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，非洲裔美国人已经被排除在个性化医疗的进步之外。迄今为止，非洲裔美国人在很大程度上缺席了许多药物遗传学研究，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）。随着我们走向更全面的生物信息学和高通量方法来评估基因组中影响药物表型的功能相关SNP，我们也在将这些发现转化为非裔美国人的临床时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基因组范围的关联，希望找到遗传发现的生物相容性。这次搜索导致了 表达数量性状基因座（eQTL）作为药物遗传学关联研究工具的应用。标记为eQTL的SNPs具有内在的生物学可解释性，因为它们与基因表达的变化显著相关。然而，尚未在非裔美国人中进行肝脏eQTL研究。通过使用肝脏特异性eQTL，我们将发现影响药物代谢酶（DME）的SNP，这将具有广泛的科学和临床影响;考虑到目前处方的大多数药物都经历某种形式的肝脏代谢。由于在非裔美国人中发现的遗传多样性增加，他们可能携带人群特异性SNP，而这些SNP永远无法通过药物基因组学研究在欧洲血统人群中单独发现。如果没有针对非洲裔美国人的药物基因组学研究，我们就有可能将非洲裔美国人排除在个性化医疗之外。我们计划使用原代肝细胞进行药物酶诱导前后的基因表达研究，以确定差异表达的基因。药物酶诱导是由增加的基因转录驱动的;因此，通过关注诱导后差异表达的基因，我们可以精确定位调节药物代谢酶的驱动因子（即基因）。然后，我们将研究这些基因内部和附近的SNP，以确定是否有任何与基因表达差异相关的SNP（称为DI-eQTL）。然后，我们将观察这些DI-eQTL是否与同一组细胞培养物中的药代动力学指标相关，从而在同一个体中有效地进行药代动力学和药物遗传学研究。我们假设药物酶诱导将为我们提供与药物药代动力学（一种临床相关表型）密切相关的DI-eQTL。为了验证这些发现，我们将查询药学上可用的数据，以在药物基因组学GWAS数据中最强相关的SNP内寻找我们的DI-eQTL的富集。基因型之间的关联，基因表达和药物药代动力学在非洲裔美国人从来没有进行过，并将提供一个宝贵的资源，药物基因组学和临床药理学，以及临床翻译在这个研究不足的人口。