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Rotterdam, Netherlands

van den Besselaar A.M.H.P.,Leiden University | Biedermann J.S.,Erasmus Medical Center | Biedermann J.S.,Star Medical Diagnostic Center | Kruip M.J.H.A.,Erasmus Medical Center | Kruip M.J.H.A.,Star Medical Diagnostic Center
Thrombosis and Haemostasis

Many patients treated with vitamin K antagonists (VKA) determine their INR using point-of-care (POC) whole blood coagulation monitors. The primary aim of the present study was to assess the INR within-subject variation in self-testing patients receiving a constant dose of VKA. The second aim of the study was to derive INR imprecision goals for whole blood coagulation monitors. Analytical performance goals for INR measurement can be derived from the average biological within-subject variation. Fifty-six Thrombosis Centres in the Netherlands were invited to select self-testing patients who were receiving a constant dose of either acenocoumarol or phenprocoumon for at least six consecutive INR measurements. In each patient, the coefficient of variation (CV) of INRs was calculated. One Thrombosis Centre selected regular patients being monitored with a POC device by professional staff. Sixteen Dutch Thrombosis Centres provided results for 322 selected patients, all using the CoaguChek XS. The median withinsubject CV in patients receiving acenocoumarol (10.2 %) was significantly higher than the median CV in patients receiving phenprocoumon (8.6 %) (p = 0.001). The median CV in low-target intensity acenocoumarol self-testing patients (10.4 %) was similar to the median CV in regular patients monitored by professional staff (10.2 %). Desirable INR analytical imprecision goals for POC monitoring with CoaguChek XS in patients receiving either low-target intensity acenocoumarol or phenprocoumon were 5.1 % and 4.3 %, respectively. The approximate average value for the imprecision of the CoaguChek XS, i. e. 4 %, is in agreement with these goals. © Schattauer 2015. Source

De Keyser C.E.,Erasmus MC | Becker M.L.,Erasmus MC | Hofman A.,Erasmus MC | Lous J.J.,Star Medical Diagnostic Center | And 6 more authors.
Pharmacogenetics and Genomics

OBJECTIVE: Recently, the minor allele of the rs13064411A>G polymorphism in the WD repeat domain 52 (WDR52) gene was associated with increased statin-induced proprotein convertase subtilisin/kexin type 9 (PCSK9) levels and with LDL cholesterol response to statins. PCSK9 promotes LDL receptor degradation, leading to increased serum LDL cholesterol. We investigated whether the polymorphism was associated with cholesterol response to statins. METHODS: We identified 1105 current, 322 past, and 4831 never statin users during follow-up in the prospective population-based Rotterdam Study. The mean delta total, LDL, and HDL cholesterol levels between current and no current statin users with the same number of minor alleles were analyzed using random-effect repeated measurements. We adjusted for age, sex, number of cholesterol measurements, and follow-up time. RESULTS: Compared with no users with the same genotype, current statin users carrying a minor allele showed a statistically significantly lower delta total and LDL cholesterol compared with reference homozygous major allele carriers [total: Δ=0.551mmol/l (AG+GG) vs. Δ=0.732mmol/l (AA), Pinteraction: 5.2×10-7; LDL: Δ=0.566mmol/l (AG+GG) vs. Δ=0.720mmol/l (AA), Pinteraction: 1.8×10-5]. The effect was stronger in women (Pinteraction: 2.0×10-5 for LDL cholesterol, 8.0×10-6 for total cholesterol) and in high-dose users (defined daily doses>1.00) (Pinteraction: 7.0×10-5 for LDL cholesterol, Pinteraction: 0.081 for total cholesterol). The polymorphism was not associated with HDL cholesterol in current statin users, or with total, LDL and HDL cholesterol in never statin users. CONCLUSION: The minor G allele of the rs13064411 polymorphism, associated with statin-induced PCSK9-levels, was associated with a decreased LDL-lowering and total cholesterol-lowering response to statins. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Source

Klijs B.,Erasmus MC | Otto S.J.,Erasmus MC | Heine R.J.,VU University Amsterdam | Heine R.J.,Eli Lilly and Company | And 3 more authors.
BMC Public Health

Background: We describe the design and present the results of the first year of a population-based study of screening for type 2 diabetes in individuals at high risk of developing the disease. High risk is defined as having abdominal obesity. Methods. Between 2006 and 2007, 79,142 inhabitants of two Dutch municipalities aged 40-74 years were approached to participate in screening. Eligible participants had a self-reported waist circumference of 80 cm for women and 94 cm for men, and no known pre-existing diabetes. Of the respondents (n=20,578; response rate 26%), 16,135 were abdominally obese. In total, 10,609 individuals gave written informed consent for participation and were randomized into either the screening (n=5305) or the control arm (n=5304). Participants in the screening arm were invited to have their fasting plasma glucose (FPG) measured and were referred to their general practitioner (GP) if it was 6.1 mmol/L. In addition, blood lipids were determined in the screening arm, because abdominal obesity is often associated with cardiovascular risk factors. Participants in both arms received written healthy lifestyle information. Between-group differences were analyzed with Chi-square tests and logistic regression (categorical variables) and unpaired t-tests (continuous variables). Results: The screening attendance rate was 84.1%. Attending screening was associated with age at randomization (OR=1.03, 95% CI 1.02-1.04), being married (OR=1.57, 95% CI 1.33-1.83) and not-smoking currently (OR=0.52, 95% CI 0.44-0.62). Of the individuals screened, 5.6% had hyperglycemia, and a further 11.6% had an estimated absolute cardiovascular disease risk of 5% or higher, according to the Systematic Coronary Risk Evaluation risk model. These participants were referred to their GP. Conclusions: Self-reported home-assessed waist circumference could feasibly detect persons at high risk of hyperglycemia or cardiovascular disease. Continuation of the large-scale RCT is warranted to test the hypothesis that targeted population-based screening for type 2 diabetes leads to a significant reduction in cardiovascular morbidity and mortality. © 2012 Klijs et al.; licensee BioMed Central Ltd. Source

De Keyser C.E.,Erasmus Medical Center | Becker M.L.,Erasmus Medical Center | Uitterlinden A.G.,Erasmus Medical Center | Hofman A.,Erasmus Medical Center | And 6 more authors.

Aim: Recently, minor alleles of two strongly linked polymorphisms in the PPARA gene, rs4253728 G>A and rs4823613 A>G, were related to decreased CYP3A4 expression and activity. We studied whether they were associated with the cholesterol-lowering effect of simvastatin. Materials and methods: We identified 123 incident users with cholesterol measurements before and after starting statin therapy in a prospective population-based cohort study. Associations between PPARA polymorphisms and change in total and low-density lipoprotein (LDL)-cholesterol levels were analyzed using linear regression. Results: The minor G allele of the rs4823613 A>G polymorphism was associated with a 0.258 mmol/l (95% CI:-0.470 to-0.046) and a 0.294 mmol/l (95% CI:-0.495 to-0.093) larger reduction in total and LDL-cholesterol, respectively, after starting simvastatin therapy. Results were similar for the rs4253728 G>A polymorphism. Conclusion: The minor alleles of the PPARA rs4253728 and rs4823613 polymorphisms are associated with a better total and LDL-cholesterol-lowering response to simvastatin, possibly through influence on CYP3A4. © 2013 Future Medicine Ltd. Source

Teichert M.,Erasmus Medical Center | Teichert M.,Scientific Institute Dutch Pharmacists | Eijgelsheim M.,Erasmus Medical Center | Uitterlinden A.G.,Erasmus Medical Center | And 7 more authors.
Pharmacogenetics and Genomics

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. CYP2C9 and CYP4F2 were of modest relevance. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins. Source

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