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（T2 D）密切相关。尽管取得了这些进展，但尚未确定增加T2 D风险的基因的确切身份。 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显示出与疾病和代谢终点相关性状相关的强有力证据，以及已在全基因组统计学意义上验证的基因座的详细精细作图。我们建议在糖尿病预防计划（DPP）中部署该阵列，该临床试验的优势包括招募来自多个种族的高风险参与者，精细的纵向表型分析，行为和药理学干预的存在，以及持续监测额外的硬终点。 我们将利用精美的表型DPP样本来1）在来自五个种族的3，548名糖尿病高风险DPP参与者中测试选定的Metabochip SNP与基线T2 D相关数量性状的关联; 2）评估选定的Metabochip SNP对DPP代谢结果发生率的影响，并确定生活方式干预是否可以改变这种风险;和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上并描述潜在有用的药物遗传学相互作用的一种方式。如果成功的话，这一提议将有助于阐明遗传变异增加T2 D风险的病理生理机制，评估其对预防T2 D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。 公共卫生相关性：最近的研究已经确定了越来越多的常见遗传变异，这些变异与2型糖尿病和相关性状可重复地相关。新开发的基因分型阵列（Metabochip）支持约200，000个单核苷酸多态性的基因分型，这些多态性显示出与疾病和代谢终点相关性状相关的强有力证据，以及经验证的遗传位点的详细精细作图。我们建议在糖尿病预防计划（DPP）中部署该阵列，该临床试验招募了来自多个种族的3，819名高风险参与者，并将他们随机分配到安慰剂，二甲双胍，曲格列酮或生活方式干预以预防糖尿病。在DPP中，我们将检测选定变异与基线糖尿病相关数量性状、代谢结局发生率、对生活方式干预的反应以及二甲双胍和曲格列酮的影响的相关性。

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.