Personal omics profiling of the progression to diabetes mellitus type 2

描述(申请人提供)：2型糖尿病影响全球超过2亿人。虽然DM2有很强的家族成分，但对单个致病基因的寻找只取得了一定的成果，而且DM2的发展被认为取决于许多遗传和环境因素的组合。随着REACH中个体全基因组测序的成本以及定量测量数万个生物分子的技术的成熟，存在着理解推动DM2进展的遗传和双分子因素的巨大机会。我们的实验室最近开发了一种名为一体化个人组学图谱(IPOP)的新管道，它将基因组、转录、蛋白质组和代谢组学图谱与计算工具结合在一起，全面研究疾病发生和发展过程中发生变化的分子和途径。我们建议对一组超重个体进行全基因组测序和纵向iPOP分析，无论是进展到DM2的高风险还是低风险个体。对于这个队列，我们将在研究开始时、体重适度增加后和体重显著下降后分析血液样本。我们假设，通过iPOP分析，我们可以阐明新的分子因素和途径，这些因素和途径会随着体重的增加和减少而改变，并且在高风险和低风险个体之间存在差异。通过这一分析，我们将提供一个前所未有的视角，了解获得性胰岛素抵抗背后不断变化的分子格局。

DESCRIPTION (provided by applicant): Diabetes Mellitus type 2 affects over 200 million individuals worldwide. While DM2 has a strong familial component, the search for individual causative genes has been only mildly fruitful and development of DM2 is thought to depend on the combination of a number of genetic and environmental factors. With the cost for whole- genome sequencing of individuals in reach as well as the maturation of technologies for quantifiably measuring tens of thousands of biomolecules, there exists a tremendous opportunity to understand the genetic and bimolecular factors which underlie the progression to DM2. Our lab has recently developed a novel pipeline termed integrative personal omics profiling (iPOP) which combines genomic, transcriptomic, proteomic and metabolomics profiles with computational tools to comprehensively investigate the molecules and pathways that change during disease onset and progression. We propose to perform whole-genome sequencing and longitudinal iPOP analysis on a cohort of overweight individuals either high-risk or low-risk for progression to DM2. For this cohort, we will analyze blood samples at the onset of the study, after a moderate weight gain and after a period of significant weight loss. We hypothesize that through iPOP analysis we can elucidate novel molecular factors and pathways which change in response to weight gain and loss and which differ between high- and low-risk individuals. Through this analysis we will offer an unprecedented view of the changing molecular landscape underlying acquired insulin resistance.