Identifying Genes for Type 2 Diabetes: FUSION

2型糖尿病（T2D）是美国和世界范围内发病率和死亡率的主要原因。虽然疾病的患病率因年龄、性别和人口而异，但据估计，2005年，2060万20岁及以上的美国人和1030万60岁及以上的美国人患有T2D。芬兰也观察到类似的T2D发病率。在美国和世界范围内，T2D的发病率和流行率都在增加。据估计，仅在美国，2002年因糖尿病引起的医疗支出总计为1320亿美元，约占美国所有医疗保健费用的10%。越来越多的年轻T2D病例扩大了T2D的社会经济影响，并增加了我们必须采取行动确定其原因和新治疗方法的紧迫性。有大量证据表明，T2D和T2D相关数量性状（QTs）的病因中存在遗传成分。芬兰-美国NIDDM遗传学调查（FUSION）研究的目标是确定易患T2D的遗传变异和导致T2D相关qt变异的遗传变异。更好地了解T2D和相关qt的遗传基础，有可能通过支持识别新的药物和疗法，使预防和治疗方法更有针对性，并提供更准确的T2D风险预测，减少当前T2D流行的影响。在本提案中，我们寻求建立在我们过去五年的成功，特别是我们的T2D和相关QTs全基因组关联研究的初步发现。具体而言，我们将(1)大幅增加表型良好的研究对象的可用样本，(2)获取组织样本（脂肪、肌肉、皮肤），并对广泛研究的研究对象子集进行功能分析，使用这些组织和更广泛的组织，这些组织是通过诱导多能干细胞（iPS）系定向分化为前体细胞系而产生的，但不限于产生胰岛样和肝细胞样组织。(3)继续并扩展我们目前的全基因组分析，通过使用我们现有的芬兰样本，本项目期间新获得的样本，以及与合作者继续进行联合和/或荟萃分析，识别更多的T2D和T2D相关的QT基因座；(4)精细绘制和识别我们已经发现或将发现的T2D和QT基因座中的易感变异，评估相关变异的等位基因谱，并评估已识别变异的预测能力。这些努力将有助于提高对T2D病因的理解，并有可能指出新的治疗和预防方法。本研究开发的方法和经验教训将有助于其他复杂遗传疾病的研究。

Type 2 diabetes (T2D) is a major cause of morbidity and mortality in the USA and worldwide. While disease prevalence varies with age, sex, and population, it is estimated that in 2005, 20.6 million Americans aged 20 years or older and 10.3 million Americans aged 60 years or older suffered from T2D. Similar rates of T2D have been observed in Finland. The incidence and prevalence of T2D are increasing in the USA and worldwide. In the USA alone, it is estimated that medical expenditures due to diabetes totaled $132 billion in 2002, ~10% of all USA health care costs. The increasing number of younger T2D cases amplifies the socioeconomic impact of T2D and increases the urgency with which we must act to identify its causes and new treatments. There is substantial evidence of a genetic component in the etiology of T2D and T2D-related quantitative traits (QTs). The goal of the Finland-United States Investigation of NIDDM Genetics (FUSION) study is to identify genetic variants that predispose to T2D and that are responsible for variability in T2D-related QTs. Improved understanding of the genetic basis of T2D and related QTs has the potential to reduce the impact of the current T2D epidemic by supporting identification of novel drugs and therapies, enabling better targeting of preventive and therapeutic approaches, and providing more accurate T2D risk prediction. In this proposal, we seek to build on our successes of the last five years, particularly the initial findings of our genome-wide association studies of T2D and related QTs. Specifically, we will (1) increase substantially our available sample of well-phenotyped study subjects, (2) obtain tissue samples (fat, muscle, skin) and carry out functional assays on an extensively studied subset of our study subjects using these tissues and the wider array of tissues made possible by the directed differentiation of induced pluripotent stem cell (iPS) lines into precursor cell lineages towards but not limited to the generation of islet-like and hepatocyte-like tissues, (3) continue and expand on our current genome-wide analyses to identify additional T2D and T2D- related-QT loci by using our existing Finnish samples, samples newly-obtained during this project period, and continued joint and/or meta-analysis with collaborators, and (4) fine map and identify predisposing variants in the T2D and QT loci we have discovered or will discover, assess the allelic spectrum of relevant variants, and assess the predictive power of identified variants. These efforts will contribute to improved understanding of the etiology of T2D, and have the potential to point the way to novel methods of treatment and prevention. Methods developed and lessons learned in this study will be useful in the study of other complex genetic diseases.