Search

Clopidogrel with aspirin is standard of care for the secondary prevention of ischemic events in patients with acute coronary syndromes. However, substantial inter-individual variation in clopidogrel response results in sub-optimal therapy in some patients and an increased risk of recurrent events. Up to 73% of the variation in clopidogrel efficacy is found to be heritable, and while key genetic variants such as CYP2C19 *2 have been identified, a large portion of the genetic heritability remains unaccounted for. To date, few studies have used clopidogrel active metabolite to evaluate clopidogrel pharmacogenomics. The evaluation of this biomarker may be particularly informative as it enables us to focus almost exclusively on clopidogrel pharmacokinetics and may allow new discoveries leading to a more thorough understanding of clopidogrel activation. Serum clopidogrel active metabolite concentration was measured by HPLC-MS/MS in 506 healthy, Amish participants of the Pharmacogenomics of Anti-Platelet Intervention (PAPI) Study after a 7-day 75-mg/day clopidogrel intervention. Genome-wide genotyping was performed using Affymetrix 5.0 and 6.0 arrays, and SNPs were imputed to the 1000 Genomes cosmopolitan panel. Mixed models analysis was conducted under an additive model and adjusted for age, sex, BMI, and relatedness among study participants with MMAP (http://edn.som.umaryland.edu/mmap). The most significant signal of our GWAS was the previously identified CYP2C19 / CYP2C9 locus (P= 9.2x10 -15 ), and was fully accounted for by the CYP2C19 *2 variant. In addition to this signal, novel genome-wide significant signals were identified in loci on Chr. 3 (rs187941554, P=4.7x10 -11 ), Chr. 7 (rs73407739, p=3.6x10 -8 ), and Chr. 17 (rs80343429, P=3.7x10 -8 ). In this study we conducted the first ever GWAS of serum clopidogrel active metabolite concentration. Novel associations for clopidogrel efficacy were identified, and further study is required to determine the impact of these variants on clinical care Continual analysis of clopidogrel active metabolite concentration will contribute to a better understanding of the clopidogrel metabolic pathway, and potentially lay the groundwork for improved anti-platelet treatment for CVD patients in the future.

Objective— The vitamin D endocrine system is essential for calcium homeostasis, and low levels of vitamin D metabolites have been associated with cardiovascular disease risk. We hypothesized that DNA sequence variation in genes regulating vitamin D metabolism and signaling pathways might influence variation in coronary artery calcification (CAC). Methods and Results— We genotyped single-nucleotide polymorphisms (SNPs) in GC , CYP27B1, CYP24A1 , and VDR and tested their association with CAC quantity, as measured by electron beam computed tomography. Initial association studies were carried out in a discovery sample comprising 697 Amish subjects, and SNPs nominally associated with CAC quantity (4 SNPs in CYP24A1 , P =0.008 to 0.00003) were then tested for association with CAC quantity in 2 independent cohorts of subjects of white European ancestry (Genetic Epidemiology Network of Arteriopathy study [n=916] and the Penn Coronary Artery Calcification sample [n=2061]). One of the 4 SNPs, rs2762939, was associated with CAC quantity in both the Genetic Epidemiology Network of Arteriopathy ( P =0.007) and Penn Coronary Artery Calcification ( P =0.01) studies. In all 3 populations, the rs2762939 C allele was associated with lower CAC quantity. Metaanalysis for the association of this SNP with CAC quantity across all 3 studies yielded a P value of 2.9×10 −6 . Conclusion— A common SNP in the CYP24A1 gene was associated with CAC quantity in 3 independent populations. This result suggests a role for vitamin D metabolism in the development of CAC quantity.