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对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家庭的大型研究中使用一种综合基因组学方法来鉴定糖尿病风险的新型候选基因中的潜在功能调节变异。这些客观选择的候选基因是使用来自1,240个圣安东尼奥家庭心脏研究参与者的淋巴细胞样品的大规模转录分析获得的。基于定量基因表达水平与禁食葡萄糖水平，主要糖尿病风险因素以及一个或多个糖尿病风险因素，包括禁食胰岛素和复合糖尿病风险指数，包括一个或多个糖尿病风险因素，基于定量基因表达水平的显着相关性的提名。使用我们独特的基于家庭基因组全基因组转录谱的资源，我们将研究100个新型候选基因，这些基因既表现出表达水平的顺式调节，又表达表达水平与糖尿病风险表型之间的显着相关性。我们先前基于连锁的证据证据可以利用作为概率的因果关系锚定，该疾病应最大化我们在近端启动子内找到功能变化的机会。对于这些客观选择的基因中的每一个，我们将：1）在182个创始人个体中，将大约两个推定启动子区域的重新设备重新等式，以识别启动子变体； 2）基因型在1,240个SAFHS样品中的100个候选基因中的每一个中检测到的所有启动子变异； 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； 5）确认在两个独立样本人群中观察到的关联。仅美国糖尿病的估计经济负担每年约为1000亿美元，这使得这种公共健康的重要性很重要。该项目获得的知识将有助于通过鉴定新型和潜在功能的候选基因来帮助理解2型糖尿病的遗传学，从而有助于开发新的预防措施和/或疗法。