Genetic and Biochemical Predictors of Type 2 DM in Women

描述（由申请人提供）：我们建议在4，300名不同种族的绝经后妇女的大型前瞻性巢式病例对照研究中检查两种炎性细胞因子（即，TNF-α和IL-6），急性期反应物（即，C-反应蛋白），内皮激活的三个标志物（即，ICAM-1、VCAM-1和E-选择素）和6个相关候选基因中的遗传变体在2型糖尿病（DM）的发展中的作用。虽然越来越多的数据表明炎症和内皮功能障碍与肥胖和胰岛素抵抗有关，这些生化标志物在2型糖尿病的病因学中起着重要作用，但很少有前瞻性数据可以检查它们作为未来2型糖尿病风险预测因子的作用，特别是在女性和少数群体中。在一项集中的系列研究中，使用了来自参与妇女健康倡议观察性研究队列的约83，000名无心血管疾病或2型糖尿病的绝经后妇女的基线血样，我们将前瞻性地确定上述生化标志物在预测未来2型糖尿病风险中的独立和联合贡献。同时，我们将研究遗传变异，特别是那些在编码区和启动子区，六个特定的候选基因，直接影响炎症/内皮细胞活化（包括TNF，NOS 3和PPARgamma）和肥胖和胰岛素抵抗（TNF-α，PPARgamma，UCP 2，CAPN 10和aP 2）。此外，我们将进行一个全面的评价多态性内的几个有前途的候选基因的2型糖尿病易感性使用单倍型频率分析与国家的最先进的基因分型技术和统计方法。此外，大多数2型糖尿病的遗传学研究来自高加索人或美洲印第安人人群，而其他种族人群的数据有限。由于之前的研究表明，不同人群的易感基因可能存在显着差异，因此比较不同种族的数据将提高我们对未来2型糖尿病风险的遗传预测因素的了解。这一系列全面而集中的分析结果可能为2型糖尿病的病因学提供新的线索，特别是在少数民族美国人中，如西班牙裔/拉丁美洲人，黑人/非洲人和亚洲人/太平洋岛民，他们承受着不成比例的高负担，但研究甚少。从这项拟议的研究中获得的知识可能会提出新的干预策略，以降低一般人群中2型糖尿病的发病率。

DESCRIPTION (provided by applicant): We propose to examine, in a large prospective nested case-control study of 4,300 ethnically diverse postmenopausal women, the roles of two inflammatory cytokines (i.e., TNF-a and IL-6), an acute-phase reactant (i.e., C-reactive protein), three markers of endothelial activation (i.e., ICAM-l, VCAM-l, and E-selectin), and genetic variants in six related candidate genes in the development of type 2 diabetes mellitus (DM). Although accumulating data linking inflammation and endothelial dysfunction to obesity and insulin resistance suggest central roles of these biochemical markers in the etiology of type 2 DM, little prospective data are available examining their roles as predictors for future risk of type 2 DM, especially among women and minority groups. In a focused series of studies employing blood samples obtained at baseline from approximately 83,000 postmenopausal women free of cardiovascular disease or type 2 DM participating in the Women's Health Initiative Observational Study Cohort, we will determine prospectively the independent and joint contributions of the above biochemical markers in predicting future risk of type 2 DM. In parallel, we will examine genetic variants, particularly those within the coding and promoter regions, of the six specific candidate genes that directly affect inflammation/endothelial activation (including TNF, NOS3, and PPARgamma) and obesity and insulin resistance (TNF-alpha, PPARgamma, UCP2, CAPN10, and aP2). In addition, we will conduct a comprehensive evaluation of polymorphisms within several promising candidate genes of type 2 DM susceptibility using analysis of haplotype frequency with state-of-the art genotyping technology and statistical methods. Furthermore, most genetic studies of type 2 DM have come from Caucasian or American-Indian populations and limited data are available from other ethnic populations. Because previous studies have demonstrated that the susceptibility genes may vary significantly across different populations, comparison of data from different ethnic groups will improve our understanding of genetic predictors for future risk of type 2 DM. Findings from this series of comprehensive yet focused analyses could shed new light on the etiology of type 2 DM, especially among minority Americans such as Hispanic/Latinos, Blacks/Africans, and Asians/Pacific Islanders who bear a disproportionately high burden of this disease yet have been poorly studied. Knowledge gained from this proposed study may suggest new intervention strategies to lower the incidence of type 2 DM in the general population.