Clopidogrel, an antiplatelet drug widely used to prevent blood coagulation in patients with cardiovascular diseases (CVDs), is associated with substantial interpatient differences in response. Genetic variation significantly contributes to response variability, and is seen across populations. AA minorities are disproportionately affected by death and disability from CVDs, and are also at a higher risk of adverse cardiovascular events (CVE) and mortality from poor antiplatelet response to clopidogrel. However, the genetic basis for response variability in AAs has not been investigated. Therefore, the broad objective of this proposal is to identify the AA population-specific genetic predictors of poor clopidogrel response that contribute to the adverse events and increased cardiovascular risk. Clopidogrel undergoes hepatic cytochrome P450 (CYP)–mediated biotransformation to an active metabolite. Regulatory single nucleotide polymorphisms (SNPs) that significantly influence CYP gene expression (known as expressed quantitative trait loci [eQTLs]), may contribute to the inadequate clopidogrel-induced platelet inhibition, accounting for differences in response. Also, SNPs that act by modifying the DNA methylation status (methylation quantitative trait loci; meQTLs), leading changes in gene expression through altered chromatin accessibility and transcription factor binding may be an additional source of variability. Evaluating the regulatory and epigenetic modulation of gene expression may uncover AA-specific factors that influence drug metabolizing enzyme (DME) expression. We hypothesize that the coordinated effects of regulatory SNPs and altered methylation of DMEs contribute to poor response to clopidogrel. Since these DMEs play a role in the metabolism of many drugs and toxic compounds, exploring the effect of the SNPs influencing their expression across extensive set of phenotypes may identify novel associations with other drug responses and disease conditions which could be of clinical relevance.
|Effective start/end date||4/2/18 → 4/1/20|
- American Heart Association (18IFUNP34080469)