{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T17:44:50Z","timestamp":1791999890934,"version":"4.4.0"},"reference-count":50,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2025,1,27]],"date-time":"2025-01-27T00:00:00Z","timestamp":1737936000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2025,5]]},"abstract":"<jats:p>\n                    Clopidogrel, an anti\u2010platelet drug, is used to prevent thrombosis after percutaneous coronary intervention. Clopidogrel resistance results in recurring ischemic events, with African Americans (AA) suffering disproportionately. The aim of this study was to discover novel biomarkers of clopidogrel resistance in African Americans using genome and transcriptome data. We conducted a genome\u2010wide association study (GWAS), including local ancestry adjustment, in 141 AA on clopidogrel to identify genetic associations with high on\u2010treatment platelet reactivity (HTPR), with validation of genome\u2010wide significant and suggestive loci in an independent cohort of AA clopidogrel patients (\n                    <jats:italic>N<\/jats:italic>\n                    \u2009=\u2009823) from the Million Veteran's Program (MVP) along with\n                    <jats:italic>in vitro<\/jats:italic>\n                    functional analysis. We performed differential gene expression (DGE) analysis in whole blood to identify transcriptomic predictors of response, followed by functional validation in MEG\u201001 cells. GWAS identified one signal on Chromosome 7 as significantly associated with increasing risk of HTPR. The lead single\u2010nucleotide polymorphism (SNP), rs7807369, within thrombospondin 7A (\n                    <jats:italic>THSD7A<\/jats:italic>\n                    ) was associated with an increased risk of HTPR (odds ratio (OR)\u2009=\u20094.02,\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20094.56\u2009\u00d7\u200910\n                    <jats:sup>\u22129<\/jats:sup>\n                    ). Higher\n                    <jats:italic>THSD7A<\/jats:italic>\n                    gene expression was associated with HTPR in an independent cohort of clopidogrel\u2010treated patients (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.004) and carrying a risk allele showed increased gene expression in primary human endothelial cells. Notably, the\n                    <jats:italic>CYP2C19*2<\/jats:italic>\n                    variants showed no association with clopidogrel response in the discovery or MVP cohorts. DGE analysis identified an association with decreased\n                    <jats:italic>LAIR1<\/jats:italic>\n                    and\n                    <jats:italic>AP3B2<\/jats:italic>\n                    expression to HTPR.\n                    <jats:italic>LAIR1<\/jats:italic>\n                    knockdown in MEG\u201001 cells resulted in increased expression of SYK and AKT1, suggesting an inhibitory role of\n                    <jats:italic>LAIR1<\/jats:italic>\n                    in the Glycoprotein VI pathway. In summary, these findings suggest that other variants and genes outside of\n                    <jats:italic>CYP2C19<\/jats:italic>\n                    star alleles play an important role in clopidogrel response in AA.\n                  <\/jats:p>","DOI":"10.1002\/cpt.3552","type":"journal-article","created":{"date-parts":[[2025,1,27]],"date-time":"2025-01-27T08:52:06Z","timestamp":1737967926000},"page":"1313-1324","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Investigation of Genomic and Transcriptomic Risk Factors of Clopidogrel Response in African Americans"],"prefix":"10.1002","volume":"117","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2920-6523","authenticated-orcid":false,"given":"Guang","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Center for Pharmacogenomics, Feinberg School of Medicine Northwestern University  Chicago Illinois USA"},{"name":"Center for Applied Bioinformatics St. Jude Children's Research Hospital  Memphis Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Alarcon","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Center for Pharmacogenomics, Feinberg School of Medicine Northwestern University  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4663-8953","authenticated-orcid":false,"given":"Catherine","family":"Chanfreau","sequence":"additional","affiliation":[{"name":"VA Informatics and Computing Infrastructure (VINCI) VA Salt Lake City Health Care System  Salt Lake City Utah USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norman H.","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Physiology George Washington University  Washington DC USA"},{"name":"GW Cancer Center George Washington University  Washington, DC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula","family":"Friedman","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Center for Pharmacogenomics, Feinberg School of Medicine Northwestern University  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edith","family":"Nutescu","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Practice Retzky College of Pharmacy, University of Illinois Chicago  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Tuck","sequence":"additional","affiliation":[{"name":"Washington DC VA Medical Center  Washington DC USA"},{"name":"The George Washington University  Washington DC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Travis","family":"O'Brien","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Physiology George Washington University  Washington DC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1739-8233","authenticated-orcid":false,"given":"Li","family":"Gong","sequence":"additional","affiliation":[{"name":"Department of Biomedical Data Science Stanford University  Stanford California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5527-6475","authenticated-orcid":false,"given":"Teri E.","family":"Klein","sequence":"additional","affiliation":[{"name":"Department of Biomedical Data Science and Department of Medicine Stanford University  Stanford California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyong\u2010Mi","family":"Chang","sequence":"additional","affiliation":[{"name":"Corporal Michael J. Crescenz VA Medical Center  Philadelphia Pennsylvania USA"},{"name":"University of Pennsylvania Perelman School of Medicine  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip S.","family":"Tsao","sequence":"additional","affiliation":[{"name":"VA Palo Alto Healthcare System and Stanford University  Palo Alto California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David O.","family":"Meltzer","sequence":"additional","affiliation":[{"name":"Section of Hospital Medicine, Department of Medicine University of Chicago  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0108-2127","authenticated-orcid":false,"given":"Julie A.","family":"Lynch","sequence":"additional","affiliation":[{"name":"VA Informatics and Computing Infrastructure (VINCI) VA Salt Lake City Health Care System  Salt Lake City Utah USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Million Veteran Program","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7007-3289","authenticated-orcid":false,"given":"Sony","family":"Tuteja","sequence":"additional","affiliation":[{"name":"Corporal Michael J. 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