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: 7676027
• 负责人: CHRISTOPHER P JENKINSON
• 金额: $ 51.34万
• 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/7676027
• 关键词: Abdomen; Adipose tissue; Age; 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; 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; Traumatic Amputation; United States Department of Veterans Affairs; Validation; Variant; Visit; Western Blotting; basal insulin; cytokine; epidemiology study; genetic epidemiology; genetic linkage; genetic linkage analysis; genetic resource; genetic variant; genome-wide; improved; in vivo; non-diabetic; novel; public health relevance; response; skeletal; subcutaneous; success; trait

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.

描述（由申请人提供）：NIDDK已将2型糖尿病（T2D）的遗传学确定为五个高优先级研究领域之一。具体地说，研究使用定量统计方法来确定人群中的糖尿病基因。糖尿病遗传资源、患者样本和遗传连锁研究方法的开发。我们在此提出一种新的双管齐下的策略来确定糖尿病易感性基因（前驱糖尿病）。这种强大的多层方法结合了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。目的1：在40对不相关的受试者中，对三个关键组织，脂肪组织，骨骼肌和单核细胞（MNCs）的体内基因表达进行高分辨率关联研究，这些受试者的空腹特异性胰岛素（FSI）是胰岛素抵抗（IR）的替代标志物。将在禁食条件下测量三种组织的基因表达，以及在骨骼肌和跨国公司胰岛素钳夹期间对胰岛素刺激的反应。目标2：一项基于家族的跨国公司基因表达连锁研究，这些研究对象来自退伍军人管理局遗传流行病学研究（VAGES）和圣安东尼奥家族糖尿病/胆囊疾病研究（SAFDGS）两项正在进行的大型遗传研究，此前已对1000名受试者进行了基因分型。我们将对研究中发现的最强候选基因进行初步的功能评估。我们之前在这些研究中报道了IR性状与6q23染色体连锁的有力证据。我们假设，在具有不同前驱糖尿病风险的受试者中，脂肪组织、骨骼肌和白细胞中参与炎症和胰岛素作用的基因表达存在差异，正如IR所表现的那样，这种差异基因表达模式有助于T2D易感性。公共卫生相关性：2型糖尿病（T2D）是失明、终末期肾病、非创伤性截肢的主要原因，它增加了其他严重医学疾病（如高血压、血脂异常和动脉粥样硬化性心血管疾病）的风险，是美国疾病相关死亡的第五大原因。因此，糖尿病是一个巨大的公共健康问题，预计在未来几十年将进一步恶化，特别是随着人口平均年龄的增加。胰岛素抵抗（IR）通常与肥胖相关，是T2D发展的主要危险因素，然而，使某些个体易患这些疾病的基因尚不清楚。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，为未来的药物治疗提供新的疾病生物标志物和治疗靶点，并有望缓解加速的糖尿病/肥胖流行。