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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：
9264413
负责人：
Minoli A Perera
金额：
$ 39.05万
依托单位：
NORTHWESTERN UNIVERSITY AT 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/9264413
关键词：
Adverse drug effect Adverse effects Adverse event Affect Africa African African American Age American Architecture Bioinformatics Biological Biology Caring Caucasians Cell Culture Techniques Cells Clinic Clinical Clinical Pharmacology Code Complex DNA Sequence DNA Sequence Alteration Data Disease Dose Drug Kinetics Drug usage Ensure Environment Enzyme Induction Enzymes European Gene Expression Genes Genetic Genetic Transcription Genetic Variation Genetic study Genome Genomics Genotype Hepatocyte In Vitro Individual Label Learning Left Linkage Disequilibrium Liver Measures Medicine Methods Minority Mutation Pharmaceutical Preparations Pharmacogenetics Pharmacogenomics Pharmacology Pharmacotherapy Phenotype Population Prediction of Response to Therapy Process Quantitative Trait Loci Regulation Regulator Genes Regulatory Pathway Research Research Personnel Resolution Resources Risk Role Sampling Single Nucleotide Polymorphism Structure System Translating Translations Treatment outcome Variant clinical care clinical translation clinically relevant cost effective differential expression drug clearance drug metabolism genetic association genome wide association study health disparity improved in vivo liver metabolism novel personalized medicine prevent protein function public health relevance response study population 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台面转移到床边，非裔美国人被排除在个性化药物的进步之外。到目前为止，非洲裔美国人基本上没有参加大量的药物遗传学研究，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(SNPs)。随着我们朝着更全面的生物信息学和高通量方法来评估影响药物表型的功能相关SNPs的基因组，我们在将这些发现转化为非裔美国人的临床中也产生了越来越大的健康差距。目前的基因组学方法正试图超越全基因组的关联，希望找到遗传学发现的生物学可信之处。这项搜索导致了表达数量性状基因座(EQTL)在药物遗传相关性研究中的应用。被标记为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密切相关。然而，还没有对非裔美国人进行肝脏eQTL研究。通过使用肝脏特异的eQTL，我们将发现影响药物代谢酶(DME)的SNPs，这将具有广泛的科学和临床影响；因为目前开出的大多数药物都经历了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，他们可能携带仅在欧洲裔人口中无法通过药物基因组学研究发现的群体特有的SNPs。如果没有以非裔美国人为重点的药物基因组学研究，我们就有可能将非裔美国人排除在个性化药物之外。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。药物酶的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，我们可以定位调控药物代谢酶的驱动因素(即基因)。然后，我们将研究这些基因内部和附近的SNP，以确定是否有与基因表达差异相关的SNP(称为DI-eQTL)。然后，我们将查看这些DI-eQTL是否与同一组细胞培养中的药代动力学措施有关，假装在同一个人身上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，我们将查询公共可用的数据，以在药物基因组Gwas数据中最相关的SNP中寻找我们的DI-eQTL的丰富。在非裔美国人中，基因型、基因表达和药物药代动力学之间的关联以前从未被研究过，这将为药物基因组学和临床药理学提供宝贵的资源，以及在这一研究不足的人群中进行临床翻译。