Identification of Prediabetes Genes by Expression Linkage Analysis

NIDDK已将2型糖尿病(T2D)的遗传学确定为五个优先领域之一 研究。具体地说，使用定量统计方法识别人类糖尿病基因的研究 遗传资源、患者样本和遗传研究方法的发展 我们在这里提出了一种新的双管齐下的策略来识别糖尿病的基因 易感性(糖尿病前期)。这种强大的多层次方法结合了全基因组的基因表达和 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：高潮 脂肪组织、骨骼肌三种关键组织体内基因表达的分辨关联研究 和单核细胞(MNC)在40对匹配的无关受试者中，他们的空腹特定胰岛素不同 (FSI)胰岛素抵抗(IR)的替代标志物。基因表达将在禁食条件下进行测量 在这三种组织中，以及在骨骼肌胰岛素钳夹期间对胰岛素刺激的反应 跨国公司。目的2：一项基于家族的基因表达连锁研究，来自1,000名受试者 之前从两项正在进行的大型基因研究中进行了基因分型，退伍军人管理局基因 流行病学研究(VAGES)和圣安东尼奥家族糖尿病/胆囊病研究(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道了IR性状与染色体6q23连锁的有力证据。我们 假设脂肪中存在炎症和胰岛素作用相关基因的差异表达 如IR所示，糖尿病前期风险不同的受试者的组织、骨骼肌和白细胞， 这种差异基因表达模式导致了T2D易感性。

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.