CYP2C19 genotype prevalence and association with recurrent myocardial infarction in British-South Asians treated with clopidogrel

Abstract

Abstract Background Pharmacogenomics examines how genes and drugs interact to explain some of the inter-individual variability in response to medications. CYP2C19 is a hepatic enzyme involved in the metabolism of clopidogrel from a prodrug to its active metabolite. Although the European Society of Cardiology and National Institute for Care Excellence recommend ticagrelor (a non CYP2C19 dependent P2Y12 antagonist) as the antiplatelet agent of choice, clopidogrel remains widely prescribed for acute coronary syndrome and myocardial infarction. CYP2C19 poor metabolizers are known to be more common in Asian ancestry but very few studies have looked specifically at South Asian populations or linked metabolizer diplotypes with clinical efficacy data in this population. The outcome studies on which clopidogrel was licensed for efficacy and safety did not include significant South Asian representation. Furthermore, South Asians are known to have a higher prevalence of cardio-metabolic disease compared with European ancestry populations. Methods We studied the Genes & Health cohort of British Bangladeshi and Pakistani ancestry participants to look at prevalence of CYP2C19 metabolizer genotypes and correlate these with recurrent myocardial infarction risk for those who had been prescribed clopidogrel in primary care. Multivariable regression was used to test for association between known CYP2C19 diptotypes and recurrent myocardial infarction in those prescribed clopidogrel, controlling for known CVD risk factors, percutaneous coronary intervention, age, and gender. Results Genes & Health cohort participants (N = 44,396) have a high prevalence (57%) of intermediate or poor CYP2C19 metabolizers, with at least 1 loss of function allele. The prevalence of poor metabolizers carrying 2 CYP2C19 loss of function alleles is 13%, which is higher than in previously studied European (2.4%) and Central/South Asian populations (8.2%). This is primarily due to the *2 LOF allele present in 56% of the population. 69% of the cohort who were diagnosed with an acute MI were prescribed clopidogrel. The presence of the poor metabolizer diplotype is significantly associated with higher risk of recurrent MI, or failed secondary prevention on clopidogrel in this population, OR 3.1 (p = 0.02), with some subsequent ischemic events already described in this young cohort (Acute MI prescribed clopidogrel N = 697, Recurrent MI in this group N=39). Conclusions A pharmacogenomic-driven approach to clopidogrel prescribing has the potential to impact significantly on clinical management and outcomes in individuals of Bangladeshi and Pakistani ancestry. In absence of genotype guided prescribing, maximal adherence to guidelines recommending non CYP2C19 dependent P2Y12 anti-platelet therapy is likely to be disproportionately beneficial in this ethnic cohort.Risk of recurrent MICentral illustration