Identifying Genes for Type 2 Diabetes: FUSION

识别 2 型糖尿病基因：FUSION

• 批准号: 7813892
• 负责人: MICHAEL L BOEHNKE
• 金额: $ 127.13万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7813892
• 关键词: 20q; Adipose tissue; Affect; Age; American; Behavioral; Biological; Biological Assay; Candidate Disease Gene; Chromosomes; Clinical Data; Collaborations; Complex; DNA; DNA Resequencing; Data; Diabetes Mellitus; Disease; Epidemic; Etiology; European; Expenditure; Family; Finland; Follow-Up Studies; Frequencies; Funding; Genes; Genetic; Genomics; Genotype; Germany; Glucose; Goals; Health Care Costs; Height; Hereditary Disease; IL6 gene; Incidence; Individual; Investigation; Joints; Leadership; Learning; Letters; Lipids; Los Angeles; Maps; Medical; Meta-Analysis; Methods; Mitochondria; Molecular Genetics; Morbidity - disease rate; Muscle; National Human Genome Research Institute; Non-Insulin-Dependent Diabetes Mellitus; Norway; Participant; Pharmacotherapy; Phenotype; Population; Predictive Value; Predisposition; Prevalence; Prevention; Preventive; Public Health; Quantitative Trait Loci; Rare Diseases; Reporting; Research Design; Risk; Sampling; Siblings; Signal Transduction; Specimen; Statistical Study; Study Subject; TCF7L2 gene; Therapeutic; Tissue Sample; United States; United States National Institutes of Health; Variant; Work; aged; base; diabetes risk; fasting glucose; follow-up; functional genomics; genetic variant; genome wide association study; genome-wide; improved; mRNA Expression; mortality; novel; public health relevance; resistin; sex; socioeconomics; success; therapy development; trait

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 e20 years and 10.3 million Americans aged e60 years 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.

2型糖尿病（T2D）是美国和全球发病率和死亡率的主要原因。而疾病 患病率随着年龄，性别和人口而异，据估计，在2005年，E20年龄的2,260万美国人 E60岁的年龄和1030万美国人患有T2D。已经观察到类似的T2D速率 在芬兰。在美国和全球，T2D的发病率和患病率正在增加。仅在美国， 据估计，由于糖尿病的医疗支出在2002年总计1,320亿美元，占美国健康健康的10％ 护理费用。年轻的T2D案件的越来越多会扩大T2D和 增加了我们必须采取行动以确定其原因和新治疗的紧迫性。有实质性 T2D和T2D相关定量性状（QTS）病因学中遗传成分的证据。目标 芬兰的国家对NIDDM遗传学的研究（融合）研究是为了鉴定遗传变异体 倾向于T2D，并导致T2D相关QT的变异性。提高了对 T2D和相关QTS的遗传基础有潜力减少当前T2D流行的影响 支持鉴定新型药物和疗法，以更好地靶向预防和治疗 接近，并提供更准确的T2D风险预测。在此提案中，我们试图以我们的为基础 过去五年的成功，特别是我们全基因组关联研究的最初发现 和相关的QT。具体而言，我们将（1）大大增加我们可用的良好研究样本 受试者，（2）获得组织样品（脂肪，肌肉，皮肤），并在经过广泛研究的 使用这些组织的研究对象的子集，并通过定向的更广泛的组织成为可能 诱导多能干细胞（IPS）线的分化为前体细胞谱系朝向但不限于 胰岛状和肝细胞状的组织的产生，（3）继续并在我们当前的全基因组上扩展 分析通过使用我们现有的芬兰样本，样本来识别其他T2D和T2D-相关QT基因座 在这个项目期间新近概括，并继续与合作者进行联合和/或荟萃分析，以及（4） 精细的地图并确定我们发现或将发现，评估的T2D和QT基因座中的易感变体 相关变体的等位基因谱，并评估已识别变体的预测能力。这些努力 将有助于提高对T2D病因的理解，并有可能指向 新颖的治疗和预防方法。开发的方法和本研究中学的教训将是有用的 在其他复杂遗传疾病的研究中。