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

Guang Yang, Department of Pharmacology, Center for Pharmacogenomics, Fienberg School of Medicine, Northwestern University, Chicago IL.
Cristina Alarcon, Department of Pharmacology, Center for Pharmacogenomics, Fienberg School of Medicine, Northwestern University, Chicago IL.
Catherine Chanfreau, VA Salt Lake City Heath Care System, Salt Lake City, UT.
Norman H. Lee, Department of Pharmacology and Physiology, George Washington University, 2300 I Street NW, Washington, DC, 20037, USA.
Paula Friedman, Department of Pharmacology, Center for Pharmacogenomics, Fienberg School of Medicine, Northwestern University, Chicago IL.
Edith Nutescu, Department of Pharmacy Practice and Center for Pharmacoepidemiology and Pharmacoeconomic Research, University of Illinois Chicago, College of Pharmacy, Chicago, IL.
Matthew Tuck, Washington DC VA Medical Center, Washington, DC and The George Washington University, Washington, DC.
Travis O'Brien, Department of Pharmacology and Physiology, George Washington University, 2300 I Street NW, Washington, DC, 20037, USA.
Li Gong, Department of Biomedical Data Science, Stanford University, Stanford, CA.
Teri E. Klein, Department of Biomedical Data Science and Department of Medicine, Stanford University, Stanford, CA.
Kyong-Mi Chang, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA.
Philip S. Tsao, VA Palo Alto Healthcare System and Stanford University, Palo Alto, CA.
David O. Meltzer, Section of Hospital Medicine, Department of Medicine, University of Chicago, Chicago, IL.

Document Type

Journal Article

Publication Date

12-7-2023

Journal

medRxiv : the preprint server for health sciences

DOI

10.1101/2023.12.05.23299140

Abstract

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 (, as significantly associated with increasing risk of HTPR (p = 4.56 × 10). Higher 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 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 expression to HTPR. knockdown in a MEG-01 cells resulted in increased expression of SYK and AKT1, suggesting an inhibitory role of in the Glycoprotein VI pathway. Notably, the variants showed no association with clopidogrel response in the discovery or MVP cohorts. In summary, these finding suggest that other variants outside of star alleles play an important role in clopidogrel response in African Americans.

Department

Pharmacology and Physiology

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