Tandon3, Vinod Scaria¶,4. & Dwaipayan. Bharadwaj*,¶,1. 1Genomics & Molecular Medicine Unit,. CSIR-Insfitute of Genomics &. Integrafive Biology, Mathura ...
RESEARCH ARTICLE Pharmacogenetic landscape of clopidogrel in north Indians suggest distinct interpopulation differences in allele frequencies Aim: Clopidogrel, a widely used antiplatelet drug, exhibits high interindividual variability; more than 80% of which could be explained by genetic polymorphisms. We built an allele frequency map of variants affecting clopidogrel response in north Indians. Materials & methods: We mined a cross-sectional population-scale genome-wide dataset of 2128 Indo-Europeans residing in north India for presence of variants associated with pharmacogenetics of clopidogrel. Results: Our analysis reveals significant differences in population-scale allele frequencies between Indians and the global population. Indians had a higher allele frequency for variants in the CYP2C9*2, CYP2C9*3 and P2RY1 genes whereas lower frequency for the ABCB1, CYP1A2, CYP2C19*2C, CYP3A5 and PON1 genes compared with the global population. Furthermore, from our study we proposed a model to explain the higher prevalence of clopidogrel metabolizers in north Indians. Conclusion: This is the largest population-scale genetic epidemiology study that provides a high-resolution map of variants associated with clopidogrel response that could be potentially valuable to clinicians to rationally plan appropriate dosage for therapy in resource poor conditions based on population level allele frequencies. Original submitted 29 August 2013; Revision submitted 2 December 2013 KEYWORDS: ABCB1 allele frequency clopidogrel genetic mining Indo-European pharmacogenomics PON1
Clopidogrel is one of the most widely used antiplatelet drugs and it is widely prescribed for prevention of ischemic cerebrovascular disease [1,2] . It is estimated that approximately 30% of treated patients show ineffective response to clopidogrel [3] . Available data suggest a wide interindividual variability in dose response in clinical settings and this remains a major issue for precisely dosing each patient for effective therapy. Clopidogrel is a prodrug and is converted into an active form by a complex sequential process including absorption, bioactivation and binding to the cognate target ( SUPPLEMENTARY FIGURE 1 ; www.futuremedicine.com/doi/suppl/10.2217/ pgs.13.241). Among various potential factors that regulate interindividual variability of clopidogrel response, genetic polymorphisms in genes (ABCB1, CYP3A4, CYP3A5, CYP2C9, CYP2C19, PON1 and P2RY12) involved in drug metabolism play a crucial role. However, under resource limited and time critical situations the screening for the variants is not practical in routine clinical settings, while genome-scale approaches towards elucidating pharmacogenomics profiles of individuals are enormously costly [4] . The differences in response to clopidogrel in individuals from different ethnic/population
backgrounds have been established. Thomson et al. in his cross sectional studies reported that clopidogrel nonresponse is prevalent among Indian patients, which was further supported by the findings of Kumar et al. who demonstrated a significant proportion of clopidogrel resistance in north Indian patients with acute coronary syndrome [5,6] . A recent study by Chan et al., demonstrated that Indians differ from Chinese and Malay individuals in harboring genetic polymorphisms that affect clopidogrel response [7] . The varied clopidogrel response among individuals from different populations and with different ethnic backgrounds could be owing to differences in genetic make up. The ethnicity-based differences in drug doses to achieve a definite response can be envisaged by analyzing relevant allele frequencies in ethnic groups. The availability of genotyping microarrays encompassing thousands of markers and popularly used for genome-wide association studies (GWAS), provides a new opportunity to analyze the genetic epidemiology of trait-associated markers in different populations. In the present study, we used genotypes from over 2000 individuals from a cross-sectional study for Type 2 diabetes to analyze the genetic epidemiology of clopidogrel pharmacogenetics [8] . To the best of
10.2217/PGS.13.241 © 2014 Future Medicine Ltd
Pharmacogenomics (2014) 15(5), 643–653
Anil K Giri‡,1, Nazir M Khan‡,1, INDICO§, Analabha Basu2, Nikhil Tandon3, Vinod Scaria¶,4 & Dwaipayan Bharadwaj*,¶,1 1
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