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

基本信息

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
项目类别：
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

项目摘要

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庭的研究中，使用综合基因组学方法来识别糖尿病风险新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 1,240 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分析而获得的。基于定量基因表达水平与空腹血糖水平（主要糖尿病危险因素，加上一种或多种糖尿病危险因素，包括空腹胰岛素和复合糖尿病风险指数）存在显着相关性，提名目标候选基因座。利用我们独特的基于家族的定量全基因组转录谱资源，我们将检查 100 个新的候选基因，这些基因既表现出表达水平顺式调节的有力证据，又表现出表达水平与糖尿病风险表型之间的显着相关性。我们之前基于连锁的顺式作用序列变异证据可以被用作概率因果锚，这应该最大限度地提高我们在近端启动子内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 个创始人个体中大约 2 KB 的推定启动子区域进行重新测序，以识别启动子变体； 2) 对我们拥有转录谱的 1,240 个 SAFHS 样本中的 100 个候选基因中的每一个中检测到的所有启动子变异进行基因分型； 3) 测试启动子序列变异是否与适当候选基因的基因表达水平相关； 4) 测试启动子序列变异与糖尿病风险表型之间的关联； 5) 确认两个独立样本群体中观察到的关联。据估计，仅美国每年因糖尿病造成的经济负担就约为 1000 亿美元，这使得这种疾病具有重大的公共卫生重要性。该项目获得的知识将通过鉴定新颖的和潜在功能性的候选基因，有助于了解 2 型糖尿病的遗传学，协助开发新的预防措施和/或疗法。