Maitland-van der Zee, A-H.

Long-term anticoagulant effects of CYP2C9 and VKORC1 genotypes in phenprocoumon users (Article)

2012-12-01T00:00:00Z

Anticoagulant treatment with phenprocoumon is challenging because of the narrow therapeutic range and the wide inter- and intra-patient variability in dose response. Frequent monitoring of the international normalized ratio (INR) is therefore required. Polymorphisms in two genes, CYP2C9 and VKORC1 explain approximately one third of the variation in dose requirements [1-3]. CYP2C9 encodes the main metabolizing enzyme of coumarins, the cytochrome P450 2C9 enzyme (CYP2C9), while VKORC1 encodes the pharmacodynamic target enzyme for coumarins, vitamin K epoxide reductase multiprotein complex 1 (VKORC1).

The effect of omeprazole and esomeprazole on the maintenance dose of phenprocoumon (Letter To Editor)

2012-12-01T00:00:00Z

The response to vitamin K antagonists (VKAs) is determined by many different factors like age, weight, height, vitamin K intake and genetic polymorphisms [1]. The proton pump inhibitors (PPIs) omeprazole and esomeprazole may enhance the effect of VKAs by inhibition of the hepatic metabolism of coumarins [2]. Some isolated cases have been reported of clinically significant elevated INRs in patients concomitantly using omeprazole and phenprocoumon, a VKA frequently used in Europe [3].Practical experience suggests an interaction between omeprazole or esomeprazole and phenprocoumon, but scientific evidence is still lacking.

Cost-effectiveness of pharmacogenetics in anticoagulation: International differences in healthcare systems and costs (Article)

2012-09-01T00:00:00Z

Genotyping patients for CYP2C9 and VKORC1 polymorphisms can improve the accuracy of dosing during the initiation of anticoagulation with vitamin K antagonists (coumarin derivatives). The anticipated degree of improvement in the safety of anticoagulation with coumarins through genotyping may vary depending on the quality of patient care, which varies both with and among countries. The management and the cost of anticoagulant care can therefore influence the cost-effectiveness of genotyping within any given country. In this article, we provide an overview of the cost-effectiveness of pharmacogenetics-guided dosing of coumarin derivatives. We describe the organization of anticoagulant care in the UK, Sweden, The Netherlands, Greece, Germany and Austria, where a genotype-guided dosing algorithm is currently being investigated as part of the EU-PACT trial. We also explore the costs of anticoagulant care for the treatment of atrial fibrillation in these countries.

Long-term anticoagulant effects of the CYP2C9 and VKORC1 genotypes in acenocoumarol users (Article)

2012-04-01T00:00:00Z

Background: The required acenocoumarol dose and the risk of underanticoagulation and overanticoagulation are associated with the CYP2C9 and VKORC1 genotypes. However, the duration of the effects of these genes on anticoagulation is not yet known. Objectives: In the present study, the effects of these polymorphisms on the risk of underanticoagulation and overanticoagulation over time after the start of acenocoumarol were investigated. Patients/methods: In three cohorts, we analyzed the relationship between the CYP2C9 and VKORC1 genotypes and the incidence of subtherapeutic or supratherapeutic International Normalized Ratio (INR) values (<2 and >3.5) or severe overanticoagulation (INR>6) for different time periods after treatment initiation. Results: Patients with polymorphisms in CYP2C9 and VKORC1 had a higher risk of overanticoagulation (up to 74%) and a lower risk of underanticoagulation (down to 45%) in the first month of treatment with acenocoumarol, but this effect diminished after 1-6months. Conclusions: Knowledge of the patient's genotype therefore might assist physicians to adjust doses in the first month(s) of therapy.

Future of Pharmacogenetics in Cardiovascular Diseases (In Book)

2012-01-01T00:00:00Z

Introduction: Pharmacogenetics is the study of variations in DNA sequence as related to drug response (European Medicines Agency [EMA], 2007). Several gene-drug interactions have been discovered in the field of cardiovascular diseases (CVDs). These gene-drug interactions can help to identify nonresponse to drugs, estimate dose requirements or identify an increased risk of developing adverse drug reactions. An individualized approach based on pharmacogenetic testing will provide physicians and pharmacists with tools for decision making about pharmacotherapy. While pharmacogenetic testing is already part of everyday practice in oncology, it is not widely implemented in the field of CVDs. However, in the near future, pharmacogenetics will probably also play a valuable role in this field as well.

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.

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.

Uncontrolled asthma at age 8: The importance of parental perception towards medication (Article)

2011-08-01T00:00:00Z

Background: Despite existing effective treatment options, asthma is uncontrolled in a considerable proportion of patients. The aim of this study was to identify determinants of uncontrolled asthma at age 8 in children participating in the PIAMA birth cohort study. Methods: One hundred seventy children using inhaled corticosteroids in the previous 12months at age 8 were included. Uncontrolled asthma was defined as: ≥3 items present in the past month: (1) day-time or (2) night-time asthma symptoms, (3) limitations in activities, (4) rescue medication use, (5) FEV1<80% predicted and (6) unscheduled physician visits because of asthma. Binomial regression was performed to study five groups of determinants representing asthma control: child and parental characteristics, environmental factors, therapy adherence and parental perception towards medication use (Beliefs about Medicines Questionnaire). Results: Seventy seven children (45%) had uncontrolled asthma. Low maternal education (RR 1.6, 95% CI: 1.0-2.4) was associated with uncontrolled asthma. Parental necessity beliefs about medication use to maintain present and future health and parental concerns about potential adverse consequences of medication were also associated with uncontrolled asthma (RR 1.6, 95% CI: 1.1-2.2; and 1.6, 95% CI: 1.0-2.5, respectively). Conclusions: Environmental factors and therapy adherence were not associated with asthma control. In our cohort, uncontrolled asthma is associated with low maternal education and with strong parental beliefs about medication necessity and higher concern about potential side effects of medication.

Pharmacogenetics: From bench to byte an update of guidelines (Article)

2011-05-01T00:00:00Z

Currently, there are very few guidelines linking the results of pharmacogenetic tests to specific therapeutic recommendations. Therefore, the Royal Dutch Association for the Advancement of Pharmacy established the Pharmacogenetics Working Group with the objective of developing pharmacogenetics-based therapeutic (dose) recommendations. After systematic review of the literature, recommendations were developed for 53 drugs associated with genes coding for CYP2D6, CYP2C19, CYP2C9, thiopurine-S-methyltransferase (TPMT), dihydropyrimidine dehydrogenase (DPD), vitamin K epoxide reductase (VKORC1), uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1), HLA-B44, HLA-B*5701, CYP3A5, and factor V Leiden (FVL).

Practical recommendations for pharmacogenomics-based prescription: 2010 ESF-UB Conference on Pharmacogenetics and Pharmacogenomics (Article)

2011-01-01T00:00:00Z

The present article summarizes the discussions of the 3rd European Science Foundation-University of Barcelona (ESF-UB) Conference in Biomedicine on Pharmacogenetics and Pharmacogenomics, which was held in June 2010 in Spain. It was focused on practical applications in routine medical practice. We provide practical recommendations for ten different clinical situations, that have either been approved or not approved by regulatory agencies. We propose some comments that might accompany the results of these tests, indicating the best drug and doses to be prescribed. The discussed examples include KRAS, cetuximab, panitumumab, EGFR-gefitinib, CYP2D6-tamoxifen, TPMT-azathioprine-6- mercaptopurine, VKORC1/CYP2C9-warfarin, CYP2C19-clopidogrel, HLA-B*5701-abacavir, HLA-B*5701-flucloxacillin, SLCO1B1-statins and CYP3A5-tacrolimus. We hope that these practical recommendations will help physicians, biologists, scientists and other healthcare professionals to prescribe, perform and interpret these genetic tests.

High agreement between parental reported inhaled corticosteroid use and pharmacy prescription data (Article)

2010-11-01T00:00:00Z

Purpose: This study was conducted to assess the validity of parental reported use of inhaled corticosteroids (ICS) in children. Methods: ICS users were identified within the Prevention and Incidence of Asthma and Mite Allergy (PIAMA) birth cohort study and the PIAMA pharmacy sub-cohort which is nested within the PIAMA study. Complete medication histories were available for the first 8 years of life for children within the PIAMA pharmacy sub-cohort. Parental reported ICS use was measured by using data from questionnaires. ICS use in the pharmacy records was determined by using the Anatomical Therapeutic Chemical (ATC) codes. The proportion of overall agreement and kappa statistics with their corresponding 95% confidence intervals were calculated to quantify agreement between self-reported medication use and pharmacy prescription data. Results: At all ages overall agreement was very high (>97%) and Cohen's kappa's ranged from 0.80 to 0.88 which also reflects excellent agreement between parental reported use of ICS and pharmacy prescription data. Conclusions: Our finding suggests that parental report of medication use is a reliable source of data to asses ICS use in children. The questionnaire-based medication data collected within the PIAMA study can be used to study asthma medication use in a large group of children.

Patterns of asthma medication use: Early asthma therapy initiation and asthma outcomes at age 8 (Article)

2010-10-01T00:00:00Z

Wheeze has many underlying pathophysiologies in childhood, but is the main reason for anti-asthma drugs prescription. This study was conducted to describe asthma medication use patterns among children in their first eight years of life. Longitudinal medication use data from 777 children participating in the PIAMA study were used. Medication patterns were described for four groups that started therapy before the third birthday, when the peak in prescriptions occurred in our cohort; short-acting β-agonists (SABA), inhaled corticosteroids (ICS), SABA + ICS or none of these. One third (n = 255) of the children received a first SABA or ICS prescription before age 8. Only three children (1.2%) used medication continuously during follow-up. Of the children who started SABA, 53.8% discontinued within 1-2 years. Of the children who started ICS before age 3, 42.1% discontinued within 1-2 years and 31.6% received additional SABA. 41.5% of the children who started SABA + ICS used this short-term (≤1-2 years) and 21.5% long-term (≥3 years). Fifteen percent of children who did not start asthma therapy in their first 3 years of life did receive prescriptions between age 3 and 8. Children prescribed SABA + ICS before age 3 had the highest prevalence of hyper responsiveness at age 8, and similar prevalence of atopy as the other groups. Asthma medication is prescribed frequently in the first 8 years of life, particularly before age 3, and only few children use it continuously. ICS and SABA prescription occurs especially in those who were more likely to develop signs of asthma at age 8.

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.

Clinical and economic consequences of pharmacogenetic-guided dosing of warfarin (Article)

2010-08-01T00:00:00Z

Patients using warfarin for oral anticoagulant therapy need to be frequently monitored because of warfarins narrow therapeutic range and the large variation in dose requirements among patients. Patients receiving the wrong dose have an increased risk of bleeding or thromboembolic events. The required dose is influenced by environmental factors, such as gender, age, diet and concomitant medication, as well as genetic factors. Pharmacogenetic testing prior to warfarin initiation might improve dosing accuracy and, therefore, safety and efficacy of warfarin treatment. Meckley et al. studied the clinical consequences and costs of genotyping before warfarin treatment. The results of their study suggest that pharmacogenetic-guided dosing of patients initiating warfarin could improve health (quality-adjusted life-years) but at a high cost per quality-adjusted life-year gained. Owing to the inevitable assumptions that have to be made in all cost-effectiveness models, great uncertainty remains regarding the cost-effectiveness of pharmacogenetic-guided warfarin dosing.

A systematic review of cost-effectiveness analyses of pharmacogenetic- guided dosing in treatment with coumarin derivatives (Article)

2010-07-01T00:00:00Z

Anticoagulant therapy with coumarin derivatives is often sub-or supra-therapeutic, resulting in an increased risk of thromboembolic events or hemorrhage, respectively. Pharmacogenetic-guided dosing has been proposed as an effective way of reducing bleeding rates. Clinical trials to confirm the safety, efficacy and effectiveness of this strategy are ongoing, but in addition, it is also necessary to consider the cost-effectiveness of this strategy. This article describes the findings of a systematic review of published cost-effectiveness analyses of pharmacogenetic-guided dosing of coumarin derivatives. Similarities and differences in the approaches used were examined and the quality of the analyses was assessed. The results of the analyses are not sufficient to determine whether or not pharmacogenetic-guided dosing of coumarins is cost effective. More reliable cost-effectiveness estimates need to become available before it is possible to recommend whether or not this strategy should be applied in clinical practice.

Asthma therapy during the first 8 years of life: A pIAMA cohort study (Article)

2010-03-01T00:00:00Z

Objective. Many studies evaluated asthma medication use in children in a cross-sectional manner, yet little is known about longitudinal use patterns. This study describes the formation of a longitudinal data set on asthma medication use and shows first results regarding the prevalence and incidence of medication use. Methods. The PIAMA (Prevention and Incidence of Asthma and Mite Allergy) study is a prospective birth cohort study among 3963 Dutch children. Recruitment took place in 1996-1997. The data of the PIAMA birth cohort study were complemented with pharmacy data. Prescription information of family members was used to determine whether medication histories were complete from birth until age 8. The prevalence and incidence of asthma medication use was studied in children for whom complete medication histories were available. Results. A first prescription for asthma medication was filled before age 8 by 280 (36%) children, with 88% starting therapy before age 5. Of all children who started therapy, 91.1% received short-acting β2-agonists and 61.1% inhaled corticosteroids. Conclusion. The applied method of data collection rendered a data set including 777 children with complete medication histories for their first 8 years of life. This data set provides the opportunity to study longitudinal medication use patterns. First analyses show that asthma medication is initiated in a rather high percentage of children in this cohort and mainly at an age at which an asthma diagnosis cannot yet be firmly established.

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.

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.

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.

Genotype-guided dosing of coumarin derivatives: the European pharmacogenetics of anticoagulant therapy (EU-PACT) trial design (Article)

2009-10-01T00:00:00Z

The narrow therapeutic range and wide interpatient variability in dose requirement make anticoagulation response to coumarin derivatives unpredictable. As a result, patients require frequent monitoring to avert adverse effects and maintain therapeutic efficacy. Polymorphisms in VKORC1 and CYP2C9 jointly account for about 40% of the interindividual variability in dose requirements. To date, several pharmacogenetic-guided dosing algorithms for coumarin derivatives, predominately for warfarin, have been developed. However, the potential benefit of these dosing algorithms in terms of their safety and clinical utility has not been adequately investigated in randomized settings. The European Pharmacogenetics of Anticoagulant Therapy (EU-PACT) trial will assess, in a single-blinded and randomized controlled trial with a follow-up period of 3 months, the safety and clinical utility of genotype-guided dosing in daily practice for the three main coumarin derivatives used in Europe. The primary outcome measure is the percentage time in the therapeutic range for international normalized ratio. This report describes the design and protocol for the trial.

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.

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.

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.

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.

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

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.