Identification of Prediabetes Genes by Expression Linkage Analysis

描述（由申请人提供）：NIDDK已将2型糖尿病（T2 D）的遗传学确定为五大优先研究领域之一。具体研究使用定量统计方法来识别人群中的糖尿病基因。 开发遗传资源、患者样本和研究糖尿病遗传连锁的方法。 我们在这里提出了一种新的双管齐下的策略，以确定糖尿病易感性（前驱糖尿病）的基因。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相结合。简而言之，本研究的两个目的如下。目标1：一项高分辨率相关性研究，在40对匹配的不相关受试者中，在三个关键组织（脂肪组织、骨骼肌和单核细胞（MNC））中进行体内基因表达，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中的基因表达，并在骨骼肌和MNC的胰岛素钳夹期间响应胰岛素刺激。目标二：一项以家族为基础的MNCs基因表达连锁研究，来自1,000名受试者，这些受试者先前已进行基因分型，来自两项正在进行的大型遗传研究，退伍军人管理局遗传流行病学研究（VAGES）和圣安东尼奥家族糖尿病/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。我们以前报道了强有力的证据，在这些研究中的连锁IR性状与染色体6 q23。我们假设，有差异表达的基因参与炎症和胰岛素作用的脂肪组织，骨骼肌和白细胞的受试者有不同的风险为糖尿病前期，表现为IR，这种模式的差异基因表达有助于T2 D的易感性。公共卫生相关性：2型糖尿病（T2 D）是导致失明、终末期肾病、非创伤性截肢的主要原因，并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，2型糖尿病是一个巨大的公共卫生问题，预计在未来几十年内会恶化，特别是随着人口平均年龄的增加。胰岛素抵抗（IR），通常与肥胖有关，是T2 D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基因的鉴定将大大提高我们对这些疾病如何发生的理解，并为未来的药物治疗提供新的疾病生物标志物和治疗靶点，并有望缓解糖尿病/肥胖症的加速流行。

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.