Fine-mapping and Characterization of Metabolic Loci in the DPP Outcomes Study

描述(由申请人提供)：越来越多的常见基因变异与2型糖尿病(T2D)密切相关，并具有重复性。尽管取得了这些进展，但与增加T2D风险相关的基因的确切身份尚未确定。新开发的代谢芯片支持约200,000个单核苷酸多态(SNPs)的基因分型，这些SNPs显示了与疾病和与代谢终点相关的特征相关的强有力证据，以及已经在全基因组统计意义上验证的详细的基因座精细图谱。我们建议将该阵列部署在糖尿病预防计划(DPP)中，这是一项临床试验，其优势包括招募来自多个种族群体的高危参与者、精致的纵向表型分析、行为和药物干预的存在，以及通过额外增加硬终点进行持续监测。我们将利用精致的表型DPP样本1)在来自五个种族的3,548名糖尿病高危人群中测试选定的代谢芯片SNPs与基线T2D相关数量性状的关联；2)评估选定的代谢芯片SNPs对DPP代谢结果发生率的影响，并确定生活方式干预是否改变了这种风险；以及3)检测二甲双胍和曲格列酮对相关SNPs的影响，以此作为将它们置于代谢途径上并描述潜在有用的药物发生相互作用的方式。如果成功，这项建议将有助于阐明基因变异增加T2D风险的病理生理学机制，评估它们对预防T2D的干预措施的影响，产生独特的资源，并帮助为药物遗传学和遗传引导的生活方式干预试验奠定基础。 与公共卫生相关：最近的研究发现，越来越多的常见基因变异与2型糖尿病和相关特征有重复的关联。一种新开发的基因分型阵列(代谢芯片)支持对大约200,000个单核苷酸多态进行基因分型，这些基因多态显示出与疾病和与代谢终点相关的特征相关的确凿证据，以及验证的遗传基因座的详细精细图谱。我们建议在糖尿病预防计划(DPP)中部署这一阵列，这是一项临床试验，招募了来自多个民族的3819名高危参与者，并随机让他们接受安慰剂、二甲双胍、曲格列酮或生活方式干预，以预防糖尿病。在DPP中，我们将测试选定的变异与基线糖尿病相关数量性状、代谢结果发生率、对生活方式干预的反应以及二甲双胍和曲格列酮的效果之间的关系。

DESCRIPTION (provided by applicant): A growing number of common genetic variants have been robustly and reproducibly associated with type 2 diabetes (T2D). Despite these advances, the precise identity of the genes involved in increasing T2D risk has not yet been established. The newly developed Metabochip supports genotyping of ~200,000 single nucleotide polymorphisms (SNPs) that display robust evidence for association with diseases and traits relevant to metabolic endpoints, as well as detailed fine-mapping of loci already validated at genome-wide statistical significance. We propose to deploy this array in the Diabetes Prevention Program (DPP), a clinical trial whose strengths include the enrollment of high-risk participants from multiple ethnic groups, exquisite longitudinal phenotyping, the presence of behavioral and pharmacologic interventions, and ongoing monitoring with additional accrual of hard endpoints. We will leverage the exquisitely phenotyped DPP samples to 1) test the association of select Metabochip SNPs with baseline T2D-related quantitative traits in 3,548 DPP participants at high risk of diabetes from five ethnic groups; 2) assess the effect of select Metabochip SNPs on the incidence of metabolic outcomes in the DPP, and establish whether a lifestyle intervention modifies this risk; and 3) examine the impact of metformin and troglitazone on relevant SNPs, as a way to place them on metabolic pathways and describe potentially useful pharmacogenetic interactions. If successful, this proposal should help clarify the pathophysiologic mechanisms by which genetic variants increase risk of T2D, assess their impact on interventions to prevent T2D, generate a unique resource, and help lay the groundwork for pharmacogenetic and genetically-guided lifestyle intervention trials. PUBLIC HEALTH RELEVANCE: Recent studies have identified a growing number of common genetic variants that are reproducibly associated with type 2 diabetes and related traits. A newly developed genotyping array (the Metabochip) supports genotyping of ~200,000 single nucleotide polymorphisms that display robust evidence for association with diseases and traits relevant to metabolic endpoints, as well as detailed fine-mapping of validated genetic loci. We propose to deploy this array in the Diabetes Prevention Program (DPP), a clinical trial which enrolled 3,819 high-risk participants from multiple ethnic groups and randomized them to placebo, metformin, troglitazone or a lifestyle intervention to prevent diabetes. In the DPP, we will test the association of select variants with baseline diabetes-related quantitative traits, incidence of metabolic outcomes, response to the lifestyle intervention, and the effects of metformin and troglitazone.