Targeted Genetic Analysis of T2D and Quantitative Traits

描述（由申请人提供）：2型糖尿病（T2D）是美国和全球发病率和死亡率的主要原因。通过为T2D的发展和治疗提供基本的生物学和临床数据，并为高危人群提供具体的生活方式改变建议，确定增加T2D易感性的基因将影响公众健康。T2D是一种复杂的疾病，具有明确的遗传和环境风险因素，但导致这种风险增加的实际基因很少被确定，T2D发展的潜在机制仍然不清楚。我们的目标是从高危家庭和人群队列中收集的大量芬兰个体样本中确定增加T2D易感性的基因和相关的数量性状（QTs）。我们在855个家族中完成了T2D和相关qt的基因组筛选。在目前的建议中，我们扩展了基因分析的范围，以包括跨越基因组的精心靶向基因。我们将根据蛋白质相互作用和基因本体选择与T2D和/或QTs相关的先前证据以及与T2D相关转录因子/共激活因子相关的基因。我们将根据QT连锁信号对基因进行优先排序。最近在高通量基因分型、单核苷酸多态性（SNP）发现和单倍型图谱（HapMap）构建方面的技术进步提供了前所未有的工具，可以比以前更彻底地分析目标基因。我们建议通过评估1185例病例、1197例对照和946例高危个体中常见的和可能具有功能的snp，对181个选定基因中的3072个snp进行深入分析。我们将对第二组1150例、1000例对照和781例高危个体的T2D和QT相关性进行随访。我们将识别潜在的易感性变异并测试它们的功能作用。我们坚信，对遗传因素及其相互作用的详细研究是确定有针对性的预防策略和治疗的必要步骤。

DESCRIPTION (provided by applicant): Type 2 diabetes (T2D) is a major cause of morbidity and mortality in the USA and worldwide. Identification of genes increasing susceptibility to T2D would impact public health by providing basic biological and clinical data about development and treatment of T2D and by advising specific lifestyle changes in at-risk individuals. T2D is a complex disease with clear genetic and environmental risk factors, however few actual genes leading to this increased risk have been identified and the underlying mechanisms by which T2D develops remain obscure. Our goal is to identify genes increasing susceptibility to T2D and related quantitative traits (QTs) in a large sample of Finnish individuals collected both from at-risk families and from population cohorts. We have completed genome screens for T2D and related QTs in the 855 families. In the current proposal, we extend the scope of our genetic analysis to include carefully targeted genes spanning the genome. We will select genes with prior evidence of association with T2D and/or QTs and genes connected to T2D-related transcription factors/coactivators based on protein interaction and gene ontology. We will prioritize genes based on QT linkage signals. Recent technical advances in high-throughput genotyping, single nucleotide polymorphism (SNP) discovery and haplotype map (HapMap) construction provide unprecedented tools enabling more thorough analysis of targeted genes than was previously possible. We propose to perform in-depth analysis of 3072 SNPs in 181 selected genes by evaluating common and likely functional SNPs in a large, well-characterized sample set of 1185 cases, 1197 controls and 946 at-risk individuals. We will follow-up promising T2D and QT associations in a second large sample set of 1150 cases, 1000 controls and 781 at-risk individuals. We will identify potential susceptibility variants and test their functional roles. We strongly believe that a detailed study of genetic factors and their interactions is an essential step to identifying targeted prevention strategies and treatments.