http://repub.eur.nl/res/aut/8892/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/39757/ 2013-05-01T00:00:00Z Objective: This study examined whether vascular alterations are associated with the presence and progression of osteoarthritis of the knee, the hip and the different hand joints in a large prospective cohort study. Methods: In this population-based study involving participants aged 55 years and older (Rotterdam Study I), men (n=2372) and women (n=3278) were analysed separately. x-Rays of the knee, hip and hand were scored using the Kellgren and Lawrence score for osteoarthritis at baseline, after 6.6 years and 10 years. Measures of atherosclerosis (carotid intima media thickness (IMT) and carotid plaque) and data on covariates (age, body mass index, hypertension, cholesterol ratio, diabetes mellitus and smoking) were collected at baseline. Multivariate logistic regression models with generalised estimated equations were used to calculate OR and corresponding 95% CI. Secondary multiple comparison adjustment resulted in a significance level of p<0.0021. Results: In women, IMT showed an independent association with the prevalence of knee osteoarthritis (adjusted OR (aOR) 1.7, 1.1 to 2.7), and carotid plaque with distal interphalangeal (DIP) osteoarthritis (aOR 1.4, 1.2 to 1.7) and with metacarpophalangeal osteoarthritis (aOR 1.5, 1.1 to 2.2). An independent association for IMT with progression of metacarpophalangeal osteoarthritis was found in women (aOR 2.9, 1.18 to 6.93). Additional adjustment for multiple testing yielded a significant association between carotid plaque and DIP osteoarthritis in women (p<0.001). Conclusions: This study showed independent associations of atherosclerosis with osteoarthritis of the knee and hand joints in women. The evidence was most solid for a relation with DIP osteoarthritis. More research is needed to confirm the associations and examine the differential association with various joints. http://repub.eur.nl/res/pub/40098/ 2013-05-01T00:00:00Z Objective Discordance between having pain and radiologic osteoarthritis (OA) is a well-established fact. It is suggested that this particularly applies to the less severe grades of OA. However, some people with a Kellgren/Lawrence (K/L) grade of 3 or 4 for OA are without pain. This study aimed to identify factors and differences in the factors associated with pain in persons with different grades of knee OA. Methods We stratified the knees of more than 5,000 participants of a population-based cohort study, the Rotterdam Study, based on the grade of knee OA. Multivariate generalized estimating equation analysis was used to analyze the association with knee pain. We tested several factors not directly related to structural damage of the knee. Results As expected, an increasing percentage of participants did not report pain with decreasing severity of knee OA: 25.8% for K/L grade 3 or 4 and 84.5% for no knee OA. Being a woman, having widespread pain, reporting general health symptoms, familial OA, and morning stiffness are factors for knee pain, but not specific for a particular grade of radiographic knee OA. Depression and hip OA showed significant interactions with the grade of OA being a factor for knee pain in knees without OA (K/L grade 0), but not in knees with OA. In addition, increasing age is protective for reporting pain in general. Conclusion Several factors are associated with knee pain, but are not specific for a grade of radiographic knee OA. Two factors were associated with knee pain in the knee without signs of OA. Copyright http://repub.eur.nl/res/pub/39851/ 2013-04-04T00:00:00Z Economic variables such as income, education, and occupation are known to affect mortality and morbidity, such as cardiovascular disease, and have also been shown to be partly heritable. However, very little is known about which genes influence economic variables, although these genes may have both a direct and an indirect effect on health. We report results from the first large-scale collaboration that studies the molecular genetic architecture of an economic variable-entrepreneurship-that was operationalized using self-employment, a widely-available proxy. Our results suggest that common SNPs when considered jointly explain about half of the narrow-sense heritability of self-employment estimated in twin data (σg2/σP2= 25%, h2= 55%). However, a meta-analysis of genome-wide association studies across sixteen studies comprising 50,627 participants did not identify genome-wide significant SNPs. 58 SNPs with p<10-5were tested in a replication sample (n = 3,271), but none replicated. Furthermore, a gene-based test shows that none of the genes that were previously suggested in the literature to influence entrepreneurship reveal significant associations. Finally, SNP-based genetic scores that use results from the meta-analysis capture less than 0.2% of the variance in self-employment in an independent sample (p≥0.039). Our results are consistent with a highly polygenic molecular genetic architecture of self-employment, with many genetic variants of small effect. Although self-employment is a multi-faceted, heavily environmentally influenced, and biologically distal trait, our results are similar to those for other genetically complex and biologically more proximate outcomes, such as height, intelligence, personality, and several diseases. http://repub.eur.nl/res/pub/33579/ 2011-12-14T00:00:00Z There are indications that in persons of older age, systolic blood pressure (SBP) is no longer associated with mortality. This raises the question whether the predictive value of SBP changes from younger to older age groups. Analysis in the Rotterdam Study, a population-based prospective cohort study among 4,612 participants aged ≥55 years without previous cardiovascular disease and with a median follow-up of 14.9 (interquartile range, 11.1-15.8) years. Within four age groups (55-64, 65-74, 75-84, ≥85 years), the predictive value of baseline SBP for mortality was studied. From age 55 to ≥85 years, risk of all-cause mortality associated with SBP ≥160 mmHg decreased from HR 1.7 (95%CI 1.2-2.2) to HR 0.7 (95%CI 0.4-1.1), p for trend <0.001. For participants with SBP 140-159 mmHg, the risk decreased from HR 1.2 (95%CI 0.9-1.5) to HR 0.7 (95%CI 0.5-1.1), p for trend <0.001. Analyses in the 5-year age groups showed an increased risk with higher SBPs up to age 75 years. After 75 years, a trend towards SBP no longer being associated with an increased mortality risk was seen in our study. These findings need to be considered with recently reported beneficial effects of antihypertensive treatment in this age group. http://repub.eur.nl/res/pub/34263/ 2011-12-01T00:00:00Z It remains largely unknown which factors determine the clinical outcome of human metapneumovirus (HMPV) infections. The aim of the present study was to analyse whether exposure to bacterial pathogens can influence HMPV infections. From 57 children, serum samples and colonization data for Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus and Streptococcus pneumoniae were collected at 1.5, 6, 14 and 24months of age. Seroconversion rates to HMPV were determined and related to bacterial carriage. Frequent nasopharyngeal carriage (≥2 times in the first 2years of life) of S. pneumoniae, but not of the other three pathogens, was associated with increased seroconversion rates of infants to HMPV at the age of 2 years (frequently vs. less exposed, 93% vs. 59%; p<0.05). Subsequently, the susceptibility of well-differentiated normal human bronchial epithelial cells (wd-NHBE) pre-incubated with bacterial pathogens to in vitro HMPV infection was evaluated. Pre-incubation of wd-NHBE with S. pneumoniae resulted in increased susceptibility to infection with HMPV-enhanced green fluorescent protein (EGFP), as determined by enumeration of EGFP-positive cells. This was not the case for cells pre-incubated with H. influenzae, M. catarrhalis on S. aureus. We conclude that exposure to S. pneumoniae can modulate HMPV infection. © 2011 The Authors. Clinical Microbiology and Infection http://repub.eur.nl/res/pub/34690/ 2011-10-11T00:00:00Z Objective: To assess whether wheezing and atopic dermatitis were associated with constipation in preschool children and to what extent shared risk factors contribute to this relationship. Methods: A population-based sample of 4651 preschool children was used. At the age of 24, 36 and 48 months, a parental report of functional constipation was available according to the Rome II criteria, and data on atopic dermatitis and wheezing were available using age-adapted questionnaires from the International Study of Asthma and Allergies in Childhood. Stepwise multivariate analyses were performed to assess whether body mass index, infection exposure, food allergy and infant nutrition, and parental stress explained the association between wheezing, atopic dermatitis and constipation. Results: Out of 4651 children, 12-17% had functional constipation between 24 and 48 months. Symptoms of wheezing decreased from 20% to 12% and atopic dermatitis decreased from 30% to 18% at the age of 24 and 48 months respectively. Between the age of 24 and 48 months, wheezing symptoms were significantly associated with functional constipation (OR 1.17; 1.02 to 1.34) but these results were mainly explained by the child's exposure to infections and use of antibiotics (adjusted odds ratio 1.08; 95% CI 0.95 to 1.24). No significant association was found between symptoms of atopic dermatitis and functional constipation (OR 1.08; 95% CI 0.94 to 1.23). Conclusions: These findings suggest that functional constipation coexists with wheezing in childhood but is mainly explained by the child's infection exposure and use of antibiotics. Therefore, an independent association between respiratory symptoms and functional bowel disorders as suggested in previous studies is questionable. http://repub.eur.nl/res/pub/30846/ 2011-10-01T00:00:00Z Background Polycystic ovary syndrome (PCOS) is characterized by ovarian dysfunction. The association with obesity and insulin resistance is well established. Steroid hormones play a central role in the regulation of both ovarian function and body composition. This study aims to assess the influence of known functional polymorphisms in genes that are responsible for the production, metabolism and signal transduction of steroid hormones on the susceptibility to and phenotype of PCOS. Methods We included 518 Caucasian women with anovulatory PCOS (2003 Rotterdam criteria) and 2996 population-based controls. Functional polymorphic variants were selected in genes that affect the production of estradiol and cortisol [aromatase (CYP19), 11-beta-hydroxysteroid dehydrogenase type I (HSD11B1) and hexose-6-phosphate dehydogenase (H6PD)] and in genes for signal transduction proteins [estrogen receptor (ESR1 and ESR2) and glucocorticoid receptor (GCR)]. Results Genotype-frequencies were similar in PCOS cases and population-based controls. We observed possible associations between GCR genotype and LH levels that suggest an inhibitory influence of GCR, i.e., lower LH levels in association with GCR alleles that are known to increase receptor sensitivity (rs6195 and rs41423247) and higher LH levels in GCR variants that may inhibit receptor sensitivity (rs6190 and rs6198). Conclusions The present study did not identify risk alleles for PCOS, although the study was limited by an absence of endocrine data for the population-based controls. However, GCR variants may influence gonadotrophin levels in women with anovulatory PCOS. We hypothesize that glucocorticoids can affect the function of the hypothalomo-pituitary-gonadal axis in humans. http://repub.eur.nl/res/pub/26622/ 2011-09-01T00:00:00Z Cathepsin D (CTSD) is a gene involved in amyloid precursor protein processing and is considered a candidate for Alzheimer's disease (AD). The aim of the current study was to examine if variation in CTSD increases the risk of AD. We performed a candidate-gene analysis in a population-based cohort study (N= 7983), and estimated the effect of CTSD on the risk of AD. Additionally, a large meta-analysis was performed incorporating our data and previously published data. The T-allele of CTSD rs17571 was associated with an increased risk of AD (p-value 0.007) in the Rotterdam Study. This association was predominantly found in APOE ε4 noncarriers. A meta-analysis of previously published data showed a significantly increased risk of AD in carriers of the T-allele of rs17571 (OR 1.22, 95% CI 1.03-1.44), irrespective of APOE ε4 carrier status. This study adds to the evidence that CTSD increases the risk of AD, although the effect size is moderate. http://repub.eur.nl/res/pub/31060/ 2011-08-30T00:00:00Z Coffee consumption is a model for addictive behavior. We performed a meta-analysis of genome-wide association studies (GWASs) on coffee intake from 8 Caucasian cohorts (N=18 176) and sought replication of our top findings in a further 7929 individuals. We also performed a gene expression analysis treating different cell lines with caffeine. Genome-wide significant association was observed for two single-nucleotide polymorphisms (SNPs) in the 15q24 region. The two SNPs rs2470893 and rs2472297 (P-values=1.6 × 10-11and 2.7 × 10-11), which were also in strong linkage disequilibrium (r2=0.7) with each other, lie in the 23-kb long commonly shared 5′ flanking region between CYP1A1 and CYP1A2 genes. CYP1A1 was found to be downregulated in lymphoblastoid cell lines treated with caffeine. CYP1A1 is known to metabolize polycyclic aromatic hydrocarbons, which are important constituents of coffee, whereas CYP1A2 is involved in the primary metabolism of caffeine. Significant evidence of association was also detected at rs382140 (P-value=3.9 × 10-09) near NRCAM-a gene implicated in vulnerability to addiction, and at another independent hit rs6495122 (P-value=7.1 × 10-09)-an SNP associated with blood pressure-in the 15q24 region near the gene ULK3, in the meta-analysis of discovery and replication cohorts. Our results from GWASs and expression analysis also strongly implicate CAB39L in coffee drinking. Pathway analysis of differentially expressed genes revealed significantly enriched ubiquitin proteasome (P-value=2.2 × 10-05) and Parkinson's disease pathways (P-value=3.6 × 10-05).Molecular Psychiatry advance online publication, 30 August 2011; doi:10.1038/mp.2011.101. http://repub.eur.nl/res/pub/26542/ 2011-08-01T00:00:00Z Objectives: Although the Kellgren and Lawrence (K&L) criteria for defining radiological osteoarthritis are widely used in epidemiological and clinical studies, the authors previously documented the existence of five different versions of these criteria. This study identifies the impact of the use of alternative versions of the K&L criteria and evaluates which description has the highest association with knee complaints. Methods: Two readers scored most radiographs of the knees of participants of the Rotterdam Study with the original K&L description (90%). In addition, each alternative description was used in a random part (20%) of the radiographs. The authors calculated reproducibility of all descriptions, and compared sensitivity and specificity of the alternative descriptions for three cut-off points with the original description as reference standard (K&L≥1, K&L≥2 and K&L≥3). The authors calculated κ statistics to compare agreement between the original and alternative descriptions, and evaluated the association with knee complaints. Results: The dataset comprises radiographs of knees of 3071 people. For cut-off K&L≥1 all four alternatives classified more people as having osteoarthritis than the original description; κ was low, and sensitivity and specificity were moderate to good. For cut-offs K&L≥2 and K&L≥3 there was little difference in the number of cases and κ, sensitivity and specificity were good to perfect. The original description and alternative 3 showed the strongest association with knee complaints. Conclusions: The different descriptions of the K&L criteria have impact on the classification of osteoarthritis in the lowest grade (K&L≥1). All descriptions have strengths and weaknesses. It depends on the purpose which is the best description. http://repub.eur.nl/res/pub/34366/ 2011-08-01T00:00:00Z http://repub.eur.nl/res/pub/34300/ 2011-07-12T00:00:00Z Recent molecular studies have implicated common alleles of small to moderate effect and rare alleles with larger effect sizes in the genetic architecture of schizophrenia (SCZ). It is expected that the reliable detection of risk variants with very small effect sizes can only be achieved through the recruitment of very large samples of patients and controls (that is tens of thousands), or large, potentially more homogeneous samples that have been recruited from confined geographical areas using identical diagnostic criteria. Applying the latter strategy, we performed a genome-wide association study (GWAS) of 1169 clinically well characterized and ethnically homogeneous SCZ patients from a confined area of Western Europe (464 from Germany, 705 from The Netherlands) and 3714 ethnically matched controls (1272 and 2442, respectively). In a subsequent follow-up study of our top GWAS results, we included an additional 2569 SCZ patients and 4088 controls (from Germany, The Netherlands and Denmark). Genetic variation in a region on chromosome 11 that contains the candidate genes AMBRA1, DGKZ, CHRM4 and MDK was significantly associated with SCZ in the combined sample (n=11 540; P=3.89 × 10-9, odds ratio (OR)=1.25). This finding was replicated in 23 206 independent samples of European ancestry (P=0.0029, OR=1.11). In a subsequent imaging genetics study, healthy carriers of the risk allele exhibited altered activation in the cingulate cortex during a cognitive control task. The area of interest is a critical interface between emotion regulation and cognition that is structurally and functionally abnormal in SCZ and bipolar disorder.Molecular Psychiatry advance online publication, 12 July 2011; doi:10.1038/mp.2011.80. http://repub.eur.nl/res/pub/26210/ 2011-07-01T00:00:00Z Objective: To estimate the prevalence of erosive hand osteoarthritis (EOA) in the general population and its relation to symptomatic hand osteoarthritis (HOA), hand pain and disability. Methods: Baseline data of participants from a population-based study (age ≥55 years) were used. Symptomatic HOA was defined as hand pain and in addition to radiographic HOA (at least one interphalangeal (IP) joint or 1st carpometacarpal joint with Kellgren-Lawrence grade ≥2). EOA was defined as having at least one IP joint with erosions according to the Verbruggen-Veys scoring method. Hand pain and disability were self-reported. Multivariate logistic regression analyses were used to estimate the effect of EOA on pain and disability. Results were presented as OR with a 95% CI, adjusted for age and sex. Results: Of 3430 participants, radiographic HOA was seen in 56% (n=1916) and symptomatic HOA in 11% (n=371). Erosions were seen in 96 subjects. The prevalence of EOA in the general, radiographic and symptomatic HOA population was 2.8%, 5.0% and 10.2%, respectively. Presence of EOA led to adjusted ORs for pain of 3.6 (95% CI 2.4 to 5.6) and for disability 2.4 (95% CI 1.1 to 5.4). In radiographic HOA, people with erosion(s) had more hand pain (adjusted OR=3.1, 95% CI 2.0 to 4.8) or disability (adjusted OR=2.5, 95% CI 1.1 to 5.8) than people without erosion(s). Conclusion: The prevalence of EOA is 2.8% in the general population and 10.2% in individuals with symptomatic HOA. It has a substantial impact on hand pain and disability. http://repub.eur.nl/res/pub/26733/ 2011-05-01T00:00:00Z Objectives: The incidence of heart failure increases with aging. Aim of the present, study was to determine whether measures body composition predict incident heart failure in older adults. Selling: Prospective community-based cohort study. 5, 868 men and women aged 55 years and older participating the Rotterdam study. Measures of body mass index and waist circumference were obtained at baseline. Information on incident heart failure was obtained during follow-up. Cox regression analyses were performed to investigate the possible association between measure of body composition and incident heart failure. Results: During a mean follow up of 10.9 (SD ±4.4) years, 765 participants had heart failure. After adjustment for age and gender, 1-standard deviation of body mass index, waist circumference and the waist-hip ratio predicted heart failure (HR 1.25; 95% CI 1.17-1.34; HR 1.26; 95% CI 1.18-1.36; and HR 1.17; 95% CI 1.08-1.27), respectively. In age-stratified analyses, 1-standard deviation of body mass index (1.17; 95% CI 1.06-1.29) and waist circumference (1.16; 95% CI 1.05-1.29) were still associated with the risk of heart failure in the oldest participants, whereas the waist-hip ratio was not (1.06; 95% CI 0.945-1.18). Conclusion: Although estimates decrease with age, measures of overall and central adiposity predict incident heart failure among community dwelling older adults. http://repub.eur.nl/res/pub/33460/ 2011-05-01T00:00:00Z Objectives: The genetic aetiology of osteoarthritis has not yet been elucidated. To enable a well-powered genome-wide association study (GWAS) for osteoarthritis, the authors have formed the arcOGEN Consortium, a UK-wide collaborative effort aiming to scan genome-wide over 7500 osteoarthritis cases in a two-stage genome-wide association scan. Here the authors report the findings of the stage 1 interim analysis. Methods: The authors have performed a genome-wide association scan for knee and hip osteoarthritis in 3177 cases and 4894 population-based controls from the UK. Replication of promising signals was carried out in silico in five further scans (44 449 individuals), and de novo in 14 534 independent samples, all of European descent. Results: None of the association signals the authors identified reach genome-wide levels of statistical significance, therefore stressing the need for corroboration in sample sets of a larger size. Application of analytical approaches to examine the allelic architecture of disease to the stage 1 genome-wide association scan data suggests that osteoarthritis is a highly polygenic disease with multiple risk variants conferring small effects. Conclusions: Identifying loci conferring susceptibility to osteoarthritis will require large-scale sample sizes and well-defined phenotypes to minimise heterogeneity. http://repub.eur.nl/res/pub/34385/ 2011-05-01T00:00:00Z Objective To unravel the mechanisms underlying the previously demonstrated associations between low birthweight and cardiovascular disease in adulthood, we examined whether maternal smoking during pregnancy leads to fetal arterial resistance adaptations, and subsequently to fetal growth retardation and changes in postnatal blood pressure and cardiac development. Design Prospective cohort study from early fetal life onwards. Setting Academic hospital. Population Analyses were based on 1120 children aged 2 years. Methods Maternal smoking during pregnancy [non-smoking, first trimester smoking, continued smoking (<5 and ≥5 cigarettes/day)] was assessed by questionnaire. Main outcome measures Third trimester placental and fetal arterial resistance indices and fetal growth were assessed by ultrasound and Doppler measurements. Postnatal blood pressure and cardiac structures (aortic root diameter, left atrial diameter, left ventricular mass) were measured at 2 years of age. Results First trimester smoking was not associated with third trimester placental and fetal blood flow adaptations. Continued smoking of ≥5 cigarettes/day was associated with an increased resistance in uterine, umbilical and middle cerebral arteries, and with a decreased flow and diameter of the ascending aorta. Among mothers who continued to smoke, the third trimester estimated fetal weights and birthweights were most affected in children with the highest umbilical artery resistance. Fetal arterial resistance indices were also associated with aortic root diameter and left atrial diameter. Conclusions Fetal arterial resistance adaptations may be involved in the pathways leading from maternal smoking during pregnancy to low birthweight and cardiovascular developmental changes in childhood in the offspring. http://repub.eur.nl/res/pub/33970/ 2011-04-01T00:00:00Z Objective: To establish the prevalence of osteoporosis, vertebral fractures (VFs), and non-VFs in acromegaly patients with long-term controlled disease and factors potentially influencing fracture risk. Design: Case-control study. Patients and measurements: Eighty-nine patients (46% male, mean age: 58 years) were included. We studied VFs and non-VFs, bone mineral density (BMD), and markers of bone turnover. In 48 patients, BMD assessment was also obtained 7 years prior to the current study. To compare VF prevalence, data from a sample of the Dutch population (n=3469) were used. Results: VF prevalence was 59% (men 64% and women 54%), significantly increased when compared with controls (odds ratio up to 6.5), and independent of the duration of disease control, BMD, markers of bone turnover, and acromegalic disease characteristics. Mean number of VFs per patient was 3.4G0.3 (range 1-8). There was no relationship between the number and severity of fractures, parameters of bone turnover, and follow-up BMD measurements. BMD did not change during prolongation of follow-up by 7 years of controlled acromegaly. Conclusion: There is a very high prevalence of VFs in acromegaly patients with long-term controlled disease, independently of BMD. In view of the significant morbidity and mortality associated with VFs in general and the inability of BMD to predict fracture risk in acromegalic patients, we propose to include VF assessment, for example by lateral conventional radiographs of the spine in the screening of patients with acromegaly, both at diagnosis and during follow-up after establishment of disease control. http://repub.eur.nl/res/pub/33526/ 2011-03-01T00:00:00Z Objective. Lumbar disc degeneration (LDD) is a serious social and medical problem which has been shown to be highly heritable. It has similarities with peripheral joint osteoarthritis (OA) in terms of both epidemiology and pathologic processes. A few known genetic variants have been identified using a candidate gene approach, but many more are thought to exist. GDF5 is a gene whose variants have been shown to play a role in skeletal height as well as predisposing to peripheral joint OA. In vitro, the gene product growth differentiation factor 5 has been shown to promote growth and repair of animal disc. This study was undertaken to investigate whether the GDF5 gene plays a role in LDD. Methods. We investigated whether the 5' upstream single-nucleotide polymorphism (SNP) variant rs143383 was associated with LDD, using plain radiography and magnetic resonance imaging to identify disc space narrowing and osteophytes, in 5 population cohorts from Northern Europe. Results. An association between LDD and the SNP rs143383 was identified in women, with the same risk allele as in knee and hip OA (odds ratio 1.72 [95% confidence interval 1.15-2.57], P = 0.008). Conclusion. Our findings in 5 population cohorts from Northern Europe indicate that a variant in the GDF5 gene is a risk factor for LDD in women. Many more such variants are predicted to exist, but this result highlights the growth and differentiation cellular pathway as a possible route to a better understanding of the process behind lumbar disc degeneration. http://repub.eur.nl/res/pub/28283/ 2010-12-01T00:00:00Z Aim: To verify self-reported information on prenatal drug use in urine because reporting in pregnancy is sensitive to stigma and might lead to misclassification. Methods: Using semiquantitative immunochemical analysis, the presence of the urinary metabolite (11-nor-Δ9-tetrahydrocannabinol- 9-carboxylic acid) was compared to self-reported prenatal cannabis use. Sensitivity and specificity for self-report and urinalysis outcomes were calculated and Yule's Y was used as an agreement measure. Results: Urine samples were available for 3,997 pregnant women. Of these women, 92 reported having used cannabis during pregnancy (2.3%) and 71 had positive urine screens (1.8%). In total 35% of the 92 women with self-reported cannabis use also had a positive urine screen. Positive urines were relatively frequent in women reporting cannabis use before pregnancy only (7.6%) and in women with missing information (2.6%). Sensitivity and specificity of urinalysis compared to self-report were 0.46 and 0.98. Sensitivity and specificity of self-report compared to urinalysis were 0.36 and 0.99. Yule's Y amounted to 0.77, indicating substantial agreement between the measures. Conclusions: Our findings illustrate the difficulties in obtaining valid information on prenatal cannabis use. To improve the quality of cannabis use data, we suggest a 2-step approach starting with self-report. Copyright http://repub.eur.nl/res/pub/27384/ 2010-11-30T00:00:00Z Objective: Diabetes mellitus has been associated with an increased risk of Alzheimer disease (AD), but how it exerts its effect remains controversial. Possible pathophysiologic mechanisms are glucose toxicity and a direct effect of insulin on amyloid metabolism. Most studies had short follow-up, and longer-term effects of diabetes on AD risk are unknown. We investigated whether fasting glucose and insulin levels and insulin resistance are associated with the risk of AD and whether this risk is constant over time. Methods: The study was based on 3,139 participants of the Rotterdam Study, a population-based cohort study. All subjects were free from dementia, did not have a history of diabetes, and had fasting levels of glucose and insulin measured at baseline. Insulin resistance was estimated with the homeostasis model assessment. We investigated how fasting glucose, insulin, and insulin resistance are related to the risk of AD in 3 different strata according to time-to-event, using Cox proportional hazards models. Results: During follow-up, 211 participants developed AD, 71 of them within 3 years of baseline. Levels of insulin and insulin resistance were associated with a higher risk of AD within 3 years of baseline. After 3 years, the risk was no longer increased. Glucose was not associated with a higher risk of AD. There was no interaction of APOE ε4 carriership and insulin metabolism on the risk of AD. ConclusionS: Our findings suggest that insulin metabolism influences the clinical manifestation of AD only within 3 years. Copyright http://repub.eur.nl/res/pub/28478/ 2010-10-01T00:00:00Z Objective: To examine whether specific pregnancy and delivery complications are risk factors for postpartum depression. Design: A prospective longitudinal study. Setting: Rotterdam, the Netherlands. Population A cohort of 4941 pregnant women who enrolled in the Generation R Study. Methods: Information on perinatal complications was obtained from the midwife and hospital registries or by questionnaire. Logistic regression analyses were used to calculate the risk of postpartum depression for the separate perinatal complications. Main outcome measures: Postpartum psychiatric symptoms were assessed 2 months after delivery using the Edinburgh postnatal depression scale. Results: Several perinatal complications were significantly associated with postpartum depression, namely: pre-eclampsia (adjusted OR, aOR 2.58, 95% CI 1.30-5.14), hospitalization during pregnancy (aOR 2.25, 95% CI 1.19-4.26), emergency caesarean section (aOR 1.53, 95% CI 1.02-2.31), suspicion of fetal distress (aOR 1.56, 95% CI 1.08-2.27), a medically indicated delivery provided by an obstetrician (aOR 2.43, 95% CI 1.56-3.78), and hospital admission of the baby (aOR 1.45, 95% CI 1.10-1.92). Unplanned pregnancy, thrombosis, meconium-stained amniotic fluid, and Apgar score were not associated with postpartum depression after adjustment for confounding factors, such as pre-existing psychopathological symptoms and sociodemographic characteristics. The risk of postpartum depression increased with the number of perinatal complications women experienced (P < 0.001). Conclusions: We showed that several pregnancy and delivery complications present a risk for women's mental health in the postpartum period. Obstetricians, midwives, general practitioners, and staff at baby well clinics should be aware that women who experienced perinatal complications-especially those with a number of perinatal complications-are at risk for developing postpartum depression. http://repub.eur.nl/res/pub/24518/ 2009-12-01T00:00:00Z The prevalence of childhood obesity is increasing rapidly. Visceral fat plays an important role in the pathogenesis of metabolic and cardiovascular diseases. Currently, computed tomography (CT) is broadly seen as the most accurate method of determining the amount of visceral fat. The main objective was to examine whether measures of abdominal visceral fat can be determined by ultrasound in children and whether CT can be replaced by ultrasound for this purpose. To assess whether preperitoneal fat thickness and area are good approximations of visceral fat at the umbilical level, we first retrospectively examined 47 CT scans of nonobese children (body mass index <30 kg/m2; median age 7.9 y [95% range 1.2 to 16.2]). Correlation coefficients between visceral and preperitoneal fat thickness and area were 0.58 (p < 0.001) and 0.76 (p < 0.001), respectively. Then, to assess how preperitoneal and subcutaneous fat thicknesses and areas measured by ultrasound compare with these parameters in CT, we examined 34 nonobese children (median age 9.5 [95% range 0.3 to 17.0]) by ultrasound and CT. Ultrasound measurements of preperitoneal and subcutaneous fat were correlated with CT measurements, with correlation coefficients ranging from 0.75-0.97 (all p < 0.001). Systematic differences of up to 24.0 cm2for preperitoneal fat area (95% confidence interval -29.9 to 77.9 cm2) were observed when analyzing the results described by the Bland-Altman method. Our findings suggest that preperitoneal fat can be used as an approximation for visceral fat in children and that measuring abdominal fat with ultrasound in children is a valid method for epidemiological and clinical studies. However, the exact agreement between the ultrasound and CT scan was limited, which indicates that ultrasound should be used carefully for obtaining exact fat distribution measurements in individual children. (E-mail: v.jaddoe@erasmusmc.nl). http://repub.eur.nl/res/pub/24882/ 2009-11-01T00:00:00Z Background: A polymorphism (rs143383; T to C) near the GDF5 gene has been associated with height and osteoarthritis (OA), but debate exists about whether its primary biological action is directed to cartilage or bone. Objective: To study the association between genetic variation in the GDF5 region and radiographic osteoarthritis (ROA) susceptibility, height, bone size parameters and fracture risk in a large population-based cohort of Caucasian elderly subjects. Methods: 6365 men and women had genotype data available. ROA was defined as a Kellgren/Lawrence (K/L) score ≥2 for hand, knee and hip joints. CTX-II levels, height, bone mineral density (BMD), bone size and fracture risk were also assessed. Results: rs143383 and three highly correlated single nucleotide polymorphisms (SNPs) in the GDF5 region were found to be independently associated with OA, height, bone size and fracture risk in women. Women with homozygotes for the rs143383 C allele had a 37% lower risk for hand OA (p=8×10-6) and a 28% lower risk for knee OA (p=0.003). In addition, they were 1.1 cm taller (p=0.001), had a larger hip axis length (HAL) (p=4×10-4) and had a 29% increased risk of incident non-vertebral fractures (p=0.02). No associations with hip OA or BMD were detected. No associations were found in men. Conclusion: This population-based study shows that GDF5 gene variants are associated with hand OA, knee OA and fracture risk in elderly women. It also replicates previous association between GDF5 variation and height. Furthermore, our findings for HAL suggest that GDF5 action is primarily directed to the long bones, rather than the axial skeleton. http://repub.eur.nl/res/pub/24545/ 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. http://repub.eur.nl/res/pub/32508/ 2008-01-01T00:00:00Z Object. The aim of this study was to analyze the presence of beaten-copper patterns (BCPs) in children with craniosynostosis before 18 months of age and its association with their IQ at a later age. Methods. The authors conducted a retrospective analysis of 538 cephalograms (obtained at a mean patient age of 1.16 years) from 95 patients. The BCP location and percentage of brain surface area covered were related to patient IQ scores obtained by the same psychologist using the Snijders-Oomen Nonverbal Intelligence Test-Revised, 51/2-17, and the Wechsler Preschool and Primary Scale of Intelligence-Revised. Results. As much as 71.6% of patients presented with a BCP before 18 months of age (mean surface area of BCP 20.3%, 93% of patients presented with bilateral BCPs). The mean IQ was 95 ± 21.3 (range 50-136) at a mean patient age of 8.4 ± 2.59 years. There was a significant increase in the surface area covered by BCPs in the first 3 years of life (p < 0.001) and a significant difference in IQs between syndromic (30 cases, mean IQ 88.9) and nonsyndromic craniosynostosis cases (54 cases, mean IQ 98.9, p = 0.03). No significant correlation was found between IQ and the appearance of BCPs on presurgery radiographs (Pearson correlation coefficient = 0.143, p = 0.19) or their location (Spearman rank correlation coefficient = 0.091, p = 0.45). The BCPs appeared predominantly in the occipital region (41.1%). Conclusions. Although the radiographic appearance of a BCP before the age of 18 months is an uncommon finding in healthy children, a craniosynostosis study group showed a preoperative BCP incidence of 71.6% and an increased incidence during the period of rapid brain expansion in the first 3 years of life. Note, however, that the presence of such a pattern had no significant long-term effect on patient intelligence levels. http://repub.eur.nl/res/pub/5852/ 2001-11-01T00:00:00Z We have previously reported a significant association between early-onset Alzheimer's disease (EOAD) and an allele in the promoter of presenilin 1 (PSEN1) significantly decreasing PSEN1 expression in vitro. For late-onset Alzheimer's disease (LOAD), numerous studies have reported inconsistent associations with a PSEN1 intronic polymorphism. We therefore hypothesized that linkage disequilibrium between the intronic PSEN1 polymorphism and the functional promoter polymorphism might explain the conflicting reports in LOAD. We analysed both variations in 356 LOAD patients and 230 controls in a population-based case-control study. In addition, we re-analysed all published literature on the PSEN1 intronic polymorphism in a meta-analysis. No significant association was found with the PSEN1 intronic or promoter polymorphism in our case-control sample. In the meta-analysis no major differences between patients and controls were found for the PSEN1 intronic variation. Together, our results do not support a major role for variable expression of PSEN1 in LOAD.