Genetic and Biochemical Predictors of Type 2 DM in Women

描述(申请人提供)：我们提议在一项对4,300名不同种族的绝经后妇女进行的大型嵌套病例对照研究中，检测两种炎症细胞因子(即肿瘤坏死因子-a和白介素6)、一种急性期反应物(即C-反应蛋白)、三种内皮激活标志物(即细胞间黏附分子-L、血管细胞黏附分子-L和E-选择素)以及六个相关候选基因的基因变异在2型糖尿病(DM)发生中的作用。尽管将炎症和内皮功能障碍与肥胖和胰岛素抵抗联系起来的累积数据表明，这些生化标记物在2型糖尿病的病因中发挥了核心作用，但很少有前瞻性数据来检验它们作为2型糖尿病未来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，我们将采用从参加妇女健康倡议观察性研究队列的大约83,000名没有心血管疾病或2型糖尿病的绝经后妇女的血液样本，前瞻性地确定上述生化标记物在预测2型糖尿病未来风险方面的独立和联合作用。同时，我们将研究直接影响炎症/内皮细胞激活(包括TNF、NOS3和PPAR伽马)以及肥胖和胰岛素抵抗(TNF-α、PPAR伽马、UCP2、CAPN10和APP2)的六个特定候选基因的遗传变异，特别是编码和启动子区域内的那些基因。此外，我们还将利用最先进的基因分型技术和统计方法，通过单倍型频率分析，对几个有希望的2型DM易感候选基因的多态性进行综合评估。此外，大多数2型糖尿病的遗传研究来自高加索人或美洲印第安人群体，从其他种族群体获得的数据有限。由于以前的研究表明，不同人群的易感基因可能存在显著差异，因此，比较不同种族的数据将有助于我们更好地理解2型糖尿病未来风险的遗传预测因素。这一系列全面而有重点的分析结果可能会为2型糖尿病的病因提供新的线索，特别是在少数族裔美国人中，如西班牙裔/拉丁裔、黑人/非洲人和亚洲人/太平洋岛民，这些人承受着不成比例的高负担，但对他们的研究很少。从这项拟议的研究中获得的知识可能会建议新的干预策略，以降低普通人群中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.