Health disparity in pharmacogenomics: African American SNPs and drug metabolism

药物基因组学中的健康差异：非裔美国人 SNP 和药物代谢

• 批准号: 9370988
• 负责人: Minoli A Perera
• 金额: $ 33.42万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-10 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9370988
• 关键词: Health; disparity; pharmacogenomics; African; American

DESCRIPTION (provided by applicant): As pharmacogenomics moves from bench-top to bed-side, African Americans have been left out of the advances personalized medicine holds. To date, African Americans have been largely absent from the numerous pharmacogenetic studies that identify predictive single nucleotide polymorphisms (SNPs) that are being used clinically to improve care. As we move toward more comprehensive bioinformatics and high- throughput methods of evaluating the genome for functionally relevant SNPs that affect drug phenotypes, we are also producing a growing health disparity in the translation of these findings into the clinic for African Americans. Current genomic methods are trying to reach beyond genome-wide association in hopes of finding biological plausibility to genetic findings. This search has led to the use of expression quantitative trait loci (eQTLs) as a tool in pharmacogenetic association studies. SNPs labeled as eQTLs have intrinsic biological plausibility since they are significantly associated with changes in gene expression. However, no liver eQTL studies have been conducted in African Americans. By using liver-specific eQTLs, we will discover SNPs that affect drug metabolizing enzymes (DMEs), which will have wide-spread scientific and clinical impact; given that most drugs currently prescribed undergo some form of hepatic metabolism. Because of the increase genetic diversity found in African Americans, they may carry population specific SNPs can never be found by pharmacogenomics studies in populations of European-descent alone. Without African American focused pharmacogenomics studies we risk excluding African Americans from personalized medicine. We plan to use primary hepatocytes to conduct gene expression studies both before and after drug enzyme induction to identify genes that are differentially expressed. Drug enzyme induction is driven by increased gene transcription; therefore, by focusing on the genes that are differentially expressed after induction we can pin-point the drivers (i.e. genes) that regulate drug metabolizing enzymes. We will then look at SNPs within and in close proximity to these genes to determine if any are associated with differences in gene expression (dubbed DI-eQTLs). We will then look to see if these DI-eQTLs are associated with pharmacokinetic measures in the same set of cell cultures, affectedly preforming a pharmacokinetic and a pharmacogenetic study in the same individual. We hypothesize that drug enzyme induction will provide us with DI-eQTLs that are strongly associated to drug pharmacokinetics, a clinically relevant phenotype. To validate these findings we will query publically available data to look for an enrichment of our DI-eQTLs within the most strongly associated SNPs in pharmacogenomic GWAS data. The association between genotype, gene expression and drug pharmacokinetics in African Americans has never been conducted before and will provide an invaluable resource for pharmacogenomics and clinical pharmacology, as well as clinical translation in this understudied population.

描述（由申请人提供）：随着药物基因组学从台式走向床边，非裔美国人被排除在个性化医疗的进步之外。迄今为止，非洲裔美国人在大量的药物遗传学研究中基本上缺席，这些研究确定了临床上用于改善护理的预测性单核苷酸多态性（snp）。随着我们向更全面的生物信息学和高通量方法迈进，以评估影响药物表型的功能相关snp的基因组，我们也在将这些发现转化为非裔美国人的临床方面产生了越来越大的健康差异。目前的基因组学方法正试图超越全基因组关联，以期找到遗传学发现的生物学合理性。这种搜索导致了