Identification of Prediabetes Genes by Expression Linkage Analysis

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度优先研究领域之一。具体地说，研究使用定量统计方法来识别人类人群中的糖尿病基因。和开发遗传资源、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来识别糖尿病易感性(糖尿病前期)的基因。这种强大的多层次方法将全基因组基因表达与遗传连锁和关联筛选结合在一起。简而言之，本研究的两个目的如下。目的：研究胰岛素抵抗(IR)的替代标志物--特定胰岛素(FSI)在40对匹配的无关受试者体内脂肪组织、骨骼肌和单个核细胞(MNC)三个关键组织中基因表达的高分辨率关联研究。基因的表达将在禁食条件下测量，并在骨骼肌和单核细胞的胰岛素钳夹期间对胰岛素刺激做出反应。目的2：从两个正在进行的大型遗传学研究，即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/胆囊病研究(SAFDGS)，对1000名先前已进行基因分型的受试者进行基于家族的单核细胞基因表达的连锁研究。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连锁的有力证据。我们假设胰岛素抵抗所显示的不同糖尿病前期风险受试者的脂肪组织、骨骼肌和白细胞中参与炎症和胰岛素作用的基因存在差异表达，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)是导致失明、终末期肾脏疾病、非创伤性截肢的主要原因，它增加了其他严重医学疾病的风险，如高血压、血脂异常和动脉粥样硬化性心血管疾病，是美国与疾病相关的死亡的第五大原因。因此，T2D是一个巨大的公共卫生问题，预计在未来几十年将恶化，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T2D的主要危险因素，然而，一些人易患这些疾病的基因尚不清楚。IR基因的识别将极大地提高我们对这些疾病发生机制的理解，为未来的药物治疗提供新的疾病生物标志物和治疗靶点，并有望缓解日益加剧的糖尿病/肥胖症流行。

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.