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

描述（由申请人提供）：越来越多的常见遗传变异与2型糖尿病（T2D）有可靠且可重复的关联。尽管取得了这些进展，但与增加T2D风险有关的基因的确切身份尚未确定。新开发的Metabochip支持约200,000个单核苷酸多态性（snp）的基因分型，这些snp显示出与疾病和与代谢终点相关的性状相关的有力证据，以及已经在全基因组统计意义上验证的位点的详细精细定位。我们建议在糖尿病预防项目（DPP）中部署这种阵列，这是一项临床试验，其优势包括来自多个种族的高风险参与者的入组，精确的纵向表型，行为和药物干预的存在，以及具有额外硬终点累积的持续监测。我们将利用精致表型的DPP样本来1)测试来自5个种族的3,548名糖尿病高风险DPP参与者的选定代谢芯片snp与基线t2d相关数量性状的关联；2)评估选定的代谢芯片snp对DPP代谢结局发生率的影响，并确定生活方式干预是否能改变这种风险；3)检查二甲双胍和曲格列酮对相关snp的影响，作为将它们置于代谢途径和描述潜在有用的药理学相互作用的一种方式。如果成功，该建议将有助于阐明遗传变异增加T2D风险的病理生理机制，评估其对预防T2D的干预措施的影响，产生独特的资源，并有助于为药物遗传学和遗传指导的生活方式干预试验奠定基础。

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.