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: 8432037
• 负责人: CHRISTOPHER P JENKINSON
• 金额: $ 49.81万
• 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 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8432037
• 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 Expression Profiling; 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; 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; screening; 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.

NIDDK 已将 2 型糖尿病 (T2D) 的遗传学确定为五个高度优先领域之一 研究。具体来说，使用定量统计方法来识别人类糖尿病基因的研究 以及遗传资源、患者样本和遗传研究方法的开发 我们在这里提出了一种新颖的双管齐下的策略来识别糖尿病基因 易感性（糖尿病前期）。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，本研究的两个目标如下。目标1：高 体内脂肪组织、骨骼肌三大关键组织基因表达解析关联研究 和单核细胞 (MNC) 在 40 对匹配的无关受试者中进行，这些受试者因空腹特定胰岛素而异 (FSI) 胰岛素抵抗 (IR) 的替代标志物。基因表达将在禁食条件下测量 在这三种组织中，以及在骨骼肌和胰岛素钳夹过程中对胰岛素刺激的反应 跨国公司。目标 2：对 1,000 名受试者的跨国公司基因表达进行基于家族的连锁研究，这些受试者 之前已根据两项正在进行的大型基因研究（退伍军人管理局基因研究）进行了基因分型 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 先前在这些研究中报告了 IR 性状与染色体 6q23 联系的有力证据。我们 假设脂肪中参与炎症和胰岛素作用的基因存在差异表达 来自具有不同糖尿病前期风险的受试者的组织、骨骼肌和白细胞，如 IR 所示， 这种差异基因表达模式会导致 T2D 易感性。

项目成果

Studies of phosphodiesterase effects on adipose tissue metabolism in obese subjects by the microdialysis technique.

通过微透析技术研究磷酸二酯酶对肥胖受试者脂肪组织代谢的影响。

• 发表时间: 2005
• 期刊: Journal of physiology and pharmacology : an official journal of the Polish Physiological Society
• 作者: Flechtner-Mors,M;Jenkinson,CP;Alt,A;Biesalski,HK;Adler,G;Ditschuneit,HH
• 通讯作者: Ditschuneit,HH

Effects of covariates and interactions on a genome-wide association analysis of rheumatoid arthritis.

协变量和相互作用对类风湿关节炎全基因组关联分析的影响。

• DOI: 10.1186/1753-6561-3-s7-s84
• 发表时间: 2009
• 期刊: BMC proceedings
• 作者: Arya,Rector;Hare,Elizabeth;DelRincon,Inmaculada;Jenkinson,ChristopherP;Duggirala,Ravindranath;Almasy,Laura;Escalante,Agustin
• 通讯作者: Escalante,Agustin

The relationship between {beta}-cell function and glycated hemoglobin: results from the veterans administration genetic epidemiology study.

• DOI: 10.2337/dc10-1352
• 发表时间: 2011-04
• 期刊: Diabetes care
• 影响因子: 16.2
• 作者: Kanat M;Winnier D;Norton L;Arar N;Jenkinson C;Defronzo RA;Abdul-Ghani MA
• 通讯作者: Abdul-Ghani MA

Norepinephrine-induced glycerol release from adipose tissue: influence of age and body mass index in obese people.

去甲肾上腺素诱导的脂肪组织甘油释放：肥胖人群年龄和体重指数的影响。

• DOI: 10.1016/s0899-9007(01)00608-6
• 发表时间: 2001
• 期刊: Nutrition (Burbank, Los Angeles County, Calif.)
• 作者: Flechtner-Mors,M;Alt,A;Adler,G;Ditschuneit,HH;Jenkinson,CP
• 通讯作者: Jenkinson,CP

Cloning and characterization of the human type II arginase gene.

• DOI: 10.1006/geno.1996.0606
• 发表时间: 1996-12
• 期刊: Genomics
• 影响因子: 4.4
• 作者: J. Vockley;C. Jenkinson;Hridayabiranjan Shukla;R. Kern;W. Grody;S. Cederbaum