Pharmacogenomics of Membrane Transporters

描述(由申请人提供)：SLC和ABC超家族中的膜转运蛋白具有巨大的药理学重要性，是药物处置和反应的关键决定因素。在之前批准周期建立的广泛基础设施的基础上，拟议的研究将侧重于肝脏和肾脏的转运体，它与几乎所有已知的药物相互作用，调节药物处置、反应和毒性。通过计算驱动的功能研究和多个临床研究，这项拟议的研究将检验膜转运蛋白中的遗传变异对药物反应差异的影响这一假说。功能基因组研究将主要侧重于非编码区的变体，扩展我们目前的努力，主要集中在非同义变体上。对于这些研究，我们建议：(A)从功能上表征转运蛋白基因调控区域内的变异体；(B)将序列变异体与转运体在肝脏和肾脏样本中的表达水平联系起来；以及(C)开发非同义变异体的底物依赖效应的预测模型。除了常见的变异体，我们还将继续研究罕见的变异体，因为我们之前的研究已经证明了它们的功能重要性。将进行三类临床研究：(A)苏菲的基因型驱动假设检验研究，这是一个独特的健康志愿者队列，他们提供了DNA，并同意被召回进行后续研究；(B)在非裔美国人中进行的一项大型全基因组关联研究，目的是研究抗糖尿病药物二甲双胍对多种药物的毒性和反应的反应；以及(C)临床样本的协作研究，其中将使用定制的转运体-ADME SNP芯片来确定转运体中的基因变异，这些变异是多种药物毒性和反应的决定因素。我们的项目招募了一支具有计算、实验和临床专业知识的世界级多学科研究团队，他们将应用创新的方法，包括RNA-SEQ、下一代测序和多阶段全基因组关联分析。生物信息学、生物统计学和基因组学这三个研究核心将为这些高度机械性和临床重要性的研究提供支持。

DESCRIPTION (provided by applicant): Membrane transporters in the SLC and ABC superfamilies are of enormous pharmacological importance, serving as critical determinants of drug disposition and response. Building on the extensive infrastructure established during the previous granting cycles, the proposed research will focus on transporters in the liver and kidney, which interact with virtually all known drugs in mediating drug disposition, response and toxicity. Through computationally driven functional studies and multiple clinical studies, the proposed research will test the hypothesis that genetic variants in membrane transporters contribute to variation in drug response. The functional genomic studies will have a major emphasis on variants in noncoding regions, expanding on our current efforts, which are focused largely on nonsynonymous variants. For these studies, we propose to: (a) functionally characterize variants within regulatory regions of transporter genes; (b) associate sequence variants with transporter expression levels in liver and kidney samples; and (c) develop predictive models for substrate-dependent effects of nonsynonymous variants. In addition to common variants, we will continue to study rare variants as our previous studies have demonstrated their functional importance. Three types of clinical studies will be performed: (a) genotype-driven hypothesis testing studies in SOPHIE, a unique cohort of healthy volunteers who have provided DNA and agreed to be called back for follow-up studies; (b) a large genomewide association study in African Americans of response to the anti-diabetic drug, metformin, a drug that interacts with multiple transporters; and (c) collaborative studies on clinical samples in which a custom-designed transporter-ADME SNP chip will be used to identify genetic variants in transporters that are determinants of toxicities and response to multiple drugs. Our project has recruited a world-class multidisciplinary research team with computational, experimental and clinical expertise, who will apply innovative methodologies including RNA-seq, Next-generation sequencing and multi-stage genomewide association analysis. Three research cores, bioinformatics, biostatistics and genomics, will provide support for these highly mechanistic and clinically important studies.