Abstract 12098: Pharmaco-omics of Clopidogrel Response in African Americans- An African-American Cardiovascular Pharmacogenetic CONsorTium Study

• Published in: Circulation (New York, N.Y.) Vol. 140; no. Suppl_1 Suppl 1; p. A12098
• Main Authors: De, Tanima, Alarcon, Cristina, Nahlawi, Layan, Avitia, Juan, Lec, Bianca, Shaazuddin, Mohammed, Nooruddin, Mohammed, Moreno, Diana, Sathyanarayanan, Myurani, Nutescu, Edith, Barbour, April, Banagan, Jeff, Gordon, Olivia, Jeyaram, Tharani, Harris, Mary, Bradbury, Sarah, Subrahmanyam, Ramesh, Tuck, Matthew, Harralson, Arthur, Friedman, Paula, Meltzer, David, O’Brien, Travis, Perera, Minoli A
• Format: Journal Article
• Language: English
• Published: by the American College of Cardiology Foundation and the American Heart Association, Inc 19.11.2019
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/circ.140.suppl_1.12098

IntroductionClopidogrel therapy is associated with substantial inter-patient differences in response. African Americans (AAs) are disproportionately affected by death and disability from cardiovascular diseases (CVDs) and are also at a higher risk of adverse cardiovascular events and mortality from poor clopidogrel response. High on-treatment platelet reactivity (HTPR) is more prevalent in AAs.HypothesisGenetic biomarkers to CVDs may influence antiplatelet response.ObjectiveIdentify the genetic variants associated with HTPR in AAs.MethodsWhole-genome genotype information and P2Y12 reaction units (PRU) were obtained for 63 AAs on clopidogrel. HTPR was defined as PRU ≥ 240. Transcriptome-wide association study (TWAS) was performed to identify candidate causal genes using genotype weights trained in Multi-Ethnic Study of Atherosclerosis (MESA) cohort from monocytes to predict gene expression associated to HTPR. Variants within and 1MB upstream/downstream of the significant genes were studied for their association with HTPR.ResultsThe study group comprised of 15 cases (mean age67.87±12.33 years, 20% women); PRU ≥ 240 and 48 controls (mean age62.81±14.93 years, 40% women); PRU < 240. TWAS identified 20 genes that reached p < 0.03. Among the genetic variants specific to the 20 genes, rs607560 (OR:7.96, CI:2.5–25.6, p=6.09x10), rs11372672 (OR:4.63, CI:1.87–11.47, p=4.96x10) and rs7624011 (OR:7.7, CI:2.4–25.1, p=6.7x10), were significantly associated with HTPR. While rs607560 increased EHD1 expression and rs7624011 increased P2RY12 expression, rs11372672 decreased PSMC5 expression. Previous studies reported increased EHD1 expression related to arrhythmias-myocardial infarction and increased P2RY12 expression associated with poor clopidogrel response. No study to date has identified regulatory variant for these important genes. Of note, the minor allele frequency (MAF) of rs607560 is 31% in AAs (6.7% in whites), while rs7624011 is specific to only African ancestry populations (MAF13.6% in AAs).ConclusionThis is the first-ever omic study focused on AAs on clopidogrel that provides insight into genetic loci and their underlying biological mechanisms related to poor clopidogrel response in AAs.