Abstract
Background High on-treatment platelet reactivity (HTPR) with clopidogrel is predictive of ischemic events in adults with coronary artery disease. Despite strong data suggesting HTPR varies with ethnicity, including clinical and genetic variables, no genome-wide association study (GWAS) of clopidogrel response has been performed among Caribbean Hispanics. This study aimed to identify genetic predictors of HTPR in a cohort of Caribbean Hispanic cardiovascular patients from Puerto Rico.
Methods Local Ancestry inference (LAI) and traditional GWASs were performed on a cohort of 511 clopidogrel-treated patients, stratified based on their P2Y12 reaction units (PRU) into responders and non-responders (HTPR).
Results The LAI GWAS identified variants within the CYP2C19 region associated with HTPR, predominantly driven by individuals of European ancestry and absent in those with native ancestry. Incorporating local ancestry adjustment notably enhanced our ability to detect associations. While no loci reached traditional GWAS significance, three variants showed suggestive significance at chromosomes 3, 14 and 22 (OSBPL10 rs1376606, DERL3 rs5030613, and RGS6 rs9323567). In addition, a variant in the UNC5C gene on chromosome 4 was associated with an increased risk of HTPR. These findings were not identified in other cohorts, highlighting the unique genetic landscape of Caribbean Hispanics.
Conclusion This is the first GWAS of clopidogrel response in Hispanics, confirming the relevance of the CYP2C19 cluster, particularly among those with European ancestry, and also identifying novel markers in a diverse patient population. Further studies are warranted to replicate our findings in other diverse cohorts and meta-analyses.
Competing Interest Statement
The authors have declared no competing interest.
Clinical Trial
NCT03419325
Funding Statement
This work was supported in part by CCRHD-RCMI grant #2U54 MD007600-33 from the National Institute on Minority Health and Health Disparities (NIMHD) of the National Institutes of Health (NIH), the 2023 Pharmacogenomics Global Research Network (PGRN) Research Collaboration Grant, the 1U54 MD010723 from the NIMHD, NIH, and by the National Institute of General Medical Sciences (NIGMS)-Research Training Initiative for Student Enhancement (RISE) Program grant R25 GM061838.
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IRB-approved protocol #A4070417. The IRB office at UPR-MSC (IORG000223; Federal-wise Assurance #FWA00005561) is approved by the Office for Human Research Protection (OHRP), Department of Health and Human Services.
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Footnotes
↵¶ As trainees, they are allowed to list their names as first author on their respective CVs.
Data Availability
The authors confirm that the main data supporting the findings of this study are available within the article and its supplementary materials. The complete data that support the findings of this study will be available in dbGaP at https://www.ncbi.nlm.nih.gov/gap/ (accession number: phs003236.v1.p1), upon request (controlled access).