Investigation of genomic and transcriptomic risk factors in clopidogrel response in African Americans.

UNLABELLED: Clopidogrel, an anti-platelet drug, used to prevent thrombosis after percutaneous coronary intervention. Clopidogrel resistance results in recurring ischemic episodes, with African Americans suffering disproportionately. The aim of this study was to identify biomarkers of clopidogrel resistance in African American patients. We conducted a genome-wide association study, including local ancestry adjustment, in 141 African Americans on clopidogrel to identify associations with high on-treatment platelet reactivity (HTPR). We validated genome-wide and suggestive hits in an independent cohort of African American clopidogrel patients (N = 823) from the Million Veteran's Program (MVP) along with in vitro functional follow up. We performed differential gene expression (DGE) analysis in whole blood with functional follow-up in MEG-01 cells. We identified rs7807369, within thrombospondin 7A ( THSD7A), as significantly associated with increasing risk of HTPR (p = 4.56 x 10 -9 ). Higher THSD7A expression was associated with HTPR in an independent gene expression cohort of clopidogrel treated patients (p = 0.004) and supported by increased gene expression on THSD7A in primary human endothelial cells carrying the risk haplotype. Two SNPs (rs1149515 and rs191786) were validated in the MVP cohort. DGE analysis identified an association with decreased LAIR1 expression to HTPR. LAIR1 knockdown in a MEG-01 cells resulted in increased expression of SYK and AKT1, suggesting an inhibitory role of LAIR1 in the Glycoprotein VI pathway. Notably, the CYP2C19 variants showed no association with clopidogrel response in the discovery or MVP cohorts. In summary, these finding suggest that other variants outside of CYP2C19 star alleles play an important role in clopidogrel response in African Americans.

KEY POINTS: SNPs within THSD7A were associated to clopidogrel resistance in African Americans. THSD7A gene expression is higher in patients with clopidogrel resistance and in endothelial cells carrying the risk variants. No association to high on therapy platelet reactivity or major adverse cardiac events was seen with CYP2C19 star alleles in either the African American cohort investigated. Decreased LAIR1 gene expression in blood was associated to risk of HTPR and showed downstream effect on SKY and AKT.