio to forced vital capacity (FEV1/FVC), an indicator of airflow obstruction. This meta-analysis included 20,890 participants of European ancestry from four CHARGE Consortium studies: Atherosclerosis Risk in Communities, Cardiovascular Health Study, Framingham Heart Study and Rotterdam Study. We identified eight loci associated with FEV 1 /FVC (HHIP, GPR126, ADAM19, AGER-PPT2, FAM13A, PTCH1, PID1 and HTR4) and one locus associated with FEV1(INTS12-GSTCD-NPNT) at or near genome-wide significance (P 5 × 10-8) in the CHARGE Consortium dataset. Our findings may offer insights into pulmonary function and pathogenesis of chronic lung disease.

Evaluation of serological trials submitted for annual re-licensure of influenza vaccines to regulatory authorities between 1992 and 2002 (Article)

2009-12-11T00:00:00Z

Background: As part of the regulatory requirements, serological evaluation of trivalent inactivated influenza vaccines must be performed before annual re-licensure in the European Union. These studies are typically set up as uncontrolled, open label trials including 2 groups of at least 50 healthy adults and healthy elderly. Methods: The serological data submitted to the Dutch Medicines Evaluation Board (MEB) for annual re-licensure purposes between 1992 and 2002, were analysed with respect to their ability to assess the immunogenic properties of the vaccines. The trials in this meta-analysis were selected by strictly applying the inclusion and exclusion criteria described in the Committee of Human Medicinal Products (CHMP) Note for Guidance on harmonisation of requirements for influenza vaccines. To select the final dataset additional exclusion criteria were defined: age outside the inclusion criterion of the trial, incomplete demographics, co-morbid conditions, antibody determination by SRH assay, incomplete dataset and sample size smaller than 50 subjects. Results: Out of 51 trials retrieved from the archives, 48 age-defined trials including 2510 adults and 2008 elderly fulfilled all the in- and exclusion criteria. A large proportion of vaccinees already met the threshold for seroprotection at baseline. Post-vaccination, the serological response was shown to be age dependent. Previous influenza vaccinations significantly affected pre-vaccination but not post-vaccination titres. Conclusions: The annual update trials performed for regulatory purposes have serious methodological limitations, which affect their ability to identify influenza vaccines with low immunogenicity. To establish clinical (protective) efficacy different trials and different assessment criteria are needed.

Common genetic variation in the ABCB1 gene is associated with the cholesterol-lowering effect of simvastatin in males (Article)

2009-12-02T00:00:00Z

Aims: The cholesterol-lowering drug simvastatin is a substrate for P-glycoprotein (P-gp). P-gp, encoded by ABCB1, is an efflux transporter and genetic variation in ABCB1 is associated with drug levels and response. We examined the Rotterdam Study, which is a population-based cohort study of people aged 55 years and older, to see whether the C1236T, G2677T/A and C3435T polymorphisms and haplotypes in the ABCB1 gene are associated with the total cholesterol and low-density lipoprotein cholesterol-lowering effect of simvastatin. Materials & methods: We identified 85 incident simvastatin users, for whom a cholesterol measurement both before and after the start of simvastatin therapy was available. Associations between the ABCB1 gene variants and reductions in cholesterol levels were analyzed. In our ana lysis we stratified for gender, because the level of P-gp expression in the liver is higher in men than in women. Results: The three ABCB1 polymorphisms were associated with total cholesterol reduction in the whole population. In men, both the 1236/2677/3435 TTT haplotype and the CGT haplotype were associated with larger reductions in total cholesterol (TTT: -0.40 mmol/l, 95% CI: -0.63 to -0.17; CGT: -0.44 mmol/l, 95% CI: -0.77 to -0.11) and low-density lipoprotein cholesterol levels (TTT: -0.51 mmol/l, 95% CI: -0.81 to -0.22; CGT: -0.53 mmol/l, 95% CI: -0.92 to -0.15) than the reference CGC haplotype. In women, genetic variation in the ABCB1 gene was not associated with total and low-density lipoprotein cholesterol levels. Conclusion: Male simvastatin users with the ABCB1 1236/2677/3435 TTT and CGT haplotype have larger reductions in total cholesterol and low-density lipoprotein cholesterol compared with the wild-type CGC haplotype. For women, no associations were found.

Reasons for non-response in observational pharmacogenetic research (Article)

2009-11-27T00:00:00Z

Purpose: In epidemiological studies, non-response may introduce bias and limit generalizability. In genetic pharmacoepidemiological research, collection of DNA might be a major reason for non-response.We determined reasons for non-response and compared characteristics of non-responders and responders in a pharmacogenetic case-control study. Methods: Myocardial infarction (MI) cases and controls, who were antihypertensive drug users, were recruited through community pharmacies that participate in the Pharmaco-Morbidity-Record-Linkage- System (PHARMO). The PHARMO database comprises drug dispensing histories of about 2 000 000 subjects from a representative sample of Dutch community pharmacies linked to the national registry of hospital discharges. Independent samples t-test and ANOVA-statistics were used to analyse the differences in continuous variables between responders and non-responders. χ2 statistics and logistic regression were used to compare categorical variables. Results: We approached 1871 cases and 14 102 controls of whom 794 MI cases (42.4%) and 4997 controls (35.4%) responded. We could not approach 2194 patients of whom 63.1% had died and 31.2% moved to another pharmacy. Main reasons for non-response were health problems or hospital stays (16.2%, OR 1.47; 95%CI: 1.00-2.16). Other reasons were old age or dementia (16.9%, OR 1.82; 95%CI: 1.24-2.65). Only a small percentage (1.1%, OR 1.43; 95%CI: 0.41-5.03) mentioned DNA sampling as a reason. About 30% of the non-responders did not give a reason. Women were statistically significantly (p<0.0005) less willing to participate than men (38.8% versus 31.3%). An association with age was also found (mean age 64.6 versus 66.5 yrs) ( p<0.0005). Conclusion: In a pharmacogenetic case-control study fear for genetic screening was not a major reported reason for non-response. Females were less willing to participate than males.

Subclinical hyperthyroidism and blood pressure in a population-based prospective cohort study (Article)

2009-11-27T00:00:00Z

Objectives: There is current controversy on the association between subclinical hyperthyroidism and hypertension. Data from cohort studies have not been available yet. The present study was designed to longitudinally investigate possible associations of subclinical hyperthyroidism with blood pressure, pulse pressure and the risk of hypertension. Methods: We used data from the population-based, prospective cohort Study of Health in Pomerania and included 2910 subjects (1469 women) aged 20-79 years with completed 5-year examination follow-up. Subjects with increased serum TSH levels or overt hyperthyroidism were excluded. Serum TSH levels below 0.25 mIU/l with free triiodothyronine and free thyroxine levels within the reference range were defined as subclinical hyperthyroidism. Blood pressure was measured according to standard methods. Results: Multivariable analyses adjusted for age, sex, overweight, obesity, smoking status and time between the examinations did not reveal any statistically significant association between subclinical hyperthyroidism and any of the blood pressure-related variables in the whole study population. Although the 5-year hypertension incidence was higher in subjects with subclinical hyperthyroidism compared with those without (31.4 vs 19.2%; risk ratio 1.64; 95% confidence interval (CI) 1.17-2.28, P=0.006), both groups did not differ with respect to the risk of hypertension, after analyses were adjusted for confounders (relative risk 1.23, 95% CI 0.91-1.68, P=0.182). Analyses yielded similar results in subjects without thyroid disease and in those who took no antihypertensive medication. Conclusion: Subclinical hyperthyroidism is not associated with changes in blood pressure, pulse pressure or incident hypertension.

The CYP2D6 4 polymorphism affects breast cancer survival in tamoxifen users (Article)

2009-11-01T00:00:00Z

Cytochrome P450 2D6 (CYP2D6) plays an important role in the formation of endoxifen, the active metabolite of tamoxifen. In this study the association between the most prevalent CYP2D6 null-allele in Caucasians (CYP2D64) and breast cancer mortality was examined among all incident users of tamoxifen in a population-based cohort study. Breast cancer mortality was significantly increased in patients with the 4/4 genotype (HR = 4.1, CI 95% 1.1-15.9, P = 0.041) compared to wild type patients. The breast cancer mortality increased with a hazard ratio of 2.0 (CI 95% 1.1-3.4, P = 0.015) with each additional variant allele. No increased risk of all-cause mortality or all-cancer mortality was found in tamoxifen users carrying a CYP2D64 allele. The risk of breast cancer mortality is increased in tamoxifen users with decreased CYP2D6 activity, consistent with the model in which endoxifen formation is dependent on CYP2D6 activity.

Determinants of DNA yield and purity collected with buccal cell samples (Article)

2009-11-01T00:00:00Z

Buccal cells are an important source of DNA in epidemiological studies, but little is known about factors that influence amount and purity of DNA. We assessed these factors in a self-administered buccal cell collection procedure, obtained with three cotton swabs. In 2,451 patients DNA yield and in 1,033 patients DNA purity was assessed. Total DNA yield ranged from 0.08 to 1078.0 μg (median 54.3 μg; mean 82.2 μg ± SD 92.6). The median UV 260:280 ratio, was 1.95. Samples from men yielded significantly more DNA (median 58.7 μg) than those from women (median 44.2 μg). Diuretic drug users had significantly lower purity (median 1.92) compared to other antihypertensive drug users (1.95). One technician obtained significantly lower DNA yields. Older age was associated with lower DNA purity. In conclusion, DNA yield from buccal swabs was higher in men and DNA purity was associated with age and the use of diuretics.

Genetic variation in NOS1AP is associated with sudden cardiac death: Evidence from the Rotterdam Study (Article)

2009-10-20T00:00:00Z

Common variation within the nitric oxide-1 synthase activator protein (NOS1AP) locus is strongly related to QT interval, a sudden cardiac death (SCD) risk factor. A recent report describes common variation in NOS1AP associated with SCD in a US population of European ancestry. The objective of the current study was to obtain additional evidence by investigating the association between NOS1AP variants and SCD in the prospective population-based Rotterdam Study. The study population consisted of 5974 European ancestry subjects, aged 55 years and older, genotyped on Illumina arrays. SCD was defined according to European Society of Cardiology guidelines. Smoking, body mass index, diabetes mellitus, hypertension, heart failure and myocardial infarction were used as covariates in Cox proportional hazard models. Results were combined with reported evidence using inverse-variance weighted meta-analysis. Two hundred and eight (109 witnessed) cases of SCD occurred during a mean follow-up of 10.4 years. Within the Rotterdam Study alone, no significant associations were observed. Upon pooling of results with existing data, we observed strengthening of existing evidence for rs16847549 (US data HR = 1.31, P = 0.0024; Rotterdam Study HR = 1.18, P = 0.16; joint HR = 1.26, P = 0.0011). When the case definition in the Rotterdam Study was restricted to witnessed SCD, association of rs16847549 with SCD became stronger (joint P = 0.00019) and additionally the association between rs12567209 and SCD gained significance (US data HR = 0.57, P = 0.0035; Rotterdam Study HR = 0.69, P = 0.23; joint HR = 0.60, P = 0.0018). In conclusion, this study provided additional evidence for association between genetic variation within NOS1AP and SCD. The mechanism by which this effect is exerted remains to be elucidated.

A genome-wide association study of acenocoumarol maintenance dosage. (Article)

2009-10-01T00:00:00Z

Several genome-wide association studies have been performed on warfarin. For acenocoumarol, the most frequently used coumarin in many countries worldwide, pharmacodynamic influences are expected to be comparable. Pharmacokinetics however might differ. We aimed to confirm known or identify new genetic variants contributing to interindividual variation on stabilized acenocoumarol dosage by a GWAS. The index population consisted of 1451 Caucasian subjects from the Rotterdam study and results were replicated in 287 subjects from the Rotterdam study extended cohort. Both cohorts were genotyped on the Illumina 550K Human Map SNP array. From polymorphisms tested for association with acenocoumarol dosage, 35 single nucleotide polymorphisms (SNPs) on chromosome 16 and 18 SNPs on chromosome 10 reached genome-wide significance. The SNP with the lowest P-value was rs10871454 on chromosome 16 linked to SNPs within the vitamin K epoxide reductase complex subunit 1 (VKORC1) (P = 2.0 x 10(-123)). The lowest P-value on chromosome 10 was obtained by rs4086116 within cytochrome P450 2C9 (CYP2C9) (P = 3.3 x 10(-24)). After adjustment for these SNPs, the rs2108622 polymorphism within cytochrome P450 4F2 (CYP4F2) gene on chromosome 19 reached genome-wide significance (P = 2.0 x 10(-8)). On chromosome 10, we further identified genetic variation in the cytochrome P450 2C18 (CYP2C18) gene contributing to variance of acenocoumarol dosage. Thus we confirmed earlier findings that acenocoumarol dosage mainly depends on polymorphisms in the VKORC1 and CYP2C9 genes. Besides age, gender, body mass index and target INR, one polymorphism within each of the VKORC1, CYP2C9, CYP4F2 and CYP2C18 genes could explain 48.8% of acenocoumarol dosage variation.

The rotterdam study: 2010 objectives and design update (Article)

2009-09-01T00:00:00Z

The Rotterdam Study is a prospective cohort study ongoing since 1990 in the city of Rotterdam in The Netherlands. The study targets cardiovascular, endocrine, hepatic, neurological, ophthalmic, psychiatric and respiratory diseases. As of 2008, 14,926 subjects aged 45 years or over comprise the Rotterdam Study cohort. The findings of the Rotterdam Study have been presented in close to a 1,000 research articles and reports (see www.epib.nl/ rotterdamstudy ). This article gives the rationale of the study and its design. It also presents a summary of the major findings and an update of the objectives and methods.

Population-based studies of antithyroid drugs and sudden cardiac death (Article)

2009-09-01T00:00:00Z

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Thyroid hormone free T4 is associated with QTc-interval prolongation, which is a risk factor for sudden cardiac death. • The association between hyperthyroidism and ventricular arrhythmias or sudden cardiac death has been reported in several case reports. WHAT THIS STUDY ADDS • We investigated in a prospective population-based cohort study and in a case-control study whether use of antithyroid drugs (as a direct cause or as an indicator of poorly controlled hyperthyroidism) is associated with an increased risk of sudden cardiac death. • Use of antithyroid drugs was associated with a threefold increased risk of sudden cardiac death. • Although this might be due to antithyroid drug use, it could be more readily explained by underlying hyperthyroidism. AIM Thyroid free T4 is associated with QTc-interval prolongation, which is a risk factor for sudden cardiac death (SCD). Hyperthyroidism has been associated with SCD in case reports, but there are no population-based studies confirming this. The aim was to investigate whether use of antithyroid drugs (as a direct cause or as an indicator of poorly controlled hyperthyroidism) is associated with an increased risk of SCD. METHODS We studied the occurrence of SCD in a two-step procedure in two different Dutch populations. First, the prospective population-based Rotterdam Study including 7898 participants (≥55 years old). Second, we used the Integrated Primary Care Information (IPCI) database, which is a longitudinal general practice research database to see whether we could replicate results from the first study. Drug use at the index date was assessed with prescription information from automated pharmacies (Rotterdam Study) or drug prescriptions from general practices (IPCI). We used a Cox proportional hazards model in a cohort analysis, adjusted for age, gender and use of QTc prolonging drugs (Rotterdam Study) and conditional logistic regression analysis in a case-control analysis, matched for age, gender, practice and calendar time and adjusted for arrhythmia and cerebrovascular ischaemia (IPCI). RESULTS In the Rotterdam Study, 375 participants developed SCD during follow-up. Current use of antithyroid drugs was associated with SCD [adjusted hazard ratio 3.9; 95% confidence interval (CI) 1.7, 8.7]. IPCI included 1424 cases with SCD and 14 443 controls. Also in IPCI, current use of antithyroid drugs was associated with SCD (adjusted odds ratio 2.9; 95% CI 1.1, 7.4). CONCLUSIONS Use of antithyroid drugs was associated with a threefold increased risk of SCD. Although this might be directly caused by antithyroid drug use, it might be more readily explained by underlying poorly controlled hyperthyroidism, since treated patients who developed SCD still had low thyroid-stimulating hormone levels shortly before death.

Outcome of the complex regional pain syndrome (Article)

2009-09-01T00:00:00Z

Objectives: The outcome of complex regional pain syndrome (CRPS) is relatively unknown. High disease resolution rates have been reported, but also long-lasting impairments in many patients. This study aims to assess CRPS outcome in a population-based cohort of CRPS patients. Methods: CRPS patients were retrospectively identified (1996 to 2005) in a Dutch general practitioners database, the integrated primary care information project, and included if at onset (ie, in the past) they had complied with the International Association for the Study of Pain (IASP) diagnostic criteria. The disease status at minimum of 2 years since onset was assessed during visits using questionnaires, interviews, and physical examination. Symptoms and signs were compared with reference patients with an identical past injury but without CRPS. Actual fulfillment of the IASP criteria, treatment status, self-reported recovery, and working status were recorded. Moreover, to identify the potential prognostic factors, baseline patient characteristics were compared across subgroups according to the CRPS outcome. These subgroups were derived by cluster analysis on actual symptoms and signs. Results: One hundred and two CRPS patients were assessed at on average 5.8 years (range: 2.1 to 10.8) since onset. CRPS patients displayed higher symptom and sign prevalences in all categories (sensory, vasomotor, sudomotor, and motor/trophic) than controls. Sixteen percent (95% CI: 9-22) reported the CRPS as still progressive, whereas 31% (95% CI: 19-43) were incapable of working. Patients in the poorest outcome cluster more often had their upper extremity affected, event other than a fracture, and cold CRPS. Discussion: Severe CRPS outcome is rare, but a majority of patients has persistent impairments at 2 or more years since onset.

Variants in ZFHX3 are associated with a trial fibrillation in individuals of European ancestry (Article)

2009-08-01T00:00:00Z

We conducted meta-analyses of genome-wide association studies for atrial fibrillation (AF) in participants from five community-based cohorts. Meta-analyses of 896 prevalent (15,768 referents) and 2,517 incident (21,337 referents) AF cases identified a new locus for AF (ZFHX3, rs2106261, risk ratio RR = 1.19; P = 2.3 × 10-7). We replicated this association in an independent cohort from the German AF Network (odds ratio = 1.44; P = 1.6 × 10-11; combined RR = 1.25; combined P = 1.8 × 10-15).

Variation in the CYP2D6 gene is associated with a lower serum sodium concentration in patients on antidepressants (Article)

2009-08-01T00:00:00Z

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Several antidepressants are metabolized by the polymorphic enzyme cytochrome P450 2D6 (CYP2D6). • The variant allele CYP2D6*4 is the main polymorphism resulting in decreased enzyme activity in Caucasians. • Decreased CYP2D6 enzyme activity potentially leads to higher plasma concentrations of antidepressants. • Consequently, patients carrying the *4 allele are more likely to suffer from adverse drug reactions such as hyponatraemia. WHAT THIS STUDY ADDS • The association between CYP2D6 genotype and serum sodium concentration in users of antidepressants has not been examined thoroughly, and most studies suffer from small numbers of poor metabolizers (PMs) of CYP2D6. • This study shows that serum sodium concentrations in users of tricyclic antidepressive drugs are lower in CYP2D6 PMs than in extensive metabolizers. AIM To study the effect of the CYP2D6*4 polymorphism on serum sodium concentration in users of antidepressants [selective serotonin reuptake inhibitors and tricyclic antidepressants (TCAs)]. METHODS In this population-based cohort study, all subjects in the Rotterdam Study were included who used an antidepressant at baseline and from whom a blood sample was available in which CYP2D6 genotype and serum sodium concentration could be determined (n = 76). Multivariate linear regression was used to study the association between CYP2D6*4 and serum sodium concentration. RESULTS CYP2D6 poor metabolizers (PMs) (*4/*4) had a significantly lower mean serum sodium concentration in comparison with CYP2D6 extensive metabolizers (EMs) (*1/*1) [difference -3.9 mmol l-1; 95% confidence interval (CI) -0.86, -7.03; P = 0.013]. In CYP2D6*4 heterozygotes (*1/*4) serum sodium concentration was 1.7 mmol l-1(95% CI -3.48, 0.18) lower compared with CYP2D6 EMs, but this difference was not statistically significant (P = 0.077). CONCLUSIONS The serum sodium concentration in PMs was lower in users of an antidepressant, especially in TCA users. Therefore CYP2D6 PMs might be at increased risk of developing symptoms of hyponatraemia.

Genome-wide association meta-analysis for total serum bilirubin levels (Article)

2009-07-10T00:00:00Z

Variation in serum bilirubin is associated with altered cardiovascular disease risk and drug metabolism. We aimed to identify genetic contributors to variability in serum bilirubin levels by combining results from three genome-wide association studies (Framingham heart study, n = 3424; Rotterdam study, n = 3847; Age, Gene, Environment and Susceptibility-Reykjavik, n = 2193). Meta-analysis showed strong replication for a genetic influence on serum bilirubin levels of the UGT1A1 locus (P < 5 × 10-324) and a 12p12.2 locus. The peak signal in the 12p12.2 region was a non-synonymous SNP in SLCO1B1 (rs4149056, P = 6.7 × 10-13), which gives rise to a valine to alanine amino acid change leading to reduced activity for a hepatic transporter with known affinity for bilirubin. There were also suggestive associations with several other loci. The top variants in UGT1A1 and SLCO1B1 explain ∼18.0 and ∼1.0% of the variation in total serum bilirubin levels, respectively. In a conditional analysis adjusted for individual genotypes for the top UGT1A1 variant, the top SLCO1B1 variant remained highly significant (P = 7.3 × 10-13), but no other variants achieved genome-wide significance. In one of the largest genetic studies of bilirubin to date (n = 9464), we confirm the substantial genetic influence of UGT1A1 variants, consistent with past linkage and association studies, and additionally provide strong evidence of a role for allelic variation in SLCO1B1. Given the involvement of bilirubin in a number of physiological and disease processes, and the roles for UGT1A1 and SLCO1B1 in drug metabolism, these genetic findings have potential clinical importance. In analyses for association with gallbladder disease or gallstones, top bilirubin SNPs in UGT1A1 and SLCO1B1 were not associated.

Genetic variants associated with cardiac structure and function: A meta-analysis and replication of genome-wide association data (Article)

2009-07-08T00:00:00Z

Context: Echocardiographic measures of left ventricular (LV) structure and function are heritable phenotypes of cardiovascular disease. Objective: To identify common genetic variants associated with cardiac structure and function by conducting a meta-analysis of genome-wide association data in 5 population-based cohort studies (stage 1) with replication (stage 2) in 2 other community-based samples. Design, Setting, and Participants: Within each of 5 community-based cohorts comprising the EchoGen consortium (stage 1; n=12 612 individuals of European ancestry; 55% women, aged 26-95 years; examinations between 1978-2008), we estimated the association between approximately 2.5 million single-nucleotide polymorphisms (SNPs; imputed to the HapMap CEU panel) and echocardiographic traits. In stage 2, SNPs significantly associated with traits in stage 1 were tested for association in 2 other cohorts (n=4094 people of European ancestry). Using a prespecified P value threshold of 5 x 10-7to indicate genome-wide significance, we performed an inverse variance-weighted fixed-effects meta-analysis of genome-wide association data from each cohort. Main Outcome Measures: Echocardiographic traits: LV mass, internal dimensions, wall thickness, systolic dysfunction, aortic root, and left atrial size. Results: In stage 1, 16 genetic loci were associated with 5 echocardiographic traits: 1 each with LV internal dimensions and systolic dysfunction, 3 each with LV mass and wall thickness, and 8 with aortic root size. In stage 2, 5 loci replicated (6q22 locus associated with LV diastolic dimensions, explaining <1%of trait variance; 5q23, 12p12, 12q14, and 17p13 associated with aortic root size, explaining 1%-3% of trait variance). Conclusions: We identified 5 genetic loci harboring common variants that were associated with variation in LV diastolic dimensions and aortic root size, but such findings explained a very small proportion of variance. Further studies are required to replicate these findings, identify the causal variants at or near these loci, characterize their functional significance, and determine whether they are related to overt cardiovascular disease.

BclI glucocorticoid receptor polymorphism and smoking in the general population (Article)

2009-07-01T00:00:00Z

We studied the hypothesis that the BclI polymorphism of the glucocorticoid receptor gene is associated with an increased probability of being a (heavy) smoker and a decreased ability to quit smoking. The study cohort consisted of all subjects in the Rotterdam Study, a Dutch population-based cohort of people aged 55 years and older, for whom BclI genotyping and smoking status at baseline were available. In prospective analyses, the smoking status was reassessed during three additional examination rounds. Logistic regression analysis was used to study the association between BclI polymorphism and being a smoker or a heavy smoker at baseline. Furthermore, the relationship between BclI polymorphism and incident smoking cessation was tested with Cox proportional hazards analysis within those who smoked at baseline. In total, 6358 subjects were included in the study. The presence of a G-allele was not associated with current smoking at baseline [odds ratio (OR) = 0.96, 95%confidence interval (CI): 0.85-1.09] or with the incidence of smoking cessation during follow-up [hazard ratio (HR) = 0.98, 95%CI: 0.80-1.19]. Within current smokers, having a G-allele was not significantly associated with the risk of being a heavy smoker when measured by pack-years smoked (OR = 1.07, 95%CI: 0.85-1.35) or daily consumption of tobacco (OR = 1.10, 95%CI: 0.88-1.37). We were not able to replicate the earlier findings indicating that the proportion of current smokers is lower among carriers of the CC-genotype of the BclI glucocorticoid receptor. Furthermore, the BclI glucocorticoid receptor polymorphism did not predict the incidence of smoking cessation in the general elderly population.

Referral and treatment patterns for complex regional pain syndrome in the Netherlands (Article)

2009-07-01T00:00:00Z

Background: Patients with complex regional pain syndrome (CRPS) are seen and treated by a variety of physicians. The present study aims to describe referral and treatment patterns for CRPS patients in the Netherlands. Methods: Patients, who were selected (1996-2005) from an electronic general practice (GP) database (Integrated Primary Care Information Project), were invited for study participation, involving diagnosis verification (International Association for the Study of Pain criteria) and assessment of referrals and treatment through information retrieved from GP journals, patients' questionnaires, pharmacy dispensing lists and specialist letters if available. Results: One hundred and two patients were included. Sixty-one percent had presented first at the GP, while 80% subsequently consulted one or more medical specialists, most frequently an anesthetist (55% of the cases) or a specialist in rehabilitation medicine (41%). Over 90% of the patients received oral or topical pharmacotherapy, 45% received intravenous therapy, 89% received non-invasive therapy (i.e. physiotherapy) and 18% received nerve blocks. Analgesics and free radical scavengers were administered early during CRPS, while vasodilating drugs and drugs against neuropathic pain (antidepressants and anti-epileptics) were administered later on. Pharmacotherapy was usually initiated by a medical specialist. Conclusion: The Dutch treatment guidelines, issued in 2006, recommend free radical scavenger prescription (plus physiotherapy) as the initial treatment step for CRPS. Until 2005 only half of the patients received a scavenger within 3 months after disease onset, and the majority presents first at the GP, in particular GPs may be encouraged to initiate treatment with scavengers, while waiting for the results of further specialist consultation.

Association between the CYP2D6*4 polymorphism and depression or anxiety in the elderly (Article)

2009-06-16T00:00:00Z

Introduction: 5-methoxytryptamine (5-MT), a precursor of serotonin, is considered to be an endogeous substrate of cytochrome P450 2D6 (CYP2D6). Homozygous carriers of the variant allele CYP2D6*4 lack CYP2D6 emzyme activity. Relative to extensive metabolizers, these poor metabolizers may have lower baseline serotonin concentrations in various brain regions, and may be more prone to depression or anxity. Aim: To test whether the CYP2D6*4/*4 genotype is associated with a predisposition to depression or anxiety disorders in the elderly. Materials & methods: We conducted a cross-sectional study within the Rotterdam Study, a population-based cohort study, among persons aged 55 years or older, who were screened for depression and anxiety disorder at two consecutive examination rounds. Logistic regression was used to analyze the association between the CYP2D6*4 polymorhism and the risk of depression or anxiety disorders. Results: The risk of major depression in CYP2D*64/*4 was not significantly different from extensive metabolizers (OR = 0.85; 95% Cl: 0.36-2.00; p = 0.72). Neither did we find an association between CYP2D6 genotype and minor depression (OR = 1.56; 95% Cl: 0.69-3.52; p = 0.28). No increased risk of anxiety disorders was found (OR = 1.19; 95% Cl: 0.68-2.09; p = 0.55). Conclusion: Variation in the CYP2D6 gene is not related to a predisposition or anxiety disorders in the elderly.

Use of antithrombotic drugs and the presence of cerebral microbleeds: The Rotterdam Scan Study (Article)

2009-06-01T00:00:00Z

Background: Cerebral microbleeds are hemosiderin deposits in the brain that are indicative of microangiopathy. Microbleeds in strictly lobar brain locations have been related to cerebral amyloid angiopathy, a bleeding-prone disease state. Objective: To investigate the relation between antithrombotic drug use and the presence of cerebral microbleeds, especially those in strictly lobar locations. Design: A population-based, cross-sectional analysis that used magnetic resonance imaging (MRI) to assess the presence and location of microbleeds. Complete information on outpatient use of platelet aggregation inhibitors and anticoagulant drugs before MRI was obtained from automated pharmacy records. Setting: The Rotterdam Scan Study, a population-based imaging study in a general elderly community in the Netherlands. Participants: A population-based sample of 1062 persons from a longitudinal cohort, 60 years and older, free of dementia, who underwent MRI examinations between August 15, 2005, and November 22, 2006. Main Outcome Measures: Presence of cerebral microbleeds on MRI. Results: Compared with nonusers of antithrombotic drugs, cerebral microbleeds were more prevalent among users of platelet aggregation inhibitors (adjusted odds ratio [OR], 1.71; 95% confidence interval [CI], 1.21-2.41). We did not find a significant association for anticoagulant drugs and microbleed presence (OR, 1.49; 95% CI, 0.82-2.71). Strictly lobar microbleeds were more prevalent among aspirin users (adjusted OR compared with nonusers, 2.70; 95% CI, 1.45-5.04) than among persons using carbasalate calcium (adjusted OR, 1.16; 95% CI, 0.66-2.02). This difference was even more pronounced when comparing persons who had used similar dosages of both drugs. Conclusions: This cross-sectional study shows that use of platelet aggregation inhibitors is related to the presence of cerebral microbleeds. Furthermore, aspirin and carbasalate calcium use may differently relate to the presence of strictly lobar microbleeds.

Reply (Article)

2009-06-01T00:00:00Z

Echocardiographic parameters and all-cause mortality: The Rotterdam Study (Article)

2009-04-03T00:00:00Z

Background: Even when heart failure has not yet become clinically manifest, preclinical ventricular dysfunction may be present, and therapeutic interventions introduced at this time may reduce morbidity and mortality. However, data on the predictive value of echocardiographic characteristics in the general population remain relatively scarce. Methods: The Rotterdam Study is a population-based cohort study in men and women aged ≥ 55 years. Participants with prevalent heart failure, myocardial infarction and atrial fibrillation and flutter at the time of echocardiography were excluded. Structural, systolic and diastolic parameters were assessed using two-dimensional, M-mode and Doppler echocardiography. Echocardiograms were available in 4425 participants. Results: During a mean follow-up of 3.0 years, 226 participants died. Increased left ventricular mass was an independent risk factor for all-cause mortality, particularly in men (hazard ratio per standard deviation of natural log transformed left ventricular mass, 1.20 (95% CI, 1.01-1.43)). Fractional shortening and left ventricular systolic function did not show a clear association with mortality. E/A ratio < 0.75 was an independent risk factor in men (age-adjusted hazard ratio 1.82 (95% CI 1.23-2.69)). This was further reflected by diastolic function: impaired relaxation was a risk factor in men, but not in women. Conclusions: Structural and diastolic echocardiographic parameters are associated with all-cause mortality in an asymptomatic population. However, the evidence is still inadequate to support the usefulness of echocardiography for screening to identify asymptomatic individuals with preclinical ventricular dysfunction.

The association between ACE inhibitors and the complex regional pain syndrome: Suggestions for a neuro-inflammatory pathogenesis of CRPS (Article)

2009-04-01T00:00:00Z

Antihypertensive drugs interact with mediators that are also involved in complex regional pain syndrome (CRPS), such a neuropeptides, adrenergic receptors, and vascular tone modulators. Therefore, we aimed to study the association between the use of antihypertensive drugs and CRPS onset. We conducted a population-based case-control study in the Integrated Primary Care Information (IPCI) database in the Netherlands. Cases were identified from electronic records (1996-2005) and included if they were confirmed during an expert visit (using IASP criteria), or if they had been diagnosed by a medical specialist. Up to four controls per cases were selected, matched on gender, age, calendar time, and injury. Exposure to angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, β-blockers, calcium channel blockers, and diuretics was assessed from the automated prescription records. Data were analyzed using multivariate conditional logistic regression. A total of 186 cases were matched to 697 controls (102 confirmed during an expert visit plus 84 with a specialist diagnosis). Current use of ACE inhibitors was associated with an increased risk of CRPS (ORadjusted: 2.7, 95% CI: 1.1-6.8). The association was stronger if ACE inhibitors were used for a longer time period (ORadjusted: 3.0, 95% CI: 1.1-8.1) and in higher dosages (ORadjusted: 4.3, 95% CI: 1.4-13.7). None of the other antihypertensive drug classes was significantly associated with CRPS. We conclude that ACE inhibitor use is associated with CRPS onset and hypothesize that ACE inhibitors influence the neuro-inflammatory mechanisms that underlie CRPS by their interaction with the catabolism of substance P and bradykinin.

Recruitment of participants through community pharmacies for a pharmacogenetic study of antihypertensive drug treatment (Article)

2009-04-01T00:00:00Z

Objective To describe the design, recruitment and baseline characteristics of participants in a community pharmacy based pharmacogenetic study of antihypertensive drug treatment. Setting: Participants enrolled from the population-based Pharmaco-Morbidity Record Linkage System. Method We designed a nested case-control study in which we will assess whether specific genetic polymorphisms modify the effect of antihypertensive drugs on the risk of myocardial infarction. In this study, cases (myocardial infarction) and controls were recruited through community pharmacies that participate in PHARMO. The PHARMO database comprises drug dispensing histories of about 2,000,000 subjects from a representative sample of Dutch community pharmacies linked to the national registrations of hospital discharges. Results In total we selected 31010 patients (2777 cases and 28233 controls) from the PHARMO database, of whom 15973 (1871 cases, 14102 controls) were approached through their community pharmacy. Overall response rate was 36.3% (n = 5791, 794 cases, 4997 controls), whereas 32.1% (n = 5126, 701 cases, 4425 controls) gave informed consent to genotype their DNA. As expected, several cardiovascular risk factors such as smoking, body mass index, hypercholesterolemia, and diabetes mellitus were more common in cases than in controls. Conclusion Furthermore, cases more often used beta-blockers and calcium-antagonists, whereas controls more often used thiazide diuretics, ACE-inhibitors, and angiotensin-II receptor blockers. We have demonstrated that it is feasible to select patients from a coded database for a pharmacogenetic study and to approach them through community pharmacies, achieving reasonable response rates and without violating privacy rules.

Genotypes associated with reduced activity of VKORC1 and CYP2C9 and their modification of acenocoumarol anticoagulation during the initial treatment period (Article)

2009-04-01T00:00:00Z

The objective of this study was to investigate the influence of genotypes associated with reduced activity of vitamin K epoxide reductase complex subunit 1 (VKORC1) and cytochrome P450 2C9 (CYP2C9) on anticoagulation with acenocoumarol during the first 6 weeks of treatment. In 1,525 patients from the Rotterdam Study who were started on anticoagulation therapy with acenocoumarol, the presence of VKORC1 1173C>T and CYP2C9*2 and *3 allele variants was determined. The first international normalized ratio (INR) after initial standard dose, risk of overanticoagulation, and mean dosage at the end of the initiation period were compared between genotypes. The initial standard dosage significantly increased the risk of severe overanticoagulation by 85% for each additional VKORC1 T-allele present. At the end of the initiation period, each VKORC1 T-allele present was shown to decrease the required acenocoumarol dosage by 5.1 mg/week, while each CYP2C9 variant allele present reduced the required dosage by 1.8 mg/week. Our conclusion was that an initial standard dosing regimen with acenocoumarol increases the risk of severe overanticoagulation in patients with variant alleles of the VKORC1 and CYP2C9 genes.

Common variants at ten loci influence QT interval duration in the QTGEN Study (Article)

2009-04-01T00:00:00Z

QT interval duration, reflecting myocardial repolarization on the electrocardiogram, is a heritable risk factor for sudden cardiac death and drug-induced arrhythmias. We conducted a meta-analysis of three genome-wide association studies in 13,685 individuals of European ancestry from the Framingham Heart Study, the Rotterdam Study and the Cardiovascular Health Study, as part of the QTGEN consortium. We observed associations at P < 5 × 108with variants in NOS1AP, KCNQ1, KCNE1, KCNH2 and SCN5A, known to be involved in myocardial repolarization and mendelian long-QT syndromes. Associations were found at five newly identified loci, including 16q21 near NDRG4 and GINS3, 6q22 near PLN, 1p36 near RNF207, 16p13 near LITAF and 17q12 near LIG3 and RFFL. Collectively, the 14 independent variants at these 10 loci explain 5.4-6.5% of the variation in QT interval. These results, together with an accompanying paper, offer insights into myocardial repolarization and suggest candidate genes that could predispose to sudden cardiac death and drug-induced arrhythmias.

Calcium channel blockers, NOS1AP, and heart-rate-corrected QT prolongation (Article)

2009-04-01T00:00:00Z

Objectives To study whether NOS1AP single nucleotide polymorphisms (SNPs), rs10494366 T>G and rs10918594 C>G, modify the heart-rate-corrected QT (QTc) prolonging effect of calcium channel blockers. Background Common variation in the NOS1AP gene has been associated with QT interval variation in several large population samples. NOS1 is presumed to influence intracellular calcium. Methods The prospective population-based Rotterdam Study includes 16 603 ECGs from 7565 participants (≥ 55 years), after exclusion of patients with left ventricular hypertrophy, left and right bundle branch block, as well as carriers of pacemakers. The endpoint was the length of the QTc interval in calcium channel blocker users and non-users with the minor alleles compared with the major alleles (wild type). We used a repeated-measurement analysis, adjusted for all known confounders. Results Use of verapamil was associated with a significant QTc interval prolongation [6.0 ms 95% confidence interval (CI) 1.7; 10.2] compared with non-users. Furthermore, users of verapamil with the rs10494366 GG genotype showed significantly more QTc prolongation than users with the TT genotype [25.4 ms (95% CI: 5.9-44.9)] (P value for multiplicative interaction 0.0038). Users of isradipine with the GG genotype showed more QTc prolongation than users with the TT genotype [19.8 ms (95% CI: 1.9-37.7)]; however, SNP rs10494366 did not modify the effect on QTc interval on a multiplicative scale (P= 0.3563). SNP rs10918594 showed similar results. Conclusion In conclusion, we showed that the minor alleles of both NOS1AP SNPs significantly potentiate the QTc prolonging effect of verapamil. Pharmacogenetics and Genomics 19:260-266

Estrogens and the risk of complex regional pain syndrome (CRPS) (Article)

2009-03-09T00:00:00Z

Objective: Since complex regional pain syndrome (CRPS) shows a clear female predominance, we investigated the association between the cumulative as well as current exposure to estrogens, and CRPS. Methods: A population-based case-control study was conducted in the Integrated Primary Care Information (IPCI) project in the Netherlands. Cases were identified from electronic records (1996-2005) and included if they were confirmed during a visit (using International Association for the Study of Pain Criteria), or had been diagnosed by a specialist. Controls were matched to cases on gender, age, calendar time, and injury. Measures of cumulative endogenous estrogen exposure were obtained by questionnaire and included age of menarche and menopause, menstrual life, and cumulative months of pregnancy and breast-feeding. Current estrogen exposure at CRPS onset was retrieved from the electronic medical records and determined by current pregnancy or by the use of oral contraceptive (OC) drugs or hormonal replacement therapy (HRT). Results: Hundred and forty-three female cases (1493 controls) were included in analyses on drug use and pregnancies, while cumulative endogenous estrogen exposure was studied in 53 cases (58 controls) for whom questionnaire data were available. There was no association between CRPS and either cumulative endogenous estrogen exposure, OC, or HRT use. CRPS onset was increased during the first 6 months after pregnancy (OR: 5.6, 95%CI: 1.0-32.4), although based on small numbers. Discussion: We did not find an association between CRPS onset and cumulative endogenous estrogen exposure or current OC or HRT use, but more powered studies are needed to exclude potential minor associations. Copyright

C-reactive protein levels, haplotypes, and the risk of incident chronic obstructive pulmonary disease (Article)

2009-03-01T00:00:00Z

Rationale: Chronic obstructive pulmonary disease (COPD) is characterized by substantial chronic inflammation in the pulmonary compartment as well as in the systemic circulation. Objectives: To investigate potentially causal association, we examined whether serum levels of high-sensitivity C-reactive protein (hsCRP) and variations in the CRP gene are associated with the risk of developing COPD. Methods: This study is part of the Rotterdam Study, a prospective population-based cohort study among subjects aged 55 years or older. At baseline, 6,836 subjects without COPD had a blood sample available for assessment of hsCRP serum levels and haplotypes of the CRP gene. We analyzed the association between hsCRP levels, CRP gene haplotypes, and incident COPD with Cox proportional hazard models, adjusted for age, sex, and other confounders. Measurements and Main Results: High levels of hsCRP (>3 mg/L) were associated with a significantly increased risk of incident COPD (hazard ratio [HR], 1.7; 95% confidence interval [CI], 1.16-2.49) compared with persons with low levels (< 1 mg/L). The risk remained increased after adjusting for potential confounders and introducing a latency period of 3 years. The risk was most pronounced in former smokers (HR, 2.2; 95% CI, 1.12-3.74). hsCRP was not a risk factor in never smokers. No CRP single nucleotide polymorphism or haplotype was associated with a significantly increased or decreased COPD risk. Conclusions: Increased hsCRP levels are predictive for the occurrence of COPD in smokers. However, haplotypes of the CRP gene, which influence hsCRP levels, are not associated with an altered risk of developing COPD.

Genetic variation in the multidrug and toxin extrusion 1 transporter protein influences the glucose-lowering effect of metformin in patients with diabetes: A preliminary study (Article)

2009-03-01T00:00:00Z

OBJECTIVE-Metformin, an oral glucose-lowering drug, is taken up in hepatocytes by the organic cation transporter (OCT) 1 and in renal epithelium by OCT2. In these cells, the multidrug and toxin extrusion (MATE) 1 protein, encoded by the SLC47A1 gene, is responsible for the excretion of metformin into the bile and urine, respectively. We studied the effect of single nucleotide polymorphisms (SNPs) in the SLC47A1 gene on the A1C-lowering effect of metformin. RESEARCH DESIGN AND METHODS-We identified all incident metformin users in the Rotterdam Study, a population- based cohort study. Associations between 12 tagging SNPs in the SLC47A1 gene and change in A1C level were analyzed. RESULTS-One hundred and sixteen incident metformin users were included in the study sample. The rs2289669 G> A SNP was significantly associated with metformin response. For the other SNPs, no associations were found. For each minor A allele at rs2289669, the A1C reduction was 0.30% (95% CI -0.51 to -0.10; P = 0.005) larger. After Bonferroni correction for multiple testing, the P value was 0.045. CONCLUSIONS-The rs2289669 G>A SNP is associated with a reduction in A1C level, consistent with a reduction in MATE1 transporter activity. These results suggest that the transporter MATE1, encoded by SLC47A1, may have an important role in the pharmacokinetics of metformin, although replication is necessary.

Prevalence, incidence, and lifetime risk for the development of COPD in the elderly the rotterdam study (Article)

2009-02-01T00:00:00Z

Background: COPD is a major cause of chronic morbidity and mortality throughout the world. Although the prevalence of COPD is already well documented, there are only few studies regarding the incidence of COPD. Methods: In a prospective population-based cohort study among subjects aged ≥ 55 years, COPD was diagnosed with an algorithm based on the validation of hospital discharge letters, files from the general practitioner, and spirometry reports. Results: In this study cohort of 7,983 participants, 648 cases were identified with incident COPD after a median follow-up time of 11 years (interquartile range, 7.8 years). This resulted in an overall incidence rate (IR) of 9.2/1,000 person-years (PY) [95% confidence interval (CI), 8.5 to 10.0]. The IR of COPD was higher among men (14.4/1,000 PY; 95% CI, 13.0 to 16.0) than among women (6.2/1,000 PY; 95% CI, 5.5 to 7.0), and higher in smokers than in never-smokers (12.8/1,000 PY; 95% CI, 11.7 to 13.9 and 3.9/1,000 PY; 95% CI, 3.2 to 4.7, respectively). Remarkable was the high incidence in the youngest female age category of 55 to 59 years (7.4/1,000 PY; 95% CI, 4.1 to 12.6). For a 55-year-old man and woman still free of COPD at cohort entry, the risk for the development of COPD over the coming 40 years was 24% and 16%, respectively. Conclusion: The overall incidence of COPD in an elderly population is 9.2/1,000 PY, with a remarkably high incidence in the youngest women, suggesting a further shift toward the female sex in the gender distribution of COPD. During their further lives, one of four men and one of six women free of COPD at the age of 55 years will have COPD develop.

Psychotropic drugs associated with corrected QT interval prolongation (Article)

2009-02-01T00:00:00Z

AIMS:: To study whether listed putative corrected QT (QTc)-prolonging psychotropic drugs indeed prolong the QTc interval under everyday circumstances and to evaluate whether this is a class effect or an individual drug effect, we conducted a prospective population-based cohort study. METHODS:: This study was conducted as part of the Rotterdam Study and included 3377 men and 4845 women (ĝ‰¥55 years) who had triennial electrocardiograms (ECGs). The primary end points of the study were the length of the QTc interval at each ECG, the difference in QTc interval between consecutive ECGs within one person, and the risk of an abnormally prolonged QTc interval. Drug use at the index date was obtained from automated dispensing records. The associations were examined by means of a repeated measurement analysis, adjusted for age, sex, diabetes mellitus, hypertension, myocardial infarction, heart failure, and use of class 1 QTc-prolonging drugs. RESULTS:: Of the 8222 participants, 813 participants (9.9%) developed QTc prolongation during follow-up and 492 participants (74.4% women) used psychotropic drugs at the time of an ECG. Starting tricyclic antidepressants increased the QTc interval significantly with 6.9 milliseconds (95% confidence interval [CI], 3.1-10.7 milliseconds) between consecutive ECGs in comparison with consecutive ECGs of participants not using tricyclic antidepressants, in particular starting amitriptyline (8.5 milliseconds; 95% CI, 2.8-14.2 milliseconds), maprotiline (13.9 milliseconds; 95% CI, 3.6-24.3 milliseconds), and nortriptyline (35.3 milliseconds; 95% CI, 8.0-62.6 milliseconds). Starting lithium also increased the QTc interval significantly (18.6 milliseconds; 95% CI, 4.8-32.4 milliseconds). CONCLUSIONS:: In this population-based prospective cohort study, we confirmed the importance of antidepressants and antipsychotics as potential contributors to QTc prolongation. Especially, starting tricyclic antidepressant drugs (as a class) is associated with a significant intraindividual increase in the QTc interval in comparison to the change in nonusers. The tricyclic antidepressants seem to prolong the QTc interval as a class effect.

Identification of a common variant at the NOS1AP locus strongly associated to QT-interval duration (Article)

2009-01-05T00:00:00Z

QT-interval prolongation is an electrophysiologic phenomenon associated with sudden cardiac death. The QT-interval in the general population is ∼35% heritable. In genome-wide association studies, a common variant (rs10494366T > G) within the nitric oxide synthase 1 adaptor protein (NOS1AP) gene was identified and consistently associated with QT-interval duration. Yet, the causal variant remains unclear. Therefore, we performed fine mapping of the association of the NOS1AP locus with QT-interval within the Rotterdam Study, a population-based, prospective cohort study of individuals of ≥55 years of age. First, we tested the association of single-nucleotide polymorphisms (SNPs) in or within ±100 kb of the NOS1AP gene with QT-interval duration, using sex-specific unstandardized residuals after regression on age and RR-interval, in 385 individuals using the combined set of SNPs present in the Affymetrix 500k and Illumina 550k chip arrays. Subsequently, we examined correspondence of the association signals in 4606 individuals using the Illumina 550k array. A C-to-T SNP at chromosome 1 position 160300514 (rs12143842, T-allele frequency = 24%) was associated with a QT-interval duration increase of 4.4 ms per additional T-allele (P = 4.4 × 10-28). For comparison, the most strongly associated variant to date, rs10494366T > G, was associated with a 3.5 ms increase (P = 1.6 × 10-23) per additional G-allele. None of the inferred haplotypes showed a stronger effect than the individual rs12143842C > T SNP. In conclusion, we found rs12143842 6 kb upstream distance of NOS1AP to be more strongly associated to QT-interval duration than rs10494366T > G. Functional analysis of this marker is warranted.

No modification of the beneficial effect of NSAIDs on colorectal cancer by CYP2C9 genotype (Article)

2009-01-01T00:00:00Z

Background: CYP2C9 enzymes are involved in non-steroidal anti-inflammatory drug (NSAID) metabolism. Therefore, we investigated whether CYP2C9*2 and *3 variant alleles, encoding for enzymes with lower activity, increased the protective effect of NSAIDs on colorectal cancer. Methods: Individual and combined associations of NSAIDs and CYP2C9*2 and 3 variant alleles with colorectal cancer were studied in 7757 Caucasian individuals of The Rotterdam Study, a population-based prospective cohort since 1990. Additive and multiplicative effect modification models were used to examine drug-gene interactions. Results: There were 212 incident cases of colorectal cancer during follow-up. A reduced risk of colorectal cancer was observed in individuals who used NSAIDs for more than a year (HR 0.45; 95% CI 0.28 to 0.71), and in carriers of an CYP2C9 variant allele associated with lower enzymatic activity (HR 0.67; 95% CI 0.47 to 0.96). The combination of both determinants was associated with a further risk reduction but without synergy. Conclusion: Both NSAID use and CYP2C9*2 and/or *3 carriage are associated with a reduced risk of colorectal cancer. However, no interaction between the determinants was found, which might indicate independent pathophysiological mechanisms.

Pharmacogenetics of cardiovascular drug therapy (Article)

2009-01-01T00:00:00Z

In developed countries cardiovascular disease is one of the leading causes of death. Cardiovascular drugs such as platelet aggregation inhibitors, oral anticoagulants, antihypertensives and cholesterol lowering drugs are abundantly prescribed to reduce risk of cardiovascular disease. Notable interindividual variation exists in the response to these pharmacotherapeutic interventions, which can be partially explained by factors such as gender, age, diet, concomitant drug use and environmental factors. Notwithstanding, a great part of this variability remains unknown. To a smaller or larger extent, genetic variability may contribute to the variability in response to these cardiovascular drugs. This review gives an overview of pharmacogenetic studies of genes that were reported to be associated with four commonly prescribed drugs/drug classes (platelet aggregation inhibitors, coumarins, antihypertensives and statins) and were studied at least 2 times with a similar outcome measure. In the field of cardiovascular drug therapy, polymorphisms in candidate genes such as the cycloxygenase-1, vitamin K reductase complex subunit 1, CYP2C9, alpha adducin and 3-hydroxy-3-methylglutaryl-CoA reductase have received a great amount of interest in the pharmacogenetics of aspirin, coumarins, antihypertensives and statins respectively. However, only variations in VKORC1 and CYP2C9 have consistently been associated with drug response (coumarins) and have clinical implications. Clinical trials should provide evidence for the effectiveness of genotyping before this procedure will be a part of every day anticoagulant therapy. In spite of the tremendous amount of publications in this field, there is no reason to advocate for genetic testing for any other drugs cardiovascular drug therapy yet. Current approaches in pharmacogenetic research do not seem to lead to results that meet our expectations of individualized medicine. Therefore, new approaches are needed addressing issues and challenges such as the number of SNPs studied, study power, study design and application of new statistical methods in (pharmaco-)genetic analysis.

Genetic variation in the CYP2D6 gene is associated with a lower heart rate and blood pressure in β-blocker users (Article)

2009-01-01T00:00:00Z

Several β-blockers are metabolized by the polymorphic enzyme cytochrome P450 2D6 (CYP2D6). CYP2D6*4 is the main polymorphism leading to decreased enzyme activity. The clinical significance of impaired elimination of β-blockers is controversial, and most studies suffer from inclusion of small numbers of poor metabolizers (PMs) of CYP2D6. In this study, the association between CYP2D6*4 and blood pressure or heart rate was examined in 1,533 users of β-blockers in the Rotterdam Study, a population-based cohort study. In CYP2D6 *4/*4 PMs, the adjusted heart rate in metoprolol users was 8.5 beats/min lower compared with *1/*1 extensive metabolizers (EMs) (P < 0.001), leading to an increased risk of bradycardia in PMs (odds ratio = 3.86; 95% confidence interval 1.68-8.86; P = 0.0014). The diastolic blood pressure in PMs was 5.4 mm Hg lower in users of β-blockers metabolized by CYP2D6 (P = 0.017) and 4.8 mm Hg lower in metoprolol users (P = 0.045) compared with EMs. PMs are at increased risk of bradycardia.

Interaction between the Gly460Trp α-adducin gene variant and diuretics on the risk of myocardial infarction (Article)

2009-01-01T00:00:00Z

Introduction: The Gly460Trp variant of the α-adducin gene has been associated with the salt-sensitive and diuretic responsive form of hypertension. Objective: The aim of the study was to determine whether the α-adducin 460Trp variant allele modifies the risk-lowering effect of diuretics on myocardial infarction (MI). Design, Setting and Participants: In a population-based registry of pharmacy records linked to hospital discharge records (PHARMO), we used a nested case-control design. We selected patients hospitalized for MI as cases if they had at least one prescription for antihypertensive drugs in the 3 months prior to their first MI and were registered in PHARMO for at least 1 year. Controls that were matched on age, sex, region and calendar date, met the same eligibility criteria as the patients, but were not hospitalized for MI. Only current users of antihypertensive drugs in whom the Gly460Trp polymorphism was genotyped were included for this study. Logistic regression analysis was used to calculate odds ratio (OR), synergy indices, 95% confidence intervals (CIs) and to adjust for the potential confounding factors high cholesterol, smoking, BMI, diabetes, physical activity, alcohol use, use of loop diuretics, coumarins, antiplatelet drugs, ischemic heart disease and number of antihypertensive drugs. Results: The study included 613 patients and 3627 controls. Compared with users of other antihypertensives, the risk of MI was significantly lower among users of thiazide diuretics (OR 0.71, 95% CI 0.55-0.92). Among patients with the adducin variant the risk of MI was similar among thiazide users as compared with users of other antihypertensives (OR 0.88, 95% CI 0.58-1.33), whereas among wild-type carriers this risk was significantly lower (OR 0.62, 95% CI 0.44-0.87). The interaction between current use of diuretics and the α-adducin polymorphism was not statistically significantly increased on the multiplicative scale (synergy index 1.41, 95% CI 0.91-2.17). In sensitivity analyses, we found a nonsignificant trend towards a difference between patients who used potassium-sparing diuretics (synergy index 0.98, 95% CI 0.45-2.12) and patients who did not use potassium-sparing diuretics (synergy index 1.60, 95% CI 0.98-2.60) and a statistically significant difference between patients on monotherapy (synergy index 0.69, 95% CI 0.30-1.59) and those on combination therapy (synergy index 1.90, 95% CI 1.04-3.47). Conclusion: This study suggests that the α-adducin gene does not play an important role in modifying the risk of nonfatal MI associated with the use of thiazide diuretics.

A common NOS1AP genetic polymorphism is associated with increased cardiovascular mortality in users of dihydropyridine calcium channel blockers (Article)

2009-01-01T00:00:00Z

AIM: Recently, a polymorphism in the NOS1AP gene (rs10494366), a regulator of neuronal nitric oxide synthase (nNOS), was associated with QTc prolongation. Both nNOS and calcium channel blockers (CCBs) regulate intracellular calcium levels and have an important role in cardiovascular homeostasis. The aim was to investigate whether this polymorphism is associated with cardiovascular mortality in users of CCBs. METHODS: The data from the Rotterdam study, a population-based closed cohort study of Caucasian individuals of ≥55 years of age, were used. We identified 1113 participants in the Rotterdam Study who were prescribed CCBs for the first time between 1991 and 2005. All-cause and cardiovascular mortality was assessed in participants who were prescribed CCBs with different NOS1AP rs10494366 genotypes using Cox proportional hazard models. RESULTS: In participants starting on dihydropyridine CCBs (amlodipine, nifedipine and others) all-cause mortality (n = 79) risks were higher in participants with the TG [hazard ratio (HR) 2.57, 95% confidence interval (CI) 1.24, 5.34] or the GG genotype (HR 3.18, 95% CI 1.18, 8.58) than in participants with the referent TT genotype. Cardiovascular mortality (n = 54) risks were 3.51 (95% CI 1.41, 8.78) for the TG genotype and 6.00 (95% CI 1.80, 20.0) for the GG genotype. No differences in all-cause mortality or cardiovascular mortality were seen in participants starting with the nondihydropyridine CCBs verapamil or diltiazem. CONCLUSION: The minor G allele of rs10494366 in the NOS1AP gene is associated with increased all-cause and cardiovascular mortality in Caucasian users of dihydropyridine CCBs. The mechanism underlying the observed association is unknown.

Statins are associated with a reduced risk of Alzheimer disease regardless of lipophilicity. The Rotterdam Study (Article)

2009-01-01T00:00:00Z

Background: Cross-sectional reports suggest that statin users are less likely to have Alzheimer disease (AD). Prospective studies have provided inconsistent evidence. Moreover, it is unclear whether the association differs for lipohilic statins, those that could more easily pass the blood-brain barrier and hydrophilic statins. Objectives: To prospectively evaluate whether use of statins is associated with the risk of AD, and to determine whether associations differ for lipophilic and hydrophilic statins. Method: 6992 participants of the prospective, population-based Rotterdam Study were followed, from baseline (1990-1993) until January 2005 for incident AD. Data on all filled prescriptions came from pharmacy records. For each date on which each event occurred, cholesterollowering drug use for the person who experienced the event and all remaining persons in the cohort was categorised as "any" or "never" use. A distinction was made between statin, lipophilic and hydrophilic statins, and non-statin cholesterol-lowering drugs. Data were analysed with the Cox regression analysis, adjusting for sex, age and potential confounders. Results: During follow-up (mean 9 years), 582 persons developed AD. Compared with never use of cholesterollowering drugs, statin use was associated with a decreased risk of AD (HR 0.57; 95% CI 0.37 to 0.90), but non-statin cholesterol-lowering drug use was not (HR 1.05; 95% CI 0.45 to 2.44). HRs were equal for lipophilic (HR 0.54; 95% CI 0.32 to 0.89) and hydrophilic statins (HR 0.54; 95% CI 0.26 to 1.11). Conclusion: In the general population, the use of statins, but not of non-statin cholesterol-lowering drugs, was associated with a lower risk of AD compared with never use of cholesterol-lowering drugs. The protective effect was independent of the lipophilicity of statins.

Incidence and recurrence of late-life depression (Article)

2008-12-01T00:00:00Z

Context: Depression is common in old age. Nevertheless, few incidence studies have established how often depression occurs in elderly persons with and without a history of depression. Objectives: To determine the incidence and recurrence rates of depression in an elderly population. Design, Setting, and Participants: A cohort study of community-dwelling elderly persons aged 56 years or older residing in Rotterdam, the Netherlands, performed between September 1993 and October 2005 and encompassing baseline and 2 follow-up examinations as well as continuous procedures. The study population consisted of 5653 participants free of dementia. Depression was identified through standardized psychiatric examinations, monitoring of medical records, registration of antidepressant use, and self-reported histories of depression. We categorized the depression as depressive syndromes, including DSM-IV-defined major depression, or clinically relevant depressive symptoms. Main Outcome Measures: Incidence and recurrence rates for depressive syndromes as well as for depressive syndromes and symptoms combined. In addition to overall rates, sex- and age-specific rates were calculated. Results: During the follow-up period of 8 years on average, 566 depressive syndromes and 1073 episodes of clinically relevant depressive symptoms occurred. For depressive syndromes, the incidence rate was 7.0 (95% confidence interval, 6.0-8.3) per 1000 person-years and the recurrence rate was 27.5 (95% confidence interval, 23.7-32.1) per 1000 person-years. The incidence and recurrence rates more than doubled when episodes of depressive symptoms were included. The recurrence rate of depressive syndromes was equal for women and men, but all other rates were almost twice as high for women compared with men. No rates seemed to change with age. Conclusions: The incidence rate of depression in the elderly population is low except when episodes of clinically relevant depressive symptoms are accounted for. Most late-life depression occurs in persons with a history of depression. Moreover, the recurrence rate of depressive syndromes does not differ between men and women.

Protective effect of a GRK5 polymorphism on heart failure and its interaction with β-adrenergic receptor antagonists (Article)

2008-11-11T00:00:00Z

β-adrenoceptor blockade therapy was developed for the treatment of hypertension but is now also a cornerstone in the treatment of heart failure. Based on the mechanisms of action and current knowledge of pathway signaling, Ligget et al. hypothesized that genetic variants within G-protein coupled receptor kinases might alter disease course and response to β-adrenoceptor blockade therapy. Following a multistep approach, a common variant in GRK5 was identified as being important in vitro and in vivo (mouse model) in β-adrenergic desensitization, and was epidemiologically related to survival and therapy response in African-Americans. Although such a variety of research approaches is appealing, owing to the large number of used methods readers remain puzzled on some issues because it is not possible to give all details of each individual study. Therefore, interpretation of the overwhelming amount of results is difficult. In an era of shifting emphasis from classic hypothesis driven pharmacogenetics to genome-wide association studies, this study shows that hypothesis driven translational research is still of high value, especially in phenotypes as investigated here.

Genetic variation in the NOS1AP gene is associated with the incidence of diabetes mellitus in users of calcium channel blockers (Article)

2008-11-01T00:00:00Z

Topical β-Blockers and Mortality (Article)

2008-11-01T00:00:00Z

Purpose: To study the associations between long-term and short-term use of topical β-blockers and mortality. Design: Prospective population-based cohort study. Participants: To examine long-term effects, 3842 participants aged 55 years and older were recruited. To examine short-term effects, 484 incident β-blocker users and 4700 age-matched controls were recruited. All participants were recruited as part of the Rotterdam Study. Methods: To examine long-term effects, associations between topical β-blocker use before and at baseline, between 1990 and 1997, and mortality between 1997 and 2005 were studied. Data were analyzed using Cox regression, and hazard ratios were adjusted for age, gender, smoking, systemic hypertension, diabetes mellitus, and angina pectoris. Short-term effects were defined as death within 3 months after the first prescription of a topical β-blocker. Mortality was compared between incident β-blocker users, that is, participants who started using a topical β-blocker between the onset of the Rotterdam Study in 1990 and October 1, 2004, and age-matched controls. Short-term effects were examined using a chi-square test. Confounding by smoking was analyzed by stratification. Main Outcome Measures: For long-term effects, hazard ratios of topical β-blocker use for all-cause mortality and cardiovascular mortality; for short-term effects, chi-square statistics between mortality of incident topical β-blocker users and age-matched controls. Results: With regard to long-term effects, mean age at baseline was 72 years (standard deviation, 7 years). Topical β-blockers were used by 228 participants. Seven hundred nine participants died during the follow-up (18%); 135 (3.5%) died of a cardiovascular cause. The hazard ratio of topical β-blocker use was 0.94 (95% confidence interval [CI], 0.71-1.25; P = 0.69) for all-cause mortality and 1.02 (95% CI, 0.56-1.86; P = 0.95) for cardiovascular mortality. With regard to short-term effects, 4 (0.8%) of the 484 incident topical β-blocker users died within 3 months after their first prescription; 65 (1.4%; P = 0.31) of the 4700 aged-matched controls died within a similar period. Conclusions: Use of topical β-blockers seems not to be associated with excess mortality. Financial Disclosure(s): The authors have no proprietary or commercial interest in any materials discussed in this article.

Medical history and the onset of complex regional pain syndrome (CRPS) (Article)

2008-10-15T00:00:00Z

Knowledge concerning the medical history prior to the onset of complex regional pain syndrome (CRPS) might provide insight into its risk factors and potential underlying disease mechanisms. To evaluate prior to CRPS medical conditions, a case-control study was conducted in the Integrated Primary Care Information (IPCI) project, a general practice (GP) database in the Netherlands. CRPS patients were identified from the records and validated through examination by the investigator (IASP criteria) or through specialist confirmation. Cases were matched to controls on age, gender and injury type. All diagnoses prior to the index date were assessed by manual review of the medical records. Some pre-specified medical conditions were studied for their association with CRPS, whereas all other diagnoses, grouped by pathogenesis, were tested in a hypothesis-generating approach. Of the identified 259 CRPS patients, 186 cases (697 controls) were included, based on validation by the investigator during a visit (102 of 134 visited patients) or on specialist confirmation (84 of 125 unvisited patients). A medical history of migraine (OR: 2.43, 95% CI: 1.18-5.02) and osteoporosis (OR: 2.44, 95% CI: 1.17-5.14) was associated with CRPS. In a recent history (1-year before CRPS), cases had more menstrual cycle-related problems (OR: 2.60, 95% CI: 1.16-5.83) and neuropathies (OR: 5.7; 95% CI: 1.8-18.7). In a sensitivity analysis, including only visited cases, asthma (OR: 3.0; 95% CI: 1.3-6.9) and CRPS were related. Psychological factors were not associated with CRPS onset. Because of the hypothesis-generating character of this study, the findings should be confirmed by other studies.

Orthostatic hypotension and risk of cardiovascular disease in elderly people: The Rotterdam study (Article)

2008-10-01T00:00:00Z

OBJECTIVES: To determine the prognostic role of orthostatic hypotension for cardiovascular disease (CVD) and all-cause mortality in elderly people. DESIGN: Prospective study. SETTING: Community based. PARTICIPANTS: Five thousand sixty-four subjects from the Rotterdam study aged 55 and older. MEASUREMENTS: Orthostatic hypotension was measured using a Dinamap automatic blood pressure recorder. Orthostatic hypotension is defined as a decline in systolic blood pressure of 20 mmHg or more or a decline in diastolic blood pressure of 10 mmHg or more from supine to standing position at any of three measurements taken 1, 2, and 3 minutes after standing. RESULTS: At baseline, 901 subjects had orthostatic hypotension. During follow-up, 668 subjects had coronary heart disease (CHD) (mean follow-up 6.0 ± 3.5 years), and 1,835 subjects died (mean follow-up period 7.8 ± 3.8 years). Orthostatic hypotension increased the risk of CHD (hazard ratio (HR)=1.31, 95% confidence interval (CI)=1.08-1.57) and all-cause mortality (HR=1.22, 95% CI=1.09-1.36), in models adjusted for age and sex. The risk was slightly lower after additional adjustment for cardiovascular risk factors. In analyses stratified for age, the HRs for all-cause mortality were 1.80 (95% CI 1.25-2.60), 1.13 (0.89-1.42), and 1.27 (95% CI=1.11-1.44), in the first, second, and third tertile of age, respectively. CONCLUSION: Orthostatic hypotension increases the risk of CHD and all-cause mortality in elderly people. The risk of CVD and mortality is strongest in younger and very old subjects.

Cerebrovascular risk factors and incident depression in community-dwelling elderly (Article)

2008-08-01T00:00:00Z

Objective: The 'vascular depression' hypothesis suggests that late-life depression results from vascular brain damage. We studied the longitudinal association between cerebrovascular risk factors and incident depression in a large population-based study. Method: Two thousand nine hundred and thirty-one persons with the age of ≥61 years were followed up. Data on a comprehensive set of cerebrovascular risk factors were collected at baseline. Participants received a psychiatric assessment 5 years later to establish DSM-IV diagnoses. Results: Only current smoking and antihypertensive drug use were independently associated with incident depressive symptoms. Diabetes mellitus and the Framingham stroke risk score were related to incident depressive disorder. No relation with depression was observed for cholesterol, diastolic and systolic blood pressure, history of cardiovascular disease, atrial fibrillation, left ventricular hypertrophy or the use of statins and anticoagulants. Conclusion: These results moderately support the 'vascular depression' hypothesis. Copyright

Selective serotonin reuptake inhibiting antidepressants are associated with an increased risk of nonvertebral fractures (Article)

2008-08-01T00:00:00Z

BACKGROUND:: Fractures related to osteoporosis and falling constitute a major health problem in the elderly population. Exposure to antidepressants is associated with an increased risk of falls and fractures, but most previous studies incriminate tricyclic antidepressants (TCAs) rather than selective serotonin reuptake inhibitors (SSRIs). OBJECTIVE:: To examine the association between antidepressants, including TCAs, SSRIs, and other antidepressants and the risk of nonvertebral fractures in elderly. DESIGN:: Prospective population-based cohort study. SETTING:: The Rotterdam Study, consisting of 7983 individuals aged 55 years and older. PARTICIPANTS:: All persons from the Rotterdam Study. RESULTS:: One thousand two hundred nineteen persons experienced a nonvertebral fracture, 25 during TCA use and 18 during SSRI use. After adjustment for age, sex, lower-limb disability, and depression, the risk of nonvertebral fracture was 2.35 (95% confidence interval, 1.32-4.18) for current users of SSRIs compared with nonusers of antidepressants. Multiple adjusting for many possible risk factors did not affect the association. To deal with potential confounding by indication, we subsequently restricted the analysis to antidepressant users (n = 1217). Compared with past users of TCAs or SSRIs, current users of SSRIs had a 2.07-fold (95% confidence interval, 1.23-3.50) increased risk of fracture, which further increased with prolonged use. In this analysis, depressive state at baseline and during follow-up did not play a role, suggesting absence of confounding by indication. The use of TCAs was associated with an increased fracture risk that decreased with prolonged use. CONCLUSIONS:: Not only users of TCAs but also of SSRIs have a significantly increased risk of nonvertebral fractures, in SSRI users especially after prolonged use. Despite fewer early adverse effects of SSRIs, physicians treating elderly depressive patients should be aware of the unfavorable long-term consequence of SSRIs on fracture risk.

Inappropriate benzodiazepine use in older adults and the risk of fracture (Article)

2008-08-01T00:00:00Z

AIMS: The Beers criteria for prescribing in elderly are well known and used for many drug utilization studies. We investigated the clinical value of the Beers criteria for benzodiazepine use, notably the association between inappropriate use and risk of fracture. METHODS: We performed a nested case-control study within the Rotterdam Study, a population-based cohort study in 7983 elderly. The proportion of 'inappropriate' benzodiazepine use according to the Beers criteria was compared between fracture patients and controls. 'Inappropriate' use for elderly implies use of some long-acting benzodiazepines and some intermediate/short-acting ones exceeding a suggested maximum daily dose. Also, alternative criteria were applied to compare the risk of fracture. Cases were defined as persons with incident fracture between 1991 and 2002 who were current benzodiazepine users on the fracture date. Controls were matched on fracture date and were also current benzodiazepine users. RESULTS: The risk of fracture in 'inappropriate' benzodiazepine users according to the Beers criteria was not significantly different from 'appropriate' users [odds ratio (OR) 1.07, 95% confidence interval (CI) 0.72, 1.60]. However, a significantly higher risk of fracture was found in 'high dose' users and a longer duration of use (14-90 days), irrespective of the type of benzodiazepine (OR 3.45, 95% CI 1.38, 8.59). CONCLUSIONS: These findings suggest that inappropriate benzodiazepine use according to the Beers criteria is not associated with increased risk of fracture. Daily dose and longer duration of use (>14 days) is associated with higher risk of fracture, irrespective of the type of benzodiazepine prescribed.

Mortality benefits of influenza vaccination in elderly people (Article)

2008-08-01T00:00:00Z

High free thyroxine levels are associated with QTc prolongation in males (Article)

2008-07-01T00:00:00Z

The literature on the effect of excess thyroid hormone on ventricular repolarization is controversial. To study whether free thyroxine (T4) and TSH are associated with QTc prolongation we conducted population-based cohort study. This study was conducted as part of the Rotterdam Study and included 365 men and 574 women aged 55 years and older with an electrocardiogram, who were randomly sampled for the assessment of thyroid status (free T4/TSH) at baseline, after exclusion of participants with hypothyroidism, use of antithyroid drugs, thyroid hormones or digoxin, left ventricular hypertrophy, and left and right bundle branch block. Endpoints were the length of the QTc interval and risk of borderline QTc prolongation. The associations were examined by means of linear and logistic regression analysis, adjusted for age and gender, diabetes mellitus, myocardial infarction, hypertension, and heart failure. Overall, there was no significant association between TSH and QTc interval (0.8 ms (95% confidence interval (Cl) -3.5, 5.2) in the first quintile compared with the fifth quintile). Subjects in the fifth quintile of free T4did not have an increased QTc interval (3.2 ms (95% Cl - 1.1, 7.6)); stratification on gender showed an increment of 10.9 ms (95% Cl 3.4, 18.3) in the fifth quintile in men and 1.1 ms (95% Cl - 4.2, 6.3) in the fifth quintile of free T4in women. When compared with subjects in the first quintile, male subjects in the fifth quintile of free T4had a significantly increased risk of a borderline QTc interval and QTc prolongation (odds ratio 2.40 (95% Cl 1.20, 4.80)). High levels of free T4are associated with substantial QTc prolongation in men of up to 10 ms. The fact that free T4is also associated with a significantly increased risk of borderline and prolonged QTc values with its risk of sudden cardiac death, endorses the clinical importance of our findings.

Effectiveness of statins in the reduction of the risk of myocardial infarction is modified by the GNB3 C825T variant (Article)

2008-07-01T00:00:00Z

INTRODUCTION: The GNB3 C825T polymorphism has been shown to affect lipid parameters, atherosclerosis progression, and incidence of myocardial infarction (MI). Therefore, we assessed whether the effectiveness of statins in reducing the risk of MI was modified by the GNB3 C825T polymorphism. METHODS: In a population-based registry of pharmacy records linked to hospital discharge records (PHARMO), we used a nested case-control design. We selected patients hospitalized for MI as cases if they used antihypertensive drugs and had a diagnosis of hypercholesterolemia before their first MI. Controls met the same eligibility criteria, but were not hospitalized for MI. Logistic regression analysis was used to calculate odds ratios (OR) and synergy index with corresponding 95% confidence intervals (CI), and to adjust for potential confounding factors. RESULTS: We included 459 cases and 1805 controls. The risk of MI was significantly lower among participants exposed to statins compared with participants not exposed to statins (adjusted OR: 0.37, 95% CI: 0.29-0.47). The GNB3T allele was associated with a reduced risk of MI (adjusted OR: 0.74, 95% CI: 0.60-0.92). Among homozygous wild-type (CC) individuals (n=1119), exposure to statins was associated with a lower risk of MI (OR: 0.48, 95% CI: 0.34-0.67). However, T allele carriers (CT and TT) who used statins had an even stronger reduced risk of MI (OR: 0.27, 95% CI: 0.19-0.39). Overall, the interaction between exposure to statins and the GNB3 C825T polymorphism was significantly increased on the multiplicative scale (synergy index: 1.67, 95% CI: 1.06-2.65). CONCLUSION: Our findings show that T allele carriers of the GNB3 C825T polymorphism have less risk of MI and are more likely to benefit from statin therapy in a hypercholesterolemic population of antihypertensive drug users.

Common variation in the NOS1AP gene is associated with reduced glucose-lowering effect and with increased mortality in users of sulfonylurea (Article)

2008-07-01T00:00:00Z

OBJECTIVE: The single nucleotide polymorphism rs10494366 in the nitric oxide synthase 1 adaptor protein (NOS1AP) gene is associated with QTc prolongation, through an effect on the intracellular Ca levels. As sulfonylurea stimulate insulin secretion by an increased influx of Ca, we hypothesized that this polymorphism is associated with the glucose-lowering effect and mortality risk in sulfonylurea users. METHODS: Associations between the NOS1AP polymorphism, prescribed doses, and mortality rates in sulfonylurea, metformin, and insulin users were assessed in the Rotterdam Study, a population-based cohort study of 7983 elderly people. RESULTS: We identified 619 participants who were prescribed oral antidiabetic drugs during follow-up. In glibenclamide users carrying the TG genotype, the prescribed doses were higher compared with the glibenclamide users carrying the TT genotype [0.38 defined daily dose units, 95% confidence interval (CI) 0.14-0.63]. Glibenclamide users with the TG or GG genotype had an increased mortality risk compared with glibenclamide users with the TT genotype [hazard ratio (HR) 2.80, 95% CI: 1.09-7.22]. Tolbutamide users with the TG or GG genotype (HR: 0.30, 95% CI: 0.14-0.63) and glimepiride users with the TG or GG genotype (HR: 0.18, 95% CI: 0.04-0.74) had a decreased mortality risk compared with tolbutamide and glimepiride users with the TT genotype. CONCLUSION: In participants with the TG or GG genotype at rs10494366 in the NOS1AP gene, glibenclamide is less effective in reducing glucose levels and mortality rates were higher compared with glibenclamide users with the TT genotype. In tolbutamide and glimepiride users, the TG and GG genotype were associated with a reduced mortality rate.

Cyclooxygenase selectivity of nonsteroidal anti-inflammatory drugs and risk of stroke (Article)

2008-06-09T00:00:00Z

Background: In clinical trials, cyclooxygenase (COX)-2-selective nonsteroidal anti-inflammatory drugs (NSAIDs) were associated with an increased risk of thromboembolic events. We studied the association between NSAID use and risk of stroke in the prospective, population-based Rotterdam Study. Methods: We followed 7636 persons free of stroke at baseline (1991-1993) for incident stroke until September 2004. Data on all filled prescriptions came from pharmacy records. With Cox regression models, we calculated crude and adjusted hazard ratios (HRs) of stroke for time-dependent current use, compared with never use, of NSAIDs grouped according to COX selectivity (COX-1 selective, nonselective, and COX-2 selective) and individual NSAIDs. Results: At baseline, the mean age of the study sample was 70.2 years, and 61.3% were female. During 70 063 person-years of follow-up (mean, 9.2 years), 807 persons developed a stroke (460 ischemic, 74 hemorrhagic, and 273 unspecified). Current users of nonselective (HR, 1.72; 95% confidence interval [CI], 1.22-2.44) and COX-2-selective (HR, 2.75; 95% CI, 1.28-5.95) NSAIDs had a greater risk of stroke, but not users of COX-1-selective NSAIDs (HR, 1.10; 95% CI, 0.41-2.97). Hazard ratios (95% CIs) for ischemic stroke were 1.68 (1.05-2.69) for nonselective and 4.54 (2.06-9.98) for COX-2-selective NSAIDs. For individual NSAIDs, current use of the nonselective naproxen (HR, 2.63; 95% CI, 1.47-4.72) and the COX-2-selective rofecoxib (HR, 3.38; 95% CI, 1.48-7.74) was associated with a greater risk of stroke. Hazard ratios (95% CIs) for diclofenac (1.60 [1.00-2.57]), ibuprofen (1.47 [0.73-3.00]), and celecoxib (3.79 [0.52-27.6]) were greater than 1.00 but were not statistically significant. Conclusions: In the general population, we found a greater risk of stroke with current use of nonselective and COX-2-selective NSAIDs. The risk of stroke was not limited to the use of COX-2-selective NSAIDs.

Cyclooxygenase selectivity of nonsteroidal anti-inflammatory drugs and risk of stroke (Article)

2008-06-01T00:00:00Z

BACKGROUND: In clinical trials, cyclooxygenase (COX)-2-selective nonsteroidal anti-inflammatory drugs (NSAIDs) were associated with an increased risk of thromboembolic events. We studied the association between NSAID use and risk of stroke in the prospective, population-based Rotterdam Study. METHODS: We followed 7636 persons free of stroke at baseline (1991-1993) for incident stroke until September 2004. Data on all filled prescriptions came from pharmacy records. With Cox regression models, we calculated crude and adjusted hazard ratios (HRs) of stroke for time-dependent current use, compared with never use, of NSAIDs grouped according to COX selectivity (COX-1 selective, nonselective, and COX-2 selective) and individual NSAIDs. RESULTS: At baseline, the mean age of the study sample was 70.2 years, and 61.3% were female. During 70 063 person-years of follow-up (mean, 9.2 years), 807 persons developed a stroke (460 ischemic, 74 hemorrhagic, and 273 unspecified). Current users of nonselective (HR, 1.72; 95% confidence interval [CI], 1.22-2.44) and COX-2-selective (HR, 2.75; 95% CI, 1.28-5.95) NSAIDs had a greater risk of stroke, but not users of COX-1-selective NSAIDs (HR, 1.10; 95% CI, 0.41-2.97). Hazard ratios (95% CIs) for ischemic stroke were 1.68 (1.05-2.69) for nonselective and 4.54 (2.06-9.98) for COX-2-selective NSAIDs. For individual NSAIDs, current use of the nonselective naproxen (HR, 2.63; 95% CI, 1.47-4.72) and the COX-2-selective rofecoxib (HR, 3.38; 95% CI, 1.48-7.74) was associated with a greater risk of stroke. Hazard ratios (95% CIs) for diclofenac (1.60 [1.00-2.57]), ibuprofen (1.47 [0.73-3.00]), and celecoxib (3.79 [0.52-27.6]) were greater than 1.00 but were not statistically significant. CONCLUSIONS: In the general population, we found a greater risk of stroke with current use of nonselective and COX-2-selective NSAIDs. The risk of stroke was not limited to the use of COX-2-selective NSAIDs.

Determinants of chronic benzodiazepine use in the elderly: A longitudinal study (Article)

2008-04-01T00:00:00Z

AIMS: The risk of adverse events due to chronic benzodiazepine use is high in the elderly. Clinicians need to be able to identify those persons who are at risk of chronic benzodiazepine use, but little is known about the determinants. This study determined social and health related factors that predict new-onset chronic benzodiazepine use in community-dwelling elderly. METHODS: This study was embedded in an ongoing cohort study among 5364 persons aged ≥57 years. Drug-dispensing medication records were available for the period between 1991 and 2003. We defined chronic benzodiazepine use as use during at least 180 days in a period of 365 consecutive days. The association of various social, psychiatric and somatic variables with new-onset chronic benzodiazepine use was studied with a Cox proportional hazards analysis. RESULTS: Symptoms of depression, hypertension, pain related joint complaints and the perception of poor physical health predicted new-onset chronic use. In the subsample of participants who had filled at least one prescription in the follow-up period, of these variables only pain related joint complaints increased the risk of new-onset chronic use. Living alone protected against chronic benzodiazepine use. CONCLUSIONS: The elderly with poor mental and physical health are at an increased risk of chronic benzodiazepine use. Living alone was found to decrease the risk of chronic use, which suggests that social factors may determine drug usage patterns. Very few characteristics predicted chronic benzodiazepine use once patients had received their first prescription. For clinicians, identification of patients at high risk is therefore not straightforward.

Influence of the CYP2D6*4 polymorphism on dose, switching and discontinuation of antidepressants (Article)

2008-04-01T00:00:00Z

Aims: To study the effect of CYP2D6*4 on antidepressant dose, switching and discontinuation of therapy. Methods: The study consisted of all subjects in the Rotterdam Study, who received a first antidepressant prescription between April 1st 1991 and July 1st 2005 and for whom data on CYP2D6 genotype were available. Binary logistic regression was performed to study the association between CYP2D6*4 and switching to any other antidepressant or discontinuation of therapy within 45 days. The difference in mean antidepressant dose was compared between CYP2D6 genotypes using t-tests and repeated measurements analyses. Results: In users of tricyclic antidepressants (TCAs) the risk of switching to another antidepressant was significantly higher in poor metabolizers (PMs:*4/*4) compared with extensive metabolizers (EMs:*1/*1), with an adjusted OR of 5.77 (95% CI 1.59, 21.03; P = 0.01). In SSRI users there was no significant difference (OR 0.91; 95% CI 0.20, 4.15; P = 0.90). Heterozygous patients did not have an increased risk of switching in both TCA and SSRI users. The mean TCA dose was significantly lower in PMs than in EMs at the third and fourth prescription (difference 0.11 DDD, P = 0.03). In SSRI users the difference in mean dose between PMs and EMs was significant at the third prescription (0.17 DDD; P = 0.02). Conclusions: The risk of switching to another antidepressant in TCA users is higher in PMs than in EMs. The maintenance doses of antidepressants were significantly lower in PMs. However, the question whether genotyping prior to the start of antidepressant therapy contributes substantially to the optimization of pharmacotherapy, requires further study.

Vitamin K epoxide reductase complex subunit 1 (VKORC1) polymorphism and aortic calcification: The Rotterdam study (Article)

2008-04-01T00:00:00Z

OBJECTIVE - Besides effects on hemostasis, vitamin K-dependent proteins play a role in bone mineralization and arterial calcification. We investigated the association between the VKORC1 1173C>T polymorphism and calcification of the aortic far wall in a large population-based cohort. METHODS AND RESULTS - Aortic calcification was diagnosed by radiographic detection of calcified deposits in the abdominal aorta. In all cohort members for whom DNA was available, the C1173T SNP of VKORC1 (rs9934438) was determined. With multivariable logistic regression analysis the association between this polymorphism and the risk of aortic calcification was calculated, adjusted for potential confounders. The T allele frequency of the VKORC1 1173C>T polymorphism was 38.8%. 1185 (37.2%) persons were homozygous CC, 1529 (48,0%) were heterozygous CT and 473 (14.8%) were homozygous TT. Persons with at least one T-allele had a statistically significant 19% (95% CI 2 to 40%) risk increase of calcification of the aortic far wall compared to CC homozygous persons, adjusted for age and gender. CONCLUSION - The T-allele of the VKORC1 1173C>T polymorphism was associated with a significantly higher risk of aortic calcification in Whites.

Common ATP-binding cassette B1 variants are associated with increased digoxin serum concentration (Article)

2008-04-01T00:00:00Z

BACKGROUND AND OBJECTIVE: Digoxin is a known substrate of ATP-binding cassette B1 (ABCB1/MDR1). The results of studies on the association between ABCB1 polymorphisms and digoxin kinetics, however, remain contradictory. Almost all studies were small and involved only single dose kinetics. The goal of this study was to establish ABCB1 genotype effect on digoxin blood concentrations in a large cohort of chronic digoxin users in a general Dutch European population. METHODS: Digoxin users were identified in the Rotterdam Study, a prospective population-based cohort study of individuals aged 55 years and above. Digoxin blood levels were gathered from regional hospitals and laboratories. ABCB1 single nucleotide polymorphisms (SNPs) 1236C→T, 2677G→T/A, and 3435C→T were assessed on peripheral blood DNA using Taqman assays. We studied the association between the ABCB1 genotypes and haplotypes, and digoxin blood levels using linear regression models adjusting for potential confounders. RESULTS: Digoxin serum levels and DNA were available for 195 participants (56.4% women, mean age 79.4 years). All three ABCB1 variants were significantly associated with serum digoxin concentration (0.18-0.21 μg/l per additional T allele). The association was even stronger for the 1236-2677-3435 TTT haplotype allele [0.26 μg/l (95% CI 0.14-0.38)], but absent for other haplotypes (CGC allele considered referent), suggesting an interaction of SNPs in a causal haplotype instead of individual SNP effects. CONCLUSION: We found that the common ABCB1 1236C→T, 2677G→T, and 3435C→T variants and the associated TTT haplotype were associated with higher digoxin serum concentrations in a cohort of elderly European digoxin users in the general population.

Renin-angiotensin system inhibitors, angiotensin I-converting enzyme gene insertion/deletion polymorphism, and cancer: The Rotterdam study (Article)

2008-02-15T00:00:00Z

BACKGROUND. Angiotensin I-converting enzyme (ACE) inhibitors, angiotensin II antagonists, and the ACE insertion/deletion (I/D) gene polymorphism all influence serum angiotensin II action. Because angiotensin II levels have been associated with cancer, the objective of the current epidemiologic study was to investigate whether renin-angiotensin system inhibitors and/or ACE genotypes were associated with an altered risk of colorectal, lung, breast, and prostate cancer. METHODS. Data were obtained from the Rotterdam Study, a population-based, prospective cohort study with 7983 participants. Participants who had a history of 1 of the cancers of interest (n = 216) or who had a medication history <6 months (n = 88) were excluded, leaving 7679 participants, of whom the ACE genotypes could be assessed in 6670 individuals. The mean follow-up was 9.6 years, during which 730 incident cancers occurred. The effect of medication, ACE I/D genotypes, and their interaction on cancer risk and progression was studied by using Cox proportional hazard models. RESULTS. Carriers of the high-activity genotype DD had an increased risk of breast cancer compared with low-activity II/ID genotype carriers (hazard ratio [HR], 1.47; 95% confidence interval [95% CI], 1.05-2.04), but no association was demonstrated for other cancers. DD carriers who were exposed to long-term and high-dose medication were at lower risk for cancer (HR, 0.28; 95% CI, 0.10-0.79). Short-term, high-dose users were at risk for colorectal cancer progression in the II/ID stratum (HR, 3.83; 95% CI, 1.67-8.79). CONCLUSIONS. Renin-angiotensin system-inhibiting drugs seemed to protect against cancer in individuals with the DD genotype, which was associated with high levels of ACE.

Cytochrome P450 2C9 2 and 3 polymorphisms and the dose and effect of sulfonylurea in type II diabetes mellitus (Article)

2008-02-01T00:00:00Z

Sulfonylurea hypoglycemics are mainly metabolized by the cytochrome P450 2C9 (CYP2C9) enzyme. The CYP2C9*2 and *3 polymorphisms encode proteins with less enzymatic activity and are correlated with elevated serum levels of sulfonylurea, as demonstrated in healthy volunteers. In this study, the effect of these variants is described for patients with diabetes mellitus treated with sulfonylurea. Associations between CYP2C9 polymorphisms, prescribed doses of sulfonylurea, and change in glucose levels after the start of sulfonylurea therapy were assessed in all patients with incident diabetes mellitus starting on sulfonylurea therapy in the Rotterdam Study, a population-based cohort study of 7,983 elderly people. In CYP2C9*3 allele carriers using tolbutamide, the prescribed dose was lower compared to patients with the wild-type CYP2C9 genotype. No differences in the prescribed dose were found in tolbutamide users with the CYP2C9*1/*2 or CYP2C9*2/*2 genotype compared to wild-type patients or in patients using other sulfonylurea. In CYP2C9*3 allele carriers, the mean decrease in fasting serum glucose levels after the start of tolbutamide therapy was larger than in patients with the wild-type genotype, although not statistically significant. Patients with diabetes mellitus who are carriers of a CYP2C9*3 allele require lower doses of tolbutamide to regulate their serum glucose levels compared to patients with the wild-type genotype.

Estrogen receptor α polymorphisms and postmenopausal breast cancer risk (Article)

2008-02-01T00:00:00Z

Background: The estrogen receptor alpha (ESR1) is a mediator of estrogen response in the breast. The most studied variants in this gene are the PvuII and XbaI polymorphisms, which have been associated to lower sensitivity to estrogen. We evaluated whether these polymorphisms were associated with breast cancer risk by means of an association study in a population of Caucasian postmenopausal women from the Rotterdam study and a meta-analysis of published data. Methods: The PvuII and XbaI polymorphisms were genotyped in 3,893 women participants of the Rotterdam Study. Baseline information was obtained through a questionnaire. We conducted logistic regression analyses to assess the risk of breast cancer by each of the ESR1 genotypes. Meta-analyses of all publications on these relations were done by retrieving literature from Pubmed and by further checking the reference lists of the articles obtained. Results: There were 38 women with previously diagnosed breast cancer. During follow-up, 152 were additionally diagnosed. The logistic regression analyses showed no difference in risk for postmenopausal breast cancer in carriers of the PvuII or XbaI genotypes neither in overall, incident or prevalent cases. No further evidence of a role of these variants was found in the meta-analysis. Conclusions: Our results suggest that the ESR1 polymorphisms do not play a role in breast cancer risk in Caucasian postmenopausal women.

Comparing treatment effects after adjustment with multivariable Cox proportional hazards regression and propensity score methods (Article)

2008-01-01T00:00:00Z

Purpose: To compare adjusted effects of drug treatment for hypertension on the risk of stroke from propensity score (PS) methods with a multivariable Cox proportional hazards (Cox PH) regression in an observational study with censored data. Methods: From two prospective population-based cohort studies in The Netherlands a selection of subjects was used who either received drug treatment for hypertension (n = 1293) or were untreated 'candidates' for treatment (n = 954). A multivariable Cox PH was performed on the risk of stroke using eight covariates along with three PS methods. Results: In multivariable Cox PH regression the adjusted hazard ratio (HR) for treatment was 0.64 (CI95%: 0.42, 0.98). After stratification on the PS the HR was 0.58 (CI95%: 0.38, 0.89). Matching on the PS yielded a HR of 0.49 (CI95%: 0.27, 0.88), whereas adjustment with a continuous PS gave similar results as Cox regression. When more covariates were added (not possible in multivariable Cox model) a similar reduction in HR was reached by all PS methods. The inclusion of a simulated balanced covariate gave largest changes in HR using the multivariable Cox model and matching on the PS. Conclusions: In PS methods in general a larger number of confounders can be used. In this data set matching on the PS is sensitive to small changes in the model, probably because of the small number of events. Stratification, and covariate adjustment, were less sensitive to the inclusion of a non-confounder than multivariable Cox PH regression. Attention should be paid to PS model building and balance checking. Copyright

Systemic Antihypertensive Medication and Incident Open-angle Glaucoma (Article)

2007-12-01T00:00:00Z

Purpose: To determine the association between systemic antihypertensive medication and incident open-angle glaucoma. Design: Prospective population-based cohort study. Participants: The study population consisted of a subset of 3842 participants of the Rotterdam Study for whom data from identical ophthalmologic examinations at baseline and follow-up were available. Methods: Use of antihypertensive medication was registered over an average follow-up period of 6.5 years. Associations between incident open-angle glaucoma and antihypertensive medication were assessed using multivariate logistic regression models adjusted for age, gender, duration of follow-up, intraocular pressure, intraocular pressure-lowering medication, and cardiovascular disease. Main Outcome Measures: Odds ratios of associations between incident open-angle glaucoma and use of antihypertensive medication. Results: During follow-up, there were 87 incident cases of open-angle glaucoma. Participants using calcium channel antagonists had a 1.8-fold (95% confidence interval [CI], 1.04-3.2; P = 0.037) higher risk of developing incident open-angle glaucoma. β-Blockers were associated with a nonsignificant risk reduction (odds ratio, 0.6; 95% CI, 0.3-1.02; P = 0.060). None of the other classes of antihypertensives was significantly associated with incident open-angle glaucoma. Conclusions: These data suggest that use of calcium channel antagonists is associated with open-angle glaucoma, but this requires confirmation. These results do not support the use of calcium channel antagonists for the treatment of normal-tension glaucoma.

The Rotterdam Study: Objectives and design update (Article)

2007-11-01T00:00:00Z

The Rotterdam Study is a prospective cohort study ongoing since 1990 in the city of Rotterdam in the Netherlands. The study targets cardiovascular, neurological, ophthalmological and endocrine diseases. As of 2008 about 15,000 subjects aged 45 years or over comprise the Rotterdam Study cohort. The findings of the Rotterdam Study have been presented in some 600 research articles and reports (see http://www.epib.nl/rotterdamstudy ). This article gives the reasons for the study and its design. It also presents a summary of the major findings and an update of the objectives and methods.

Serum cholesterol, use of lipid-lowering drugs, and risk of Parkinson disease [4] (Article)

2007-10-15T00:00:00Z

Nonsteroidal anti-inflammatory drugs and the risk of Parkinson disease (Article)

2007-10-01T00:00:00Z

Background: Several lines of evidence suggest a role of inflammatory processes in Parkinson disease, although it is still unclear whether inflammation is a cause or rather a consequence of neurodegeneration. Methods: In a prospective population-based cohort study among 6,512 participants aged ≥55 years, with repeated in-person examination, we evaluated the association between cumulative use of nonsteroidal anti-inflammatory drugs (NSAIDs) and the risk of Parkinson disease. Complete information on filled prescriptions was available from automated pharmacy records. Data were analyzed by means of Cox proportional hazards regression analysis, adjusted for age, sex, smoking habits and coffee consumption. Results: After an average 9.4 years of follow-up, 88 new cases of Parkinson disease were detected. No association was found between use of NSAIDs and the risk of Parkinson disease (adjusted hazard ratio for any NSAID use, 1.50; 95% confidence interval, 0.95-2.37). Conclusion: Our findings do not support the hypothesis that NSAIDs might decrease the risk of Parkinson disease. Copyright

Diuretic-gene interaction and the risk of myocardial infarction and stroke (Article)

2007-10-01T00:00:00Z

This study investigates whether the interaction between diuretics and alpha-adducin (ADD1) G460W or G-protein β3-subunit (GNB3) rs2301339 polymorphism modifies the risk of myocardial infarction (MI) or stroke. Data were used from the Rotterdam Study. The drug-gene interaction was determined with a Cox proportional hazard model with adjustment for each drug class as time-dependent covariates. The risk of MI in current users of low-ceiling diuretics with one or two copies of the ADD1 W-allele (hazard ration (HR)=0.92) was similar compared to the expected joint effect of the W-allele and low-ceiling diuretics on a multiplicative scale (1.04 × 0.90=0.94) (synergy index (SI):0.99; 95% confidence interval (CI): 0.43-2.27). No drug-gene interaction was found on the risk of stroke (SI:0.66; 95% CI:0.43-1.27). In addition, a trend towards an interaction was found between current use and the GNB3 rs230119 G/A polymorphism on the risk of MI (SI: 0.51; 95% CI: 0.23-1.15), whereas no interaction on the risk of stroke was found (SI: 0.84; 95% CI: 0.46-1.56).

Polymorphisms of the renin-angiotensin system are associated with blood pressure, atherosclerosis and cerebral white matter pathology (Article)

2007-10-01T00:00:00Z

BACKGROUND: The renin-angiotensin system is involved in the development of hypertension, atherosclerosis and cardiovascular disease. We studied the association between the M235T polymorphism of the angiotensinogen gene (AGT) and the C573T polymorphism of the angiotensin II type 1 receptor (AT1R) and blood pressure, carotid atherosclerosis and cerebrovascular disease. METHODS: We genotyped over 6000 subjects from the Rotterdam Study and more than 1000 subjects from the Rotterdam Scan Study. We used logistic regression and univariate analyses, adjusting for age and sex with, for AGT, the MM and, for AT1R, the TT genotype as reference. RESULTS: We found that AGT-235T increased systolic (p for trend = 0.03) and diastolic blood pressure (p for trend = 0.04). The prevalence of carotid plaques was increased 1.25-fold (95% CI 1.02-1.52) in AGT-TT carriers. There was a significant increase in mean volume deep subcortical white matter lesions (WML) for AGT-TT carriers (1.78 ml vs 1.09 ml in the reference group; p = 0.008). A significant interaction was found between AGT and AT1R, further increasing the effect on periventricular and subtotal WML (p for interaction = 0.02). We found a non-significant increased risk of silent brain infarction for AGT-TT carriers and AT1R-CC carriers, but no effect on stroke. CONCLUSION: We found an association between AGT and blood pressure, atherosclerosis and WML. Also, we found synergistic effects between AGT and AT1R on the development of WML. These findings raise the question of whether the renin-angiotensin system may be a therapeutic target for the prevention of cerebral white matter pathology.

Can echocardiographic findings predict falls in older persons? (Article)

2007-07-25T00:00:00Z

Background. The European and American guidelines state the need for echocardiography in patients with syncope. 50% of older adults with syncope present with a fall. Nonetheless, up to now no data have been published addressing echocardiographic abnormalities in older fallers. Method and Findings. In order to determine the association between echocardiographic abnormalities and falls in older adults, we performed a prospective cohort study, in which 215 new consecutive referrals (age 77.4 SD 6.0) of a geriatric outpatient clinic of a Dutch university hospital were included. During the previous year, 139 had experienced a fall. At baseline, all patients underwent routine two-dimensional and Doppler echocardiography. Falls were recorded during a three-month follow-up. Multivariate adjustment for compounders was performed with a Cox proportional hazards model. 557 patients (26%) fell at least once during follow-up. The adjusted hazard ratio of a fall during follow-up was 135 (95% Cl, 1.08-1.71) for pulmonary hypertension, 1.66 (95% Cl, 1.01 to 2.89) for 4-initial regurgitation, 2.41 (95% Cl, 1.32 to 4.37) for tricuspid regurgitation and 1.76 (95% Cl, 1.03 to 3.01) for pulmonary regurgitation. For aoitic regurgitation the risk of a fall was also increased, but non-significantly. (hazard ratio, 1.57 [95% Cl 0.85 to 2.92]). Trend analysis of the severity of the difterent regurgitations showed a significant relationship for mitral, tricuspid and pulmonary valve regurgitation and pulmonary hypertension. Conclusions. Echo(Dopler)cardiography can be useful in order to identify risk indicators for falling. Presence of pulmonary hypertension or regurgitation of mitral, tricuspid or pulmonary valves was associated with a higher fall risk. Our study indicates that the diagnostic work-up for falls in older adults might be improved by adding an echo(Doppler)cardiogram in selected groups.

Epistatic effect of cholesteryl ester transfer protein and hepatic lipase on serum high-density lipoprotein cholesterol levels (Article)

2007-07-01T00:00:00Z

Objectives: Polymorphisms in the hepatic lipase (LIPC -514C > T) and cholesteryl ester transfer protein (CETP I405V) genes affect high-density lipoprotein cholesterol (HDL-c) levels, but their relationship with cardiovascular disease and their combined effect is unclear. The objectives of the current study were to characterize the effect of the hepatic lipase variant, and its interaction with the CETP variant, in terms of cholesterol levels, atherosclerosis, and risk of myocardial infarction (MI). Design: The study was conducted in the Rotterdam Study, a large single-center prospective cohort study in people aged 55 yr and older. Lipid levels were analyzed using linear regression models, and risk of MI was assessed with Cox proportional hazards models. Results: The hepatic lipase variant was associated with an increase in serum HDL-c levels of 0.11 mmol/liter in both genders, whereas an increased risk of MI was observed only in men [hazard ratio, 1.32 (95% confidence interval, 1.05-1.66) for CT vs. CC and 1.75 (95% confidence interval, 1.39-2.20) for TT vs. CC]. This effect was independent of serum HDL-c. LIPC -514C > T interacted with CETP I405V with respect to serum HDL-c concentrations. Those homozygous for both mutations saw a marked elevation in HDL-c levels (0.29 mmol/liter, Pinteraction= 0.05). These increased HDL-c levels, however, were not inversely associated with atherosclerosis or MI risk. Conclusions: LIPC genotype affects HDL-c levels and risk of MI in males. The interaction of this variant with CETP on HDL-c levels helps elucidate the underlying mechanisms and suggests that the beneficial effects of CETP inhibition may vary in particular subgroups. Copyright

Effects of the renin-angiotensin system genes and salt sensitivity genes on blood pressure and atherosclerosis in the total population and patients with type 2 diabetes (Article)

2007-07-01T00:00:00Z

Most studies on the genetic determinants of blood pressure and vascular complications of type 2 diabetes have focused on the effects of single genes. These studies often have yielded conflicting results. Therefore, we examined the combined effects of three renin-angiotensin system (RAS) genes and three salt sensitivity genes in relation to blood pressure and atherosclerosis in the total population and type 2 diabetic patients. The study was a part of the Rotterdam Study, a population-based cohort study. We have genotyped three RAS gene polymorphisms and three salt sensitivity gene polymorphisms. Diabetic patients with three risk genotypes of the RAS genes had a 6.9 mmHg higher systolic blood pressure (P for trend = 0.04) and a 6.0 mmHg higher pulse pressure (P for trend = 0.03) than those who did not carry any risk genotypes. Diabetic patients with three risk genotypes of the salt sensitivity genes had a 9.0 mmHg higher systolic blood pressure (P = 0.19) and a 13.1 mmHg higher pulse pressure (P = 0.02). Diabetic patients who carried three risk genotypes for the RAS genes had a higher mean intima-media thickness than those with two risk genotypes (mean difference 0.04 mm, P = 0.02). We found that among type 2 diabetic patients, mean systolic blood pressure, pulse pressure, and risk of hypertension increased with the number of risk genotypes for the RAS genes and the salt sensitivity genes.

Common NOS1AP variants are associated with a prolonged QTc interval in the rotterdam study (Article)

2007-07-01T00:00:00Z

BACKGROUND - QT prolongation is an important risk factor for sudden cardiac death. About 35% of QT-interval variation is heritable. In a recent genome-wide association study, a common variant (rs10494366) in the nitric oxide synthase 1 adaptor protein (NOS1AP) gene was found to be associated with QT-interval variation. We tested for association of 2 NOS1AP variants with QT duration and sudden cardiac death. METHODS AND RESULTS - The Rotterdam Study is a population-based, prospective cohort study of individuals ≥55 years of age. The NOS1AP variants rs10494366 T>G and rs10918594 C>G were genotyped in 6571 individuals. Heart rate-corrected QT interval (QTc) was determined with ECG analysis software on up to 3 digital ECGs per individual (total, 11108 ECGs from 5374 individuals). The association with QTc duration was estimated with repeated-measures analyses, and the association with sudden cardiac death was estimated by Cox proportional-hazards analyses. The rs10494366 G allele (36% frequency) was associated with a 3.8-ms (95% confidence interval, 3.0 to 4.6; P=7.8×10) increase in QTc interval duration for each additional allele copy, and the rs10918594 G allele (31% frequency) was associated with a 3.6-ms (95% confidence interval, 2.7 to 4.4; P=6.9×10) increase per additional allele copy. None of the inferred NOS1AP haplotypes showed a stronger effect than the individual single-nucleotide polymorphisms. There were 233 sudden cardiac deaths over 11.9 median years of follow-up. No significant association was observed with sudden cardiac death risk. CONCLUSIONS - Common variants in NOS1AP are strongly associated with QT-interval duration in an elderly population. Larger sample sizes are needed to confirm or exclude an effect on sudden cardiac death risk.

IGF-1 CA repeat variant and breast cancer risk in postmenopausal women (Article)

2007-07-01T00:00:00Z

IGF-I is an important growth factor for the mammary gland. We evaluated the relationship of the IGF-I CAnpolymorphism with breast cancer risk in Caucasian postmenopausal women and performed a meta-analysis of published data. The IGF-I CAnpolymorphism was genotyped in 4091 from the Rotterdam Study. A disease-free survival analysis was performed along with a meta-analysis of all available data on IGF-I CAnpolymorphism and breast cancer risk. During follow-up 159 women were diagnosed with breast cancer. The disease-free survival analysis adjusted for age at entry, age at menopause, body mass index and waist hip ratio yielded a HR = 0.97 (95% CI=0.59-1.58) for CA19non-carriers against carriers. The meta-analysis using the random-effects model gave a pooled OR of 1.26 (95% CI = 0.95-1.82) for IGF-I CA19non-carriers versus CA19homozygous carriers. According to these results, the IGF-I CA19promoter polymorphism is not likely to predict the risk of breast cancer.

The risk of myocardial infarction in patients with reduced activity of cytochrome P450 2C9 (Article)

2007-07-01T00:00:00Z

OBJECTIVE: The aim of the present follow-up study was to investigate whether the enzyme activity of the human cytochrome P450 (CYP) 2C9 isoenzyme is associated with myocardial infarction. METHODS: We investigated whether the variant alleles CYP2C9*2 and CYP2C9*3 or the use of CYP2C9 substrates or inhibitors was associated with an increased risk of myocardial infarction in 2210 men and 3534 women from the Rotterdam Study, a prospective population-based cohort study of individuals aged 55 years or older. RESULTS: In women, the use of CYP2C9 substrates or inhibitors was significantly associated with incident myocardial infarction with a hazard ratio of 2.48 (95% confidence interval: 1.55-3.96). Within the group of female carriers of a variant allele, the use of CYP2C9 substrates or inhibitors was associated with a fourfold increased risk of myocardial infarction (hazard ratio 3.86, 95% confidence interval: 1.93-7.75), as compared with non-use. Neither the use of CYP2C9 inhibitors or substrates nor the variant CYP2C9 alleles were associated with an increased risk of myocardial infarction in men. CONCLUSIONS: Drugs that are metabolized by CYP2C9 increase the risk of myocardial infarction in women. This risk was even higher in women with allelic variants of CYP2C9 with reduced enzyme activity.

Hospitalisations and emergency department visits due to drug-drug interactions: A literature review (Article)

2007-06-01T00:00:00Z

Purpose: Our objective was to evaluate the incidence of adverse patient outcomes due to drug-drug interactions (D-DIs), the type of drugs involved and the underlying reason. As a proxy for adverse patient outcomes, emergency department (ED) visits, hospital admissions and re-hospitalisations were assessed. Methods: A literature search in the Medline and Embase database (1990-2006) was performed and references were tracked. An overall cumulative incidence was estimated by dividing the sum of the cases by the sum of the study populations. Results: Twenty-three studies were found assessing the relationship between D-DIs and ED-visits, hospitalisations or re-hospitalisations. The studies with a large study size showed low incidences and vice versa. D-DIs were held responsible for 0.054% of the ED-visits, 0.57% of the hospital admissions and 0.12% of the re-hospitalisations. In the elderly population, D-DIs were held responsible for 4.8% of the admissions. Drugs most often involved were NSAIDs and cardiovascular drugs. The reasons for admissions or ED-visits, which were most often found were GI-tract bleeding, hyper- or hypotension and cardiac rhythm disturbances. Conclusion: This review provides information on the overall incidence of D-DIs as a cause of adverse patient outcomes, although there is still uncertainty about the impact of D-DIs on adverse patient outcomes. Our results suggest that a limited number of drugs are involved in the majority of cases and that the number of reasons for admission as a consequence of D-DIs seems to be modest. Copyright

Measuring orthostatic hypotension with the Finometer device: Is a blood pressure drop of one heartbeat clinically relevant? (Article)

2007-06-01T00:00:00Z

OBJECTIVE: The role of orthostatic hypotension in falls in older people is generally accepted. Because of the high degree of intra- and interobserver variability in conventional measurements of orthostatic hypotension, application of continuous measurement systems has been proposed. The clinical relevance of a blood pressure drop lasting one heartbeat, however, is unknown. We therefore investigated which time average of continuous-finger-blood-pressure measurement (Finometer) showed the best association between orthostatic hypotension and falls. This was also compared with conventional sphygmomanometer measurements. METHODS: In 217 geriatric outpatients supine and standing (finger) blood pressure to diagnose orthostatic hypotension was monitored with Finometry (beat-to-beat and 1, 5, 10, 15, 20 and 30 s averages) and sphygmomanometry. History of fall incidents (previous year) was registered. RESULTS: The best association (C=0.22, P=0.003) with falls history was found for the 5-s average of Finometry, whereas falls and orthostatic hypotension assessed by sphygmomanometry did not correlate. The odds ratio of a fall according to orthostatic hypotension using the 5-s average was 2.54 (95% CI: 1.37 to 4.71). CONCLUSIONS: Orthostatic hypotension and falls are correlated when using Finometry, with the best association found when using 5-s averages. As the etiology of falls is often multifactorial, orthostatic hypotension and falls are poorly correlated, irrespective of the method or time average that is applied.

The cholesteryl ester transfer protein I405V polymorphism is associated with increased high-density lipoprotein levels and decreased risk of myocardial infarction: The Rotterdam Study (Article)

2007-06-01T00:00:00Z

BACKGROUND AND DESIGN: The effect of the cholesteryl ester transfer protein (CETP) I405V polymorphism on lipid levels, atherosclerosis and myocardial infarction (MI) was examined in 6421 participants from the Rotterdam Study. METHODS: Quantitative outcomes were studied with linear models; Cox models were used to assess MI risk. RESULTS: High-density lipoprotein cholesterol (HDL) increased by 0.06 [95% confidence interval (CI): 0.03, 0.09] mmol/l in VV carriers. The V allele was further associated with decreased MI risk in men [hazard ratio (95% confidence interval)=0.57 (0.45, 0.73), VV versus II] (Ptrend=0.02). CONCLUSION: This study provides additional evidence for the association of CETP with HDL levels and suggests that CETP is an atherogenic protein increasing the risk of MI.

Withdrawal of fall-risk-increasing drugs in older persons: Effect on tilt-table test outcomes (Article)

2007-05-01T00:00:00Z

OBJECTIVES: To determine whether outcomes of tilt-table tests improved after withdrawal of fall-risk-increasing drugs (FRIDs). DESIGN: Prospective cohort study. SETTING: Geriatric outpatient clinic. PARTICIPANTS: Two hundred eleven new, consecutive outpatients, recruited from April 2003 until December 2004. MEASUREMENTS: Tilt-table testing was performed on all participants at baseline. Subsequently, FRIDs were withdrawn in all fallers in whom it was safely possible. At a mean follow-up of 6.7 months, tilt-table testing was repeated in 137 participants. Tilt-table testing addressed carotid sinus hypersensitivity (CSH), orthostatic hypotension (OH), and vasovagal collapse (VVC). Odds ratios (ORs) of tilt-table-test normalization according to withdrawal (discontinuation or dose reduction) of FRIDs were calculated using multivariate logistic regression analysis. RESULTS: After adjustment for confounders, the reduction of abnormal test outcomes (ORs) according to overall FRID withdrawal was 0.34 (95% confidence interval (CI)=0.06-1.86) for CSH, 0.35 (95% CI=0.13-0.99) for OH, and 0.27 (95% CI=0.02-3.31) for VVC. For the subgroup of cardiovascular FRIDs, the adjusted OR was 0.13 (95% CI=0.03-0.59) for CSH, 0.44 (95% CI=0.18-1.0) for OH, and 0.21 (95% CI=0.03-1.51) for VVC. CONCLUSION: OH improved significantly after withdrawal of FRIDs. Subgroup analysis of cardiovascular FRID withdrawal showed a significant reduction in OH and CSH. These results imply that FRID withdrawal can cause substantial improvement in cardiovascular homeostasis. Derangement of cardiovascular homeostasis may be an important mechanism by which FRID use results in falls.

The incidence of complex regional pain syndrome: A population-based study (Article)

2007-05-01T00:00:00Z

The complex regional pain syndrome (CRPS) is a painful disorder that can occur in an extremity after any type of injury, or even spontaneously. Data on the incidence of CRPS are scarce and mostly hospital based. Therefore the size of the problem and its burden on health care and society are unknown. The objective of the present study was to estimate the incidence of CRPS in the general population. A retrospective cohort study was conducted during 1996-2005 in the Integrated Primary Care Information (IPCI) project, a general practice research database with electronic patient record data from 600,000 patients throughout the Netherlands. Potential CRPS cases were identified by a sensitive search algorithm including synonyms and abbreviations for CRPS. Subsequently, cases were validated by electronic record review, supplemented with original specialist letters and information from an enquiry of general practitioners. The estimated overall incidence rate of CRPS was 26.2 per 100,000 person years (95% CI: 23.0-29.7). Females were affected at least three times more often than males (ratio: 3.4). The highest incidence occurred in females in the age category of 61-70 years. The upper extremity was affected more frequently than the lower extremity and a fracture was the most common precipitating event (44%). The observed incidence rate of CRPS is more as four times higher than the incidence rate observed in the only other population-based study, performed in Olmsted County, USA. Postmenopausal woman appeared to be at the highest risk for the development of CRPS.

All-cause mortality associated with atypical and typical antipsychotics in demented outpatients (Article)

2007-05-01T00:00:00Z

Purpose: To estimate the association between use of typical and atypical antipsychotics and all-cause mortality in a population of demented outpatients. Methods: The study cohort comprised all demented patients older than 65 years and registered in the Integrated Primary Care Information (IPCI) database, during 1996-2004. First, mortality rates were calculated during use of atypical and typical antipsychotics. Second, we assessed the association between use of atypical and typical antipsychotics and all-cause mortality through a nested case-control study in the cohort of demented patients. Each case was matched to all eligible controls at the date of death by age and duration of dementia. Odds ratios were estimated through conditional logistic regression analyses. Results: The crude mortality rate was 30.1 (95%CI: 18.2-47.1) and 25.2 (21.0-29.8) per 100 person-years (PY) during use of atypical and typical antipsychotics, respectively. No significant difference in risk of death was observed between current users of atypical and typical antipsychotics (OR = 1.3; 95%CI: 0.7-2.4). Both types of antipsychotics were associated with a significantly increased risk of death as compared to non-users (OR= 2.2, 1.2-3.9 for atypical antipsychotics; OR= 1.7, 1.3-2.2 for typical antipsychotics). Conclusions: Conventional antipsychotic drug should be included in the FDA's Public Health advisory, which currently warns only of the increased risk of death with the use of atypical antipsychotics in elderly demented persons. Copyright

Determinants of potential drug-drug interaction associated dispensing in community pharmacies in the Netherlands (Article)

2007-04-01T00:00:00Z

Objective: There are many drug-drug interactions (D-DI) of which some may cause severe adverse patient outcomes. Dispensing interacting drug combinations should be avoided when the risks are higher than the benefits. The objective of this study was to identify determinants of dispensing undesirable interacting drug combinations by community pharmacies in the Netherlands. Methods: A total of 256 Dutch community pharmacies were selected, based on the dispensing of 11 undesirable interacting drug combinations between January 1st, 2001 and October 31st, 2002. These pharmacies were sent a questionnaire by the Inspectorate for Health Care (IHC) concerning their process and structure characteristics. Main outcome measure: The number of times the 11 undesirable interacting drug combinations were dispensed. Results: Two hundred and forty-six questionnaires (response rate 96.1%) were completed. Dispensing determinants were only found for the D-DI between macrolide antibiotics and digoxin but not for the other 10 D-DIs. Pharmacies using different medication surveillance systems differed in the dispensing of this interacting drug combination, and pharmacies, which were part of a health care centre dispensed this interacting drug combination more often. Conclusion: Medication surveillance in Dutch community pharmacies seems to be effective. Although for most D-DIs no determinants were found, process and structure characteristics may have consequences for the dispensing of undesirable interacting drug combinations.

Angiotensinogen M235T polymorphism and the risk of myocardial infarction and stroke among hypertensive patients on ACE-inhibitors or β-blockers (Article)

2007-04-01T00:00:00Z

Angiotensinogen is an essential component of the renin-angiotensin system. ACE-inhibitors and β-blockers both have a direct influence on this system. To investigate whether the association between use of ACE-inhibitors or β-blockers and the risk of myocardial infarction (MI) or stroke is modified by the T-allele of the angiotensinogen M235T polymorphism. In this study, 4097 subjects with hypertension, aged 55 years and older, were included from the Rotterdam Study, a population-based prospective cohort study in the Netherlands, from July 1, 1991 onwards. Follow-up ended at the diagnosis date of MI, stroke, death, or the end of the study period (January 1, 2002). The drug-gene interaction on the risk of MI or stroke was determined with a Cox proportional hazard model with adjustments for each drug class as time-dependent covariates. The risk of MI was increased in current use of ACE-inhibitors with the MT or TT genotype compared to ACE-inhibitors with the MM genotype (Synergy Index (SI): 4.00; 95% CI: 1.32-12.11). A significant drug-gene interaction was not found on the risk of stroke (SI: 1.83; 95% CI: 0.95-3.54) in ACE-inhibitor users or between current use of β-blockers and the AGT M235T polymorphism on the risk of MI or stroke. ACE-inhibitor users with at least one copy of the 235T-allele of the AGT gene might have an increased risk of MI and stroke.

Differential roles of Angiotensinogen and Angiotensin Receptor type 1 polymorphisms in breast cancer risk. (Article)

2007-03-01T00:00:00Z

While angiotensinogen (AGT) seems to have anti proliferative properties, angiotensin II (ATII) is a potent growth factor and it mediates its actions through the angiotensin type 1 receptor (AGTR1). In the AGT gene, the M235T polymorphism has been associated with the variation in angiotensinogen levels and in the AGTR1 gene; the C573T variant is associated with different pathologies. We aimed to evaluate the relationship of these two variants and the risk of breast cancer. These polymorphisms were genotyped in 3787 women participating the Rotterdam Study. We performed a logistic regression and a disease free survival analysis by genotype. The logistic regression yielded an odds ratio of 1.4 (95% CI: 1.1-1.9) for the MM genotype carriers versus the T allele carriers. The breast cancer free survival by AGT genotype was significantly reduced in MM genotype carriers compared to non-carriers (hazard ratio (HR) = 1.5; 95% CI: 1.1-2.2). We did not find any association of the AGTR1 polymorphism and breast cancer risk or disease free survival. Our results suggest that AGT plays a role in breast cancer risk in postmenopausal women, whereas the role of AGTR1 needs further studying.

Risk of falls after withdrawal of fall-risk-increasing drugs: A prospective cohort study (Article)

2007-02-01T00:00:00Z

Aims: Falling in older persons is a frequent and serious clinical problem. Several drugs have been associated with increased fall risk. The objective of this study was to identify differences in the incidence of falls after withdrawal (discontinuation or dose reduction) of fall-risk-increasing drugs as a single intervention in older fallers. Methods: In a prospective cohort study of geriatric outpatients, we included 139 patients presenting with one or more falls during the previous year. Fall-risk-increasing drugs were withdrawn, if possible. The incidence of falls was assessed within 2 months of follow-up after a set 1 month period of drug withdrawal. Multivariate adjustment for potential confounders was performed with a Cox proportional hazards model. Results: In 67 patients, we were able to discontinue a fall-risk-increasing drug, and in eight patients to reduce its dose. The total number of fall incidents during follow-up was significantly lower in these 75 patients, than in those who continued treatment (mean number of falls: 0.3 vs. 3.6; P value 0.025). The hazard ratio of a fall during follow-up was 0.48 (95% confidence interval (CI) 0.23, 0.99) for overall drug withdrawal, 0.35 (95% CI 0.15, 0.82) for cardiovascular drug withdrawal and 0.56 (95% CI 0.23, 1.38) for psychotropic drug withdrawal, after adjustment for age, gender, use of fall-risk-increasing drugs, baseline falls frequency, comorbidity, Mini-Mental State Examination score, and reason for referral. Conclusions: Withdrawal of fall-risk-increasing drugs appears to be effective as a single intervention for falls prevention in a geriatric outpatient setting. The effect was greatest for withdrawal of cardiovascular drugs.

Transforming-growth factor β1 Leu10Pro polymorphism and breast cancer morbidity (Article)

2007-01-01T00:00:00Z

TGF-β1has a dual role in carcinogenesis. In this gene, a leucine to proline substitution in codon 10 leads to higher circulating levels of TGF-β1. This variant has been studied in relationship to the risk for breast cancer yielding contradicting results. We aim to unravel the relationship of this polymorphism and the risk of breast cancer. Women participating in the Rotterdam Study including 143 patients with incident breast cancer were genotyped for this polymorphism. We carried out a logistic regression and a survival analysis using age as the time variable. The logistic regression analysis showed an increased risk of breast cancer for Proline carriers (OR = 1.4; 95% confidence interval (CI) = 1.1-2.0) versus non-carriers. The survival analysis showed that carriers of the same allele had an increased risk of breast cancer (HR = 1.4, 95% CI = 1.1-2.0) against non-carriers. Our data suggest that the TGF-β1Leu10Pro polymorphism might play a role in breast cancer risk.

Spironolactone and risk of upper gastrointestinal events: population based case-control study (Article)

2006-01-01T00:00:00Z

OBJECTIVE: To confirm and quantify any association between spironolactone and upper gastrointestinal bleeding and ulcers. DESIGN: Population based case-control study. SETTING: A primary care information database in the Netherlands. PARTICIPANTS: All people on the database who were aged 18 or more between 1 January 1996 and 30 September 2003. Patients with a history of alcoholism or gastrointestinal cancer were excluded. Ten controls were matched to each case of gastroduodenal ulcer or upper gastrointestinal bleeding by age (year of birth), sex, and index date. MAIN OUTCOME MEASURES: The occurrence of an upper gastrointestinal event (bleeding or ulcers), adjusted for potential confounders with conditional logistic regression analysis. RESULTS: Within the source population of 306 645 patients, 523 cases of gastric or duodenal ulcer or upper gastrointestinal bleeding were identified and matched to 5230 controls. Current use of spironolactone was associated with a 2.7-fold (95% confidence interval 1.2 to 6.0) increased risk of a gastrointestinal event. CONCLUSION: The risk of gastroduodenal ulcers or upper gastrointestinal bleeding is significantly increased in patients using spironolactone.

Non-cardiac QTc-prolonging drugs and the risk of sudden cardiac death. (Article)

2005-10-01T00:00:00Z

AIMS: To assess the association between the use of non-cardiac QTc-prolonging drugs and the risk of sudden cardiac death. METHODS AND RESULTS: A population-based case-control study was performed in the Integrated Primary Care Information (IPCI) project, a longitudinal observational database with complete medical records from more than 500,000 persons. All deaths between 1 January 1995 and 1 September 2003 were reviewed. Sudden cardiac death was classified based on the time between onset of cardiovascular symptoms and death. For each case, up to 10 random controls were matched for age, gender, date of sudden death, and general practice. The exposure of interest was the use of non-cardiac QTc-prolonging drugs. Exposure at the index date was categorized into three mutually exclusive groups of current use, past use, and non-use. The study population comprised 775 cases of sudden cardiac death and 6297 matched controls. Current use of any non-cardiac QTc-prolonging drug was associated with a significantly increased risk of sudden cardiac death (adjusted OR: 2.7; 95% CI: 1.6-4.7). The risk of death was highest in women and in recent starters. CONCLUSION: The use of non-cardiac QTc-prolonging drugs in a general population is associated with an increased risk of sudden cardiac death.

Angiotensin-converting enzyme gene insertion/deletion polymorphism and breast cancer risk. (Article)

2005-09-01T00:00:00Z

BACKGROUND: The renin-angiotensin system plays an important role in homeostasis and lately, its main effector, angiotensin II, has been attributed with angiogenic and growth factor actions in the breast tissue. Previous studies have shown that the insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme (ACE) gene accounts for the variability of ACE plasma concentrations. The use of ACE inhibitors and the ACE I/D polymorphism may be linked to breast cancer risk. In this study, we evaluate the relationship of the ACE I/D polymorphism with breast cancer risk in Caucasian postmenopausal women. METHODS: The ACE I/D polymorphism was genotyped in 4,117 women participants in the Rotterdam Study. Baseline information was obtained through a questionnaire. We conducted a logistic regression and survival analysis to assess the risk of breast cancer by the ACE genotype. RESULTS: The DD carriers showed a significantly increased risk of developing breast cancer when compared with the II carriers (odds ratio, 1.86; 95% confidence interval, 1.06-3.27; P = 0.03). This association remained after adjusting for other risk factors, including body mass index, age at menarche, age at menopause, hormone replacement therapy, and hypertension. Our survival analysis showed that the cancer-free survival was significantly reduced in DD compared with II carriers (hazard ratio, 1.80; 95% confidence interval, 1.07-3.01; P = 0.03). CONCLUSIONS: Our results suggest that the ACE I/D polymorphism plays an important role in breast cancer risk and disease-free survival in Caucasian postmenopausal women.

A promoter polymorphism of the insulin-like growth factor-I gene is associated with left ventricular hypertrophy (Article)

2005-01-01T00:00:00Z

Angiotensin converting enzyme insertion/deletion polymorphism and the risk of heart failure in hypertensive subjects. (Article)

2004-12-01T00:00:00Z

AIMS: Cardiac angiotensin-I converting enzyme (ACE) activity is influenced by the ACE I/D polymorphism. Evidence suggests that the DD-genotype may be a risk factor for cardiac hypertrophy and heart failure, especially in hypertensive subjects. We assessed the relation between the ACE I/D polymorphism and the risk of incident heart failure in normotensive and hypertensive subjects. METHODS AND RESULTS: We investigated 4264 normotensive and 2174 hypertensive participants of the Rotterdam Study, a population based prospective cohort study. All subjects were available for follow-up from 1990 until 2000. Incidence rates (IR) of heart failure in normotensive subjects were the same over all genotype strata (10 per 1000 person-years). In hypertensive subjects, the IR increased with the number of D-alleles present (II: IR=13, ID: IR=18 and DD: IR=20 per 1000 person-years). Hypertensive subjects carrying the II-genotype did not have an increased risk of heart failure compared to normotensive II subjects. However, hypertensive subjects carrying one or two copies of the D-allele did have a significantly increased risk of heart failure (ID: RR: 1.4 (1.1-1.9) and DD: RR: 1.5 (1.2-2.1)). CONCLUSION: Our findings suggest that the ACE I/D polymorphism may play a modifying role in the development of heart failure in hypertensive subjects.

Annual revaccination against influenza and mortality risk in community-dwelling elderly persons. (Article)

2004-11-03T00:00:00Z

CONTEXT: Although large-scale observational studies have demonstrated the effectiveness of influenza vaccination, no large studies have systematically addressed the clinical benefit of annual revaccinations. OBJECTIVE: To investigate the effect of annual influenza revaccination on mortality in community-dwelling elderly persons. DESIGN, SETTING, AND PARTICIPANTS: A population-based cohort study using the computerized Integrated Primary Care Information (IPCI) database in the Netherlands including community-dwelling individuals aged 65 years or older from 1996 through 2002. For each year, we computed the individual cumulative exposure to influenza vaccination since study start. MAIN OUTCOME MEASURE: Association between the number of consecutive influenza vaccinations and all-cause mortality vs no vaccination after adjusting for age, sex, chronic respiratory and cardiovascular disease, hypertension, diabetes mellitus, renal failure, and cancer. RESULTS: The study population included 26,071 individuals, of whom 3485 died during follow-up. Overall, a first vaccination was associated with a nonsignificant annual reduction of mortality risk of 10% (hazard ratio [HR], 0.90; 95% confidence interval [CI], 0.78-1.03) while revaccination was associated with a reduced mortality risk of 24% (HR, 0.76; 95% CI, 0.70-0.83). Compared with a first vaccination, revaccination was associated with a reduced annual mortality risk of 15% (HR, 0.85; 95% CI, 0.75-0.96). During the epidemic periods this reduction was 28% (HR, 0.72; 95% CI, 0.53-0.96). Similar estimates were obtained for persons with and without chronic comorbidity and those aged 70 years or older at baseline. Overall, influenza vaccination is estimated to prevent 1 death for every 302 vaccinees at a vaccination coverage that varied between 64% and 74%. CONCLUSION: Annual influenza vaccination is associated with a reduction in all-cause mortality risk in a population of community-dwelling elderly persons, particularly in older individuals.

Quantifying the heart failure epidemic: prevalence, incidence rate, lifetime risk and prognosis of heart failure The Rotterdam Study. (Article)

2004-09-01T00:00:00Z

AIMS: To determine the prevalence, incidence rate, lifetime risk and prognosis of heart failure. METHODS AND RESULTS: The Rotterdam Study is a prospective population-based cohort study in 7983 participants aged > or =55. Heart failure was defined according to criteria of the European Society of Cardiology. Prevalence was higher in men and increased with age from 0.9% in subjects aged 55-64 to 17.4% in those aged > or =85. Incidence rate of heart failure was 14.4/1000 person-years (95% CI 13.4-15.5) and was higher in men (17.6/1000 man-years, 95% CI 15.8-19.5) than in women (12.5/1000 woman-years, 95% CI 11.3-13.8). Incidence rate increased with age from 1.4/1000 person-years in those aged 55-59 to 47.4/1000 person-years in those aged > or =90. Lifetime risk was 33% for men and 29% for women at the age of 55. Survival after incident heart failure was 86% at 30 days, 63% at 1 year, 51% at 2 years and 35% at 5 years of follow-up. CONCLUSION: Prevalence and incidence rates of heart failure are high. In individuals aged 55, almost 1 in 3 will develop heart failure during their remaining lifespan. Heart failure continues to be a fatal disease, with only 35% surviving 5 years after the first diagnosis.

Insulin-like growth factor-I gene polymorphism and risk of heart failure (the Rotterdam Study) (Article)

2004-08-01T00:00:00Z

We studied 4,963 participants of the population-based Rotterdam Study and found that a genetically determined chronic exposure to low insulin-like growth factor-I (IGF-I) levels is associated with an increased risk for heart failure in elderly patients.

Cholesterol and age-related macular degeneration: is there a link? (Article)

2004-04-01T00:00:00Z

PURPOSE: To examine the relation among serum cholesterol, apolipoprotein E genotype (APOE), and the risk of early and late age-related macular degeneration (AMD). DESIGN: The Rotterdam Study, a population based prospective cohort study. METHODS: Serum levels of total and high-density lipoprotein (HDL) cholesterol as well as APOE genotype were determined at baseline. Of 3,944 subjects, 400 were diagnosed with incident early and late AMD after a mean follow-up of 5.2 years. RESULTS: Serum HDL, but not total, cholesterol was associated with an increased risk of AMD (odds ratio/SD, 1.20; 95% confidence interval; 1.06-1.35). The association remained unchanged after adjustment for APOE genotype. When stratifying for APOE genotype, the association was strongest in persons with the e 4 allele; an inverse association seemed to be present for e 2 carriers. CONCLUSION: Elevated HDL but not total cholesterol is associated with an increased risk of AMD. Apolipoprotein E genotype does not explain this association but may be an effect modifier.

Apolipoprotein E ε4 allele is associated with left ventricular systolic dysfunction (Article)

2004-04-01T00:00:00Z

BACKGROUND: Apolipoprotein (APOE) epsilon4 allele has been associated with cardiac dysfunction in Alzheimer's disease and beta-thalassemia. We investigated the association between APOE genotypes and left ventricular dysfunction in a population of community-dwelling elderly subjects. METHODS: This study was performed in the Rotterdam Study, a population-based prospective cohort study among elderly subjects. For 2206 participants, a baseline echocardiogram and blood specimens for APOE typing were available. Cardiac dysfunction was considered present when fractional shortening was or=65 years. CONCLUSION: The APOE epsilon4 allele is an independent risk factor for cardiac dysfunction in elderly people. Besides well-known effects on atherosclerosis and cholesterol levels, there may be other mechanisms, such as apoptosis, through which this allele exerts negative effects on myocardial performance.

Unlicensed and off-label prescription of respiratory drugs to children (Article)

2004-01-01T00:00:00Z

Many respiratory drugs are not available in formulations suitable for infants and toddlers. Efficacy and safety research is mostly restricted to older children. However, respiratory drugs are frequently used in children for common diseases like asthma, upper and lower respiratory tract infections, rhinitis and sinusitis. The unlicensed and off-label use of respiratory drugs in children were studied. A population-based cohort study was conducted by using the computerised medical records in the Integrated Primary Care Information project. The study population comprised a random sample from all children aged 0-16 yrs who were registered with a general practitioner in 1998. All prescriptions for respiratory drugs during the study period were classified according to their licensing and off-label status. The study population comprised 13,426 patients (51.7% male, median age 8.7 yrs), of whom 2,502 (19%) received 5,253 prescriptions for respiratory drugs in 1998. A total of 3,306 (62.9%) prescriptions concerned licensed drugs. Of the remaining 1,947 prescriptions (37.1%), 882 (16.8%) were unlicensed for use in children, and 1,065 (20.3%) were prescribed off-label. The 1-yr cumulative risk of receiving an unlicensed or off-label prescription was 45% among children with at least one prescription for a respiratory drug. This population-based study showed that a large proportion of respiratory drugs prescribed by the general practitioner are unlicensed for use in children, or licensed but prescribed in an off-label manner. Results have to be interpreted with caution because they may unjustly suggest inaccurate prescribing, whereas it may be difficult to treat children with respiratory symptoms and diseases, because for many respiratory drugs paediatric data on safety and efficacy are insufficient. These findings underline the importance of research on suitable formulations, dosages and efficacy of respiratory drugs in children.

The risk of bleeding complications in patients with cytochrome P450 CYP2C92 or CYP2C93 alleles on acenocoumarol of phenprocoumon (Article)

2004-01-01T00:00:00Z

The principal enzyme involved in coumarin metabolism is CYP2C9. Allelic variants of CYP2C9, CYP2C9*2 and CYP2C9*3, code for enzymes with reduced activity. Despite increasing evidence that patients with these genetic variants require lower maintenance doses of anticoagulant therapy, there is lack of agreement among studies on the risk of bleeding and CYP2C9 polymorphisms. It was, therefore, our objective to study the effect of the CYP2C9 polymorphisms on bleeding complications during initiation and maintenance phases of coumarin anticoagulant therapy. The design of the study was a population-based cohort in a sample of the Rotterdam Study, a study in 7,983 subjects. All patients who started treatment with acenocoumarol or phenprocoumon in the study period from January 1, 1991 through December 31, 1998 and for whom INR data were available were included. Patients were followed until a bleeding complication, the end of their treatment, death or end of the study period. Proportional hazards regression analysis was used to estimate the risk of a bleeding complication in relation to CYP2C9 genotype after adjustment for several potentially confounding factors such as age, gender, target INR level, INR, time between INR measurements, and aspirin use. The effect of variant genotype on bleeding risk was separately examined during the initiation phase of 90 days after starting therapy with coumarins. The 996 patients with analysable data had a mean follow-up time of 481 days (1.3 years); 311 (31.2%) had at least 1 variant CYP2C9 allele and 685 (68.8%) had the wild type genotype. For patients with the wild type genotype, the rate of minor bleeding, major bleeding and fatal bleeding was 15.9, 3.4 and 0.2 per 100 treatment-years, respectively. For patients with a variant genotype, the rate of minor, major and fatal bleeding was 14.6, 5.4 and 0.5 per 100 treatment-years. Patients with a variant genotype on acenocoumarol had a significantly increased risk for a major bleeding event (HR 1.83, 95% CI: 1.01-3.32). During the initiation phase of therapy we found no effect of variant genotype on bleeding risk. In this study among outpatients of an anticoagulation clinic using acenocoumarol or phenprocoumon, having a variant allele of CYP2C9 was associated with an increased risk of major bleeding events in patients on acenocoumarol, but not in patients on phenprocoumon. Although one might consider the assessment of the CYP2C9 genotype of a patient for dose adjustment before starting treatment with acenocoumarol, a prospective randomised trial should demonstrate whether this reduces the increased risk of major bleeding events.

Detection, verification, and quantification of adverse drug reactions (Article)

2004-01-01T00:00:00Z

Marketing in the lay media and prescriptions of terbinafine in primary care: Dutch cohort study (Article)

2004-01-01T00:00:00Z

Thiazide diuretics and the risk for hip fracture (Article)

2003-01-01T00:00:00Z

BACKGROUND: Since most hip fractures are related to osteoporosis, treating accelerated bone loss can be an important strategy to prevent hip fractures. Thiazides have been associated with reduced age-related bone loss by decreasing urinary calcium excretion. OBJECTIVE: To examine the association between dose and duration of thiazide diuretic use and the risk for hip fracture and to study the consequences of discontinuing use. DESIGN: Prospective population-based cohort study. SETTING: The Rotterdam Study. PARTICIPANTS: 7891 individuals 55 years of age and older. MEASUREMENTS: Hip fractures were reported by the general practitioners and verified by trained research assistants. Details of all dispensed drugs were available on a day-to-day basis. Exposure to thiazides was divided into 7 mutually exclusive categories: never use, current use for 1 to 42 days, current use for 43 to 365 days, current use for more than 365 days, discontinuation of use since 1 to 60 days, discontinuation of use since 61 to 120 days, and discontinuation of use since more than 120 days. RESULTS: 281 hip fractures occurred. Relative to nonuse, current use of thiazides for more than 365 days was statistically significantly associated with a lower risk for hip fracture (hazard ratio, 0.46 [95% CI, 0.21 to 0.96]). There was no clear dose dependency. This lower risk disappeared approximately 4 months after thiazide use was discontinued. CONCLUSIONS: Thiazide diuretics protect against hip fracture, but this protective effect disappears within 4 months after use is discontinued.

Adherence to and dosing of beta-hydroxy-beta-methylglutaryl coenzyme a reductase inhibitors in the general population differs according to apolipoprotein E-genotypes (Article)

2003-01-01T00:00:00Z

Discontinuation and poor adherence to therapy are major problems during long-term treatment, particularly with cholesterol lowering drugs. Several studies have indicated that the cholesterol lowering effect of statins differs according to apolipoprotein (apo)E genotypes. Low-density lipoprotein-cholesterol lowering capacity appears to be smaller in subjects with the epsilon(4) allele. To assess whether the use of statins in daily practice differs according to apoE genotypes, we used data from the Rotterdam Study, a population-based prospective cohort study in the Netherlands, which started in 1990 and included 7983 subjects aged 55 years or more. During follow-up, there were 798 subjects who started to use statins. We used a Cox proportional hazard model to determine the rate of discontinuation in the first 3 years of statin use. Subjects on statin therapy with epsilon(2)epsilon(2) and epsilon(4)epsilon(4) genotypes showed a trend towards higher dosages than subjects with the other genotypes. Relative to subjects with the epsilon(2)epsilon(3) genotype, those with the epsilon(4)epsilon(4) genotype had a risk of 2.28 [95% confidence interval (CI) 1.02-5.12] to discontinue statins within 3 years. In women, this relative risk was 1.70 (CI 0.53-5.42) versus 3.18 (CI 1.01-10.03) in men. The apoE genotype is associated with discontinuation of statins. This suggests that subjects who are genetically prone to develop hypercholesterolemia show the highest risk of discontinuation of treatment.

Cholesterol lowering drugs and risk of age related maculopathy: prospective cohort study with cumulative exposure measurement (Article)

2003-01-01T00:00:00Z

Pharmacologic agents associated with a preventive effect on Alzheimer's disease: a review of the epidemiologic evidence (Article)

2002-01-01T00:00:00Z

Unlicensed and off label prescription of drugs to children: population based cohort study (Article)

2002-01-01T00:00:00Z

Fluoroquinolones and risk of Achilles tendon disorders: case-control study (Article)

2002-01-01T00:00:00Z

Nonsteroidal antiinflammatory drugs and the risk of Alzheimer's disease (Article)

2001-01-01T00:00:00Z

BACKGROUND: Previous studies have suggested that the use of nonsteroidal antiinflammatory drugs (NSAIDs) may help to prevent Alzheimer's disease. The results, however, are inconsistent. METHODS: We studied the association between the use of NSAIDs and Alzheimer's disease and vascular dementia in a prospective, population-based cohort study of 6989 subjects 55 years of age or older who were free of dementia at base line, in 1991. To detect new cases of dementia, follow-up screening was performed in 1993 and 1994 and again in 1997 through 1999. The risk of Alzheimer's disease was estimated in relation to the use of NSAIDs as documented in pharmacy records. We defined four mutually exclusive categories of use: nonuse, short-term use (1 month or less of cumulative use), intermediate-term use (more than 1 but less than 24 months of cumulative use), and long-term use (24 months or more of cumulative use). Adjustments were made by Cox regression analysis for age, sex, education, smoking status, and the use or nonuse of salicylates, histamine Hz-receptor antagonists, antihypertensive agents, and hypoglycemic agents. RESULTS: During an average follow-up period of 6.8 years, dementia developed in 394 subjects, of whom 293 had Alzheimer's disease, 56 vascular dementia, and 45 other types of dementia. The relative risk of Alzheimer's disease was 0.95 (95 percent confidence interval, 0.70 to 1.29) in subjects with short-term use of NSAIDs, 0.83 (95 percent confidence interval, 0.62 to 1.11) in those with intermediate-term use, and 0.20 (95 percent confidence interval, 0.05 to 0.83) in those with long-term use. The risk did not vary according to age. The use of NSAIDs was not associated with a reduction in the risk of vascular dementia. CONCLUSIONS: The long-term use of NSAIDs may protect against Alzheimer's disease but not against vascular dementia.

Prevention of relapse in patients with congestive heart failure: the role of precipitating factors (Article)

1998-01-01T00:00:00Z

Relapse of congestive heart failure (CHF) frequently occurs and has serious consequences in terms of morbidity, mortality, and health care expenditure. Many studies have investigated the aetiological and prognostic factors of CHF, but there are only limited data on the role of precipitating factors that trigger relapse of CHF. Knowledge of potential precipitating factors may help to optimise treatment and provide guidance for patients with CHF. The literature was reviewed to identify factors that may influence haemodynamic homeostasis in CHF. Precipitating factors that may offer opportunities for preventing relapse of CHF were selected. Potential precipitating factors are discussed in relation to the pathophysiology of CHF: alcohol, smoking, psychological stress, uncontrolled hypertension, cardiac arrhythmias, myocardial ischaemia, poor treatment compliance, and inappropriate medical treatment. Poor treatment compliance in particular is frequently encountered in patients with CHF. Furthermore, studies of medical treatment under everyday circumstances indicate that some aspects of the management of CHF can be improved. In conclusion, the identification of precipitating factors for relapse of CHF may strongly contribute to optimal treatment. Improvement of treatment compliance and optimalisation of medical treatment may offer important possibilities to clinicians to reduce the number of relapses in patients with CHF.