Pharmacogenomic polygenic risk score for clopidogrel responsiveness among Caribbean Hispanics: A candidate gene approach

This multicenter clinical study was aimed at conducting a targeted pharmacogenomic association analysis of residual on-clopidogrel platelet reactivity in 474 Caribbean Hispanic patients. Platelet reactivity was measured using the VerifyNow P2Y12 assay and clopidogrel resistance was defined as P2Y12 reaction units (PRUs) greater than or equal to 208. Genotyping was performed using the whole-genome Infinium MEGA BeadChip array. An ancestry-adjusted, weighted polygenic risk score (wPGxRS) was developed to account for the effect of multiple variants on PRU and compared between clopidogrel responders and non-responders. The mean PRU across the study cohort was 173.8 +/- 68.5 and 333% of patients were defined as clopidogrel resistant. Multivariate linear regression showed that 19% of PRU variability was attributed to nine independent predictors, with CYP2C19*2 (rs4244285) accounting for similar to 7% of observed PRU variation (p < 0.001). PON1 rs662, ABCB1/MDR1 rs2032582, PEAR1 rs12041331 carrier status, and the interaction between African ancestry and rs12041331 carriers also predicted PRU among the participants (p < 0.05). A clear gene-dose effect was detected between PRU and CYP2C19*2 genotype, consistent with previous studies in European patient populations, as well as rs12777823. Importantly, a significant positive correlation was detected between our novel wPGxRS (4 variants) and PRU among the Hispanic patient population (r p = 0.35, p < 0.001). Moreover, the wPGxRS discriminated between nonresponders and responders = 0.003), indicating that this multigene-based score is a useful predictor of clopidogrel resistance among Caribbean Hispanics. Taken together, these results help close the gap of knowledge on clopidogrel pharmacogenomics and its potential clinical implementation in this under-represented population. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? CYP2C19*2 is significantly associated with an impaired response to clopidogrel in patients of mainly European ancestry, but this genetic variant accounts for only a small fraction of observed variability in clopidogrel resistance. WHAT QUESTION DID THIS STUDY ADDRESS? This study answers the question of whether there is an association of relevant candidate pharmacogenes involved in clopidogrel absorption, metabolism, and pharmacodynamics with antiplatelet response among Caribbean Hispanics using a multigene-based score approach. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? This study closes the existing gap of knowledge about clopidogrel pharmacogenomics in Caribbean Hispanics by both confirming and identifying relevant genetic determinants of clopidogrel responsiveness in this underrepresented population after developing an ancestry-based polygenic risk score model. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? By gaining a better understanding of underlying determinants of poor clopidogrel response among marginally represented groups, such as Caribbean Hispanics, worldwide efforts to translate such findings into a global precision medicine paradigm of true benefit for everyone can finally bring cardiovascular health equity to the population at large.