Investigation of Genomic and Transcriptomic Risk Factors of Clopidogrel Response in African Americans

Clopidogrel, an anti-platelet drug, is used to prevent thrombosis after percutaneous coronary intervention. Clopidogrel resistance results in recurring ischemic events, with African Americans (AA) suffering disproportionately. The aim of this study was to discover novel biomarkers of clopidogrel resistance in African Americans using genome and transcriptome data. We conducted a genome-wide association study (GWAS), including local ancestry adjustment, in 141 AA on clopidogrel to identify genetic associations with high on-treatment platelet reactivity (HTPR), with validation of genome-wide significant and suggestive loci in an independent cohort of AA clopidogrel patients (N = 823) from the Million Veteran's Program (MVP) along with in vitro functional analysis. We performed differential gene expression (DGE) analysis in whole blood to identify transcriptomic predictors of response, followed by functional validation in MEG-01 cells. GWAS identified one signal on Chromosome 7 as significantly associated with increasing risk of HTPR. The lead single-nucleotide polymorphism (SNP), rs7807369, within thrombospondin 7A (THSD7A) was associated with an increased risk of HTPR (odds ratio (OR) = 4.02, P = 4.56 × 10^-9). Higher THSD7A gene expression was associated with HTPR in an independent cohort of clopidogrel-treated patients (P = 0.004) and carrying a risk allele showed increased gene expression in primary human endothelial cells. Notably, the CYP2C19*2 variants showed no association with clopidogrel response in the discovery or MVP cohorts. DGE analysis identified an association with decreased LAIR1 and AP3B2 expression to HTPR. LAIR1 knockdown in MEG-01 cells resulted in increased expression of SYK and AKT1, suggesting an inhibitory role of LAIR1 in the Glycoprotein VI pathway. In summary, these findings suggest that other variants and genes outside of CYP2C19 star alleles play an important role in clopidogrel response in AA.