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

Abstract

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 nonresponders. The mean PRU across the study cohort was 173.8 ± 68.5 and 33.5% 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 ~ 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 (rp = 0.35, p < 0.001). Moreover, the wPGxRS discriminated between nonresponders and responders (p = 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.

Evaluation of race and ethnicity disparities in outcome studies of CYP2C19 genotype-guided antiplatelet therapy

“…lacking. A notable exception is a recent study conducted in an admixed population of 474 Caribbean Hispanic ACS/PCI patients treated with clopidogrel across multiple sites in Puerto Rico (68). The average European, Native American, and African ancestry genomic proportions in the study population were 70, 11, and 19%, respectively.…”

“…Furthermore, because minority populations have been underrepresented in clopidogrel pharmacogenomics discovery studies, the presence and magnitude of effect of CYP2C19 no function alleles on antiplatelet effects and MACE risk in Black, Hispanic, and other underrepresented minority populations (e.g., Native American, Pacific Islander) remains unclear. It is possible that the effect size of these associations varies across populations and genotypes beyond CYP2C19 could be important in non-European and non-East Asian populations ( 68 , 93 ). Therefore, in the absence of outcome evidence, it may not be appropriate to assume effectiveness and generalize clinical recommendations for CYP2C19 genotype-guided antiplatelet therapy in populations that are underrepresented or excluded from these studies.…”

“…Rigorous studies seeking to identify genetic predictors of clopidogrel response in patients of African ancestry, Hispanic ethnicity, and other underrepresented populations have been lacking. A notable exception is a recent study conducted in an admixed population of 474 Caribbean Hispanic ACS/PCI patients treated with clopidogrel across multiple sites in Puerto Rico ( 68 ). The average European, Native American, and African ancestry genomic proportions in the study population were 70, 11, and 19%, respectively.…”

“…Notably, African ancestry was a significant independent predictor of clopidogrel response and an interaction between African ancestry and the PEAR1 variant was observed. Overall, approximately 19% of the variability in clopidogrel response was attributed to independent genetic and clinical factors, with CYP2C19*2 accounting for approximately 7% of the variability in this population ( 68 ). Together, these important and novel results demonstrated that CYP2C19 no function alleles are associated with reduced clopidogrel response in a diverse population of Caribbean Hispanic patients and suggest that the effect size of the CYP2C19*2 allele may be smaller compared to White populations, other genetic variants and ancestry may contribute to variation in clopidogrel response independent of CYP2C19 , and these effects may be augmented in patients of African ancestry.…”

Effect of CYP4F2 Polymorphisms on Ticagrelor Pharmacokinetics in Healthy Chinese Volunteers

“…Moreover, genetic variants of SLCO1B1 rs113681054, SLCO1B1*5 (rs4149056), and CYP3A5*3 (rs776746) were also reported to have no relevance in the PK of ticagrelor in healthy Chinese volunteers (Li et al, 2017a). Platelet endothelial aggregation receptor (PEAR1; location: 1q23.1) plays a vital role in platelet adhesion and platelet aggregation via sustaining αIIbβ3 activation (Duconge et al, 2021). Prior studies have confirmed that PEAR1 triggers PI3K/AKT/PTEN signaling, which leads to megakaryopoiesis and neoangiogenesis (Kauskot et al, 2013).…”