Identification of Regulatory Variants in Novel Candidate Genes for Diabetes

描述(申请人提供)：2型糖尿病现在被认为是21世纪对人类健康的主要威胁之一。在这个项目中，我们建议使用一种整合的基因组学方法，在一项基于家庭的大型研究中，在糖尿病风险的新候选基因中识别潜在的功能调节变异。这些客观选择的候选基因是通过对1240名圣安东尼奥家庭心脏研究参与者的淋巴细胞样本进行大规模转录图谱获得的。根据定量基因表达水平与主要糖尿病风险因素空腹血糖水平以及一个或多个糖尿病风险因素(包括空腹胰岛素和综合糖尿病风险指数)之间存在显著相关性，提名目标候选基因座。利用我们独特的基于家族的全基因组定量转录图谱资源，我们将研究100个新的候选基因，这些基因既显示了表达水平顺式调控的强有力证据，也显示了表达水平与糖尿病风险表型之间的显著相关性。我们先前基于连锁的顺式作用序列变异的证据可以被用作概率因果锚，这应该会最大限度地增加我们在近端启动子中发现功能变异的机会。对于这些客观选择的基因中的每一个，我们将：1)对182名创始人中约2个碱基的潜在启动子区域进行重新测序以确定启动子变体；2)在我们拥有其转录谱的1,240个SAFHS样本中的每个候选基因中，检测到所有检测到的启动子变异；3)测试启动子序列变体是否与适当候选基因的基因表达水平相关；4)测试启动子序列变体与糖尿病风险表型之间的关联；以及5)确认在两个独立样本群体中观察到的关联。据估计，仅在美国，糖尿病每年造成的经济负担就约为1000亿美元，这使得这种疾病对公共卫生具有重大意义。通过这个项目获得的知识将有助于通过识别新的和潜在的功能候选基因来帮助理解2型糖尿病的遗传学，帮助开发新的预防措施和/或治疗方法。

DESCRIPTION (provided by applicant): Type 2 diabetes is now considered one of the main threats to human health in the 21st century. In this project, we propose to use an integrative genomics approach to identify potentially functional regulatory variants in novel candidate genes for diabetes risk, in a large family based study. These objectively chosen candidate genes were obtained using large-scale transcriptional profiling of lymphocyte samples from 1,240 San Antonio Family Heart Study participants. Target candidate loci were nominated based on the existence of significant correlations of quantitative gene expression levels with fasting glucose levels, a major diabetes risk factor, plus one or more diabetes risk factors including fasting insulin and composite diabetes risk index. Using our unique family-based resource of quantitative genome-wide transcriptional profiles, we will examine 100 novel candidate genes that exhibit both strong evidence for cis-regulation of expression levels and significant correlations between expression levels and diabetes risk phenotypes. Our prior linkage-based evidence for cis-acting sequence variation can be exploited as a probabilistic causal anchor that should maximize our chance for finding functional variation within proximal promoters. For each of these objectively chosen genes, we will: 1) resequence approximately two kilobases of putative promoter region in 182 founder individuals to identify promoter variants; 2) genotype all detected promoter variation in each of the 100 candidate genes in the 1,240 SAFHS samples for whom we have transcriptional profiles; 3) test whether promoter sequence variants are associated with gene expression levels of the appropriate candidate gene; 4) test for associations between promoter sequence variants and diabetes risk phenotypes; and 5) confirm observed associations in two independent sample populations. The estimated economic burden of diabetes in the United States alone is approximately $100 billion per year, making this disease of major public health importance. The knowledge gained by this project will help contribute to the understanding of the genetics of type 2 diabetes through the identification of novel and potentially functional candidate genes, assisting in the development of new preventative measures and/or therapies.