Identification of Regulatory Variants in Novel Candidate Genes for Diabetes

糖尿病新候选基因调控变异的鉴定

• 批准号: 7302573
• 负责人: JOANNE E. CURRAN
• 金额: $ 36.09万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7302573
• 关键词: Affect; Age; Base Pairing; Behavioral; Candidate Disease Gene; Characteristics; Cis-Acting Sequence; Cohort Studies; Complex; DNA Resequencing; Data; Development; Diabetes Mellitus; Disease; Disease susceptibility; Economic Burden; Elements; Enrollment; Epidemic; Ethnic Origin; European; Exhibits; Family; Fasting; Fatty acid glycerol esters; Gallbladder; Gene Expression; Genes; Genetic; Genetic Polymorphism; Genetic Research; Genetic Transcription; Genetic Variation; Genome; Genomics; Genotype; Glucose; Health; Heart; Hour; Human; Hyperglycemia; Impairment; Individual; Insulin; Insulin Resistance; Knowledge; Life Style; Location; Lymphocyte; Measurement; Measures; Meta-Analysis; Metabolic; Metabolic syndrome; Mexican Americans; Modification; Molecular Analysis; Non-Insulin-Dependent Diabetes Mellitus; Nucleotides; Obesity; Participant; Pathogenesis; Phenotype; Population; Predisposition; Prevalence; Procedures; Promoter Regions; Public Health; Regulation; Regulatory Element; Relative (related person); Research Personnel; Resources; Risk; Risk Factors; Sampling; Sampling Studies; Source; Standards of Weights and Measures; Testing; Transcript; Transcription Initiation Site; United States; Variant; Wisconsin; base; diabetes risk; functional genomics; genetic analysis; genetic linkage analysis; impaired glucose tolerance; indexing; insulin secretion; interest; novel; pandemic disease; programs; promoter; sedentary; sex; trait

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.

描述（由申请人提供）：2型糖尿病现在被认为是21世纪人类健康的主要威胁之一。在这个项目中，我们建议在一项基于大型家族的研究中，使用整合基因组学方法来识别糖尿病风险的新型候选基因中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谱分析获得的。根据定量基因表达水平与空腹血糖水平（糖尿病的主要危险因素）以及包括空腹胰岛素和糖尿病综合危险指数在内的一个或多个糖尿病危险因素之间存在显著相关性，提名候选靶点位点。利用我们独特的基于家族的全基因组定量转录谱资源，我们将研究100个新的候选基因，这些基因在表达水平的顺式调节和表达水平与糖尿病风险表型之间的显著相关性方面都表现出强有力的证据。我们先前关于顺式作用序列变异的基于链接的证据可以作为一个概率因果锚来利用，它应该最大限度地提高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，我们将：1)在182个创始人个体中对大约2千碱基的假定启动子区域进行重测序，以确定启动子变异；2)基因型在1,240个SAFHS样本中检测到100个候选基因的启动子变异，我们对其进行了转录谱分析；3)检测启动子序列变异是否与相应候选基因的基因表达水平相关；4)启动子序列变异与糖尿病风险表型的相关性检验；5)在两个独立的样本群体中证实观察到的关联。据估计，仅在美国，每年糖尿病的经济负担就约为1000亿美元，使这种疾病成为重要的公共卫生问题。通过该项目获得的知识将有助于通过鉴定新的和潜在功能的候选基因来了解2型糖尿病的遗传学，协助开发新的预防措施和/或治疗方法。