Single nucleotide polymorphism of CYP3A5*3 contributes to clopidogrel resistance in coronary artery disease patients among Tamilian population

Abstract

Clopidogrel is an antiplatelet drug. It is used for the treatment as well as for the prophylaxis of coronary artery disease. Clopidogrel resistance is an emerging problem in clinical settings. The aim of the present study was to evaluate the effect of CYP3A5*3 genetic polymorphism on clopidogrel resistance. One hundred and forty-seven patients from outpatient Department of Cardiology on 75 mg/day of clopidogrel as maintenance dose were recruited from April 2010 to July 2011. All subjects gave written informed consent to participate in the study. DNA extraction was performed using phenol chloroform extraction procedure and genotyping by standard Taqman based RT-PCR method. Platelet aggregation was done at the end of 7th and 14th day by using chronolog lumi Aggregometer which is expressed as impedance in ohms. Impedance values of >5 ohms at the end of 6 min were considered as clopidogrel resistance. Subjects (N = 147) were analysed for CYP3A5*3 polymorphism, of which 49 (33%) were found to be clopidogrel resistant. Homomutants of CYP3A5*3 gene had 2.78 (0.97-7.98; p < 0.05) fold risk and heteromutants had 2.4 (0.93-6.46; p < 0.05) fold risk of developing clopidogrel resistance. Carriers of defective allele G of CYP3A5*3 had higher propensity to cause clopidogrel resistance with an odds ratio of 1.63. Variant alleles and genotypes of CYP3A5*3 polymorphism contributed significantly to clopidogrel resistance with a higher odds ratio. Thus, pharmacogenomics paves way for the emergence of stratified medicine in clopidogrel therapy and personalised pharmacotherapy in ischaemic heart disease.

Association of Cytochrome P450 Genetic Variants with Clopidogrel Resistance and Outcomes in Acute Ischemic Stroke

“…SNPs may affect clopidogrel activation, which could also contribute to the adverse events of this prodrug. Variant alleles and genotypes of CYP3A5*3 polymorphism contributed significantly to clopidogrel resistance with a higher OR 32) . Suh et al 33) also revealed an increased frequency of atherothrombotic events within six months after coronary angioplasty in patients with the CYP3A5 nonexpression genotype ( CYP3A5*3 ).…”

No Effect of <i>SLCO1B1</i> and <i>CYP3A4/5</i> Polymorphisms on the Pharmacokinetics and Pharmacodynamics of Ticagrelor in Healthy Chinese Male Subjects

“…43) Evidence also revealed that CYP3A5*3 was associated with clopidogrel response and clinical outcomes. [44][45][46] Currently, few studies investigated the association of genetic polymorphisms with ticagrelor response. The polymorphisms in P2Y12, P2Y1, and ITGB3 have no effect on platelet aggregation in ticagrelor-treated patients with atherosclerotic disease.…”

Cytochrome allelic variants and clopidogrel metabolism in cardiovascular diseases therapy

“…Park et al, for example, concluded that CYP3A5 genetic status plays an important role in the clinical efficacy of clopidogrel in a prospective cohort study involved 1258 Caucasian patients; out of which the wild type number was 509 and the variant CYP3A5*3 was 749 [35]. Among the Tamil population, it was found that a single nucleotide polymorphism (SNP) of the cytochrome CYP3A5*3 contributes to clopidogrel resistance [36].…”