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

基本信息

批准号：
8776182
负责人：
Minoli A Perera
金额：
$ 39.35万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
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/8776182
关键词：
Accounting Adverse drug effect Adverse effects Adverse event Affect Africa African African American Age American Architecture Beds Bioinformatics Biological Biology Caring Caucasians Caucasoid Race Cell Culture Techniques Cells Clinic Clinical Clinical Pharmacology Code Complex DNA Sequence Data Disease Dose Drug Kinetics Drug usage Ensure Environment Enzyme Induction Enzymes European Gene Expression Gene Mutation Genes Genetic Genetic Transcription Genetic Variation Genome Genomics Genotype Hepatic Hepatocyte In Vitro Individual Label Lead Learning Left Linkage Disequilibrium Liver Measures Medicine Metabolism Methods Minority Mutation Pharmaceutical Preparations Pharmacogenetics Pharmacogenomics Pharmacology Pharmacotherapy Phenotype Population Population Study Process Quantitative Trait Loci Regulation Regulatory Pathway Research Research Personnel Resolution Resources Risk Role Sampling Side Single Nucleotide Polymorphism Structure System Translating Translations Treatment outcome Variant clinical care clinically relevant cost effective drug clearance drug metabolism genome wide association study health disparity improved in vivo liver metabolism novel prevent protein function public health relevance response tool trait

项目摘要

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板凳顶向床的移动，非洲裔美国人被排除在个性化的医学上。迄今为止，在众多的药物遗传学研究中，非洲裔美国人在很大程度上缺乏，这些研究鉴定了预测性的单核苷酸多态性（SNP），这些核苷酸多态性（SNP）在临床上用于改善护理。随着我们朝着更全面的生物信息学和高吞吐量的方法评估影响药物表型的功能相关SNP的基因组时，我们还在将这些发现转化为非裔美国人诊所的健康差异越来越大。当前的基因组方法试图超越全基因组关联，以期找到对遗传发现的生物学合理性。此搜索已导致使用表达定量性状基因座（EQTL）作为药物遗传学研究研究的工具。标记为EQTL的SNP具有内在的生物学合理性，因为它们与基因表达的变化显着相关。但是，在非洲裔美国人中没有进行肝EQTL研究。通过使用肝特异性EQTL，我们将发现影响药物代谢酶（DME）的SNP，该酶将具有广泛的科学和临床影响；鉴于目前规定的大多数药物都经历了某种形式的肝代谢。由于非洲裔美国人发现的遗传多样性增加，因此仅在欧洲偏僻的人群中，药物基因组学研究就永远无法携带特定人群SNP。如果没有非裔美国人以专注的药物基因组学研究，我们有可能将非裔美国人排除在个性化医学之外。我们计划使用原发性肝细胞在药物诱导前后进行基因表达研究，以鉴定差异表达的基因。药物酶诱导是由基因转录增加驱动的。因此，通过关注诱导后差异表达的基因，我们可以将调节药物代谢酶的驱动因素（即基因）固定。然后，我们将观察与这些基因的SNP，并在基因表达（被称为di-eqtls）上的差异相关。然后，我们将研究这些DI-EQTL是否与同一细胞培养物中的药代动力学措施有关，并在同一个体中影响了药代动力学和药物遗传学研究。我们假设药物诱导将为我们提供与药物药代动力学密切相关的DI-EQTL，这是一种临床相关的表型。为了验证这些发现，我们将查询公开可用的数据，以寻找在药物基因组GWAS数据中最相关的SNP中的DI-EQTL的富集。非洲裔美国人的基因型，基因表达和药物药代动力学之间的关联从未进行过，并将为药物基因组学和临床药理学提供宝贵的资源，以及在这个被忽视的人群中的临床翻译。