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 Veterans 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 allele. 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.

The authors have declared no competing interest.

Funding/support: Funding for ACCOuNT was provided by 1U54MD010723-01 from NIHMD (G.Y, C.A, N.H.L, E.N, M. T, T.O, L.G, T. K, D.M, M. A. P). This research is based on data from the Million Veteran Program, Office of Research and Development, Veterans Health Administration, and was supported by award #I01-BX003362 for MVP-003/028 to K.M.C., P.S.T. This work was supported using resources and facilities of the Department of Veterans Affairs (VA) Informatics and Computing Infrastructure (VINCI), VA HSR RES 13-457.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The study protocol was approved by the University of Chicago, University of Illinois, Chicago, Northwestern University, George Washington University and the DC Veterans Administration Hospital Institutional Review Boards. All participants provided written consent prior to the start of study procedures.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Genomic and de-identified clinical data for the ACCOuNT participants will be shared on the GEN3 platform at https://gen3.datacommons.io/discovery/ACCOuNT_Clopidogrel_Arm through a control access application. All relevant genetic data for the MVP cohort are available in the main paper and supplemental data. Individual data cannot be shared publicly according to the Data Access Policy of the Million Veteran Program in the VA Office of R&D in Veterans Health Administration.