Discovery of Ancestry-specific Variants Associated with Clopidogrel Response among Caribbean Hispanics.

Autor:	Yang G; Department of Pharmacology, Center for Pharmacogenomics, Feinberg School of Medicine, Northwestern University, Chicago IL 60611, United States., González P; Department of Pharmacology, School of Medicine, University of Puerto Rico - Medical Sciences Campus, San Juan, Puerto Rico, 00936, United States., Moneró M; Department of Pharmacology, School of Medicine, University of Puerto Rico - Medical Sciences Campus, San Juan, Puerto Rico, 00936, United States., Carrasquillo K; Research Centers in Minority Institutions (RCMI) Program, Center for Collaborative Research in Health Disparities (CCRHD), Academic Affairs Deanship, University of Puerto Rico - Medical Sciences Campus, San Juan, Puerto Rico, 00936, United States., Renta JY; Research Centers in Minority Institutions (RCMI) Program, Center for Collaborative Research in Health Disparities (CCRHD), Academic Affairs Deanship, University of Puerto Rico - Medical Sciences Campus, San Juan, Puerto Rico, 00936, United States., Hernandez-Suarez DF; Department of Translational Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, United States., Botton MR; Transplant Immunology and Personalized Medicine Unit, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil., Melin K; Department of Pharmacy Practice, School of Pharmacy, University of Puerto Rico - Medical Sciences Campus, San Juan, Puerto Rico, 00936, United States., Scott SA; Department of Pathology, Stanford University, Palo Alto, CA 94304, United States., Ruaño G; Institute of Living at Hartford Hospital, Hartford, CT 06102, United States., Roche-Lima A; Research Centers in Minority Institutions (RCMI) Program, Center for Collaborative Research in Health Disparities (CCRHD), Academic Affairs Deanship, University of Puerto Rico - Medical Sciences Campus, San Juan, Puerto Rico, 00936, United States., Alarcon C; Department of Pharmacology, Center for Pharmacogenomics, Feinberg School of Medicine, Northwestern University, Chicago IL 60611, United States., Ritchie MD; Department of Genetics and Institute for Biomedical Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, United States., Perera MA; Department of Pharmacology, Center for Pharmacogenomics, Feinberg School of Medicine, Northwestern University, Chicago IL 60611, United States., Duconge J; Research Centers in Minority Institutions (RCMI) Program, Center for Collaborative Research in Health Disparities (CCRHD), Academic Affairs Deanship, University of Puerto Rico - Medical Sciences Campus, San Juan, Puerto Rico, 00936, United States.; Department of Pharmaceutical Sciences, School of Pharmacy, University of Puerto Rico - Medical Sciences Campus, San Juan, Puerto Rico, 00936, United States.
Jazyk:	angličtina
Zdroj:	MedRxiv : the preprint server for health sciences [medRxiv] 2023 Oct 02. Date of Electronic Publication: 2023 Oct 02.
DOI:	10.1101/2023.09.29.23296372
Abstrakt:	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 Interests: Conflicts of Interest: The authors have no conflict of interest to declare.
Databáze:	MEDLINE
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