Identification of Prediabetes Genes by Expression Linkage Analysis

通过表达连锁分析鉴定糖尿病前期基因

• 批准号: 8241964
• 负责人: CHRISTOPHER P JENKINSON
• 金额: $ 49.01万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-15 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8241964
• 关键词: Abdomen; Adipose tissue; Age; Amputation; Area; Atherosclerosis; Biological Markers; Biopsy; Blindness; Blood; Blood specimen; Candidate Disease Gene; Cells; Cessation of life; Chromosomes; Clinical; Clinical Research; Complex; DNA Resequencing; DNA Sequence; Data; Development; Diabetes Mellitus; Disease; Dyslipidemias; Eligibility Determination; End stage renal failure; Environment; Epidemic; Evaluation; Family; Fasting; Fatty acid glycerol esters; Future; Gall Bladder Diseases; Gender; Gene Expression; Gene Frequency; Genes; Genetic; Genetic Markers; Genetic Predisposition to Disease; Genotype; Health; Human; Hypertension; Individual; Inflammation; Infusion procedures; Inherited; Insulin; Insulin Resistance; Leukocytes; Link; Maps; Measurable; Measurement; Measures; Medical; Methods; Minor; Mononuclear; Muscle; National Institute of Diabetes and Digestive and Kidney Diseases; Non-Insulin-Dependent Diabetes Mellitus; OGTT; Obesity; Participant; Patients; Pattern; Pharmacotherapy; Phase; Physiological; Population; Prediabetes syndrome; Predisposition; Promoter Regions; Proteomics; Public Health; Quantitative Trait Loci; RNA; Reporting; Research; Resolution; Risk; Risk Factors; SNP genotyping; Sampling; Screening procedure; Serum; Skeletal Muscle; Statistical Methods; Surrogate Markers; Susceptibility Gene; Testing; Time; Tissue Sample; Tissue-Specific Gene Expression; Tissues; Transcriptional Regulation; United States Department of Veterans Affairs; Validation; Variant; Visit; Western Blotting; basal insulin; cytokine; epidemiology study; genetic association; genetic epidemiology; genetic linkage; genetic linkage analysis; genetic resource; genetic variant; genome-wide; improved; in vivo; non-diabetic; novel; response; subcutaneous; success; trait

The NIDDK has identified the genetics of type 2 diabetes mellitus (T2D) as one of five high priority areas for research. Specifically ¿Studies using quantitative statistical methods to identify diabetes genes in human populations.¿ and ¿Development of genetic resources, patient samples and methods for studying genetic linkage for diabetes.¿ We propose here a novel two pronged strategy to identify genes for diabetes susceptibility (prediabetes). This powerful multilayered approach combines genome-wide gene expression with genetic linkage and association screening. In brief, the two Aims of this study are as follows. Aim 1: A high resolution association study of gene expression in vivo in three key tissues, adipose tissue, skeletal muscle and mononuclear cells (MNCs) in 40 matched pairs of unrelated subjects who differ by fasting specific insulin (FSI) a surrogate marker of insulin resistance (IR). Gene expression will be measured under fasted conditions in the three tissues, and in response to insulin stimulation during an insulin clamp for skeletal muscle and MNCs. Aim 2: A family-based linkage study of gene expression in MNCs from 1,000 subjects, who have previously been genotyped, from two large ongoing genetic studies, the Veterans Administration Genetic Epidemiology Study (VAGES) and the San Antonio Family Diabetes/Gallbladder Disease Study (SAFDGS). We will perform preliminary functional evaluation of the strongest candidate genes identified in the study. We previously reported strong evidence in those studies of linkage of IR traits with chromosome 6q23. We hypothesize that there is differential expression of genes involved in inflammation and insulin action in adipose tissue, skeletal muscle and leukocytes from subjects with differential risk for prediabetes, as manifested by IR, and that this pattern of differential gene expression contributes to T2D susceptibility. RELEVANCE TO PUBLIC HEALTH: Type 2 diabetes mellitus (T2D) is the leading cause of blindness, end stage renal disease, non-traumatic amputations, and it increases the risk for other serious medical disorders such as hypertension, dyslipidemia, and atherosclerotic cardiovascular disease, and is the fifth leading cause of disease-related death in the US. Thus, T2D represents a huge public health problem that is projected to worsen in the coming decades, particularly as the mean age of the population increases. Insulin resistance (IR), usually associated with obesity, is a major risk factor for the development of T2D, however, the genes which predispose some individuals to these diseases are unknown. Identification of IR genes will greatly improve our understanding of how these diseases occur and provide new biomarkers of disease and treatment targets for future drug therapy and hope for alleviation of the accelerating diabetes/obesity epidemic.

NIDDK已将2型糖尿病（T2 D）的遗传学确定为五个高度优先领域之一， research.具体而言，使用定量统计方法确定人类糖尿病基因的研究 人口。开发遗传资源、患者样本和遗传研究方法 糖尿病的联系。我们在这里提出了一种新的双管齐下的策略来确定糖尿病的基因 易感性（前驱糖尿病）。这种强大的多层方法将全基因组基因表达与 遗传连锁和关联筛选。简而言之，本研究的两个目的如下。目标1：高 三种关键组织，脂肪组织，骨骼肌，体内基因表达的分辨率关联研究 和单核细胞（MNCs）在40对匹配的不相关的受试者， (FSI)胰岛素抵抗（IR）的替代标志物。将在禁食条件下测量基因表达 在这三种组织中，以及在骨骼肌的胰岛素钳夹期间对胰岛素刺激的响应， 跨国公司。目的2：对来自1,000名受试者的MNC中的基因表达进行基于家族的连锁研究， 以前被基因分型，从两个大的正在进行的遗传研究，退伍军人管理局遗传 流行病学研究（VAGES）和圣安东尼奥家庭糖尿病/胆囊疾病研究（SAFDGS）。 我们将对研究中确定的最强候选基因进行初步功能评估。我们 先前报道了IR性状与染色体6 q23连锁的那些研究中的强有力证据。我们 假设在脂肪组织中存在参与炎症和胰岛素作用基因的差异表达， 组织、骨骼肌和白细胞，如IR所示， 并且这种差异基因表达模式有助于T2 D易感性。与公共卫生的相关性：2型糖尿病（T2 D）是导致失明的主要原因， 阶段性肾病，非创伤性截肢，并增加其他严重医疗疾病的风险 如高血压、血脂异常和动脉粥样硬化性心血管疾病，是第五大病因 在美国与疾病有关的死亡。因此，T2 D代表了一个巨大的公共卫生问题，预计将 在未来几十年中，特别是随着人口平均年龄的增加，这种情况将进一步恶化。胰岛素抵抗 (IR)，通常与肥胖有关，是T2 D发展的主要风险因素，然而， 使某些个体易患这些疾病的原因尚不清楚。IR基因的鉴定将极大地 提高我们对这些疾病如何发生的理解，并提供疾病和治疗的新生物标志物 未来药物治疗的目标和减轻加速的糖尿病/肥胖症流行的希望。