Type 2 Diabetes Gene Discovery Linked to 3p in Hispanics

描述（由申请人提供）：2型糖尿病（T2 DM）的发病率持续上升，并且越来越多地影响所有种族群体中所有年龄段的个体;然而，某些种族群体（包括墨西哥裔美国人）的个体发生T2 DM的倾向增加。墨西哥裔美国人T2 DM风险增加可能表明遗传易感性增加。因此，我们在圣安东尼奥家庭糖尿病/胆囊研究（SAFDGS）中进行了全基因组连锁扫描以定位这些基因，SAFDGS是一项扩展的系谱研究，包括39个墨西哥裔美国人家庭，906名个体。使用使用每个受试者最近的糖尿病状态的随访数据，我们观察到糖尿病和糖尿病发病年龄与染色体3 p上的遗传区域（经验多点LOD得分为3.76，p=0.000016）的关联的显著证据。该区域先前已被许多独立的研究与糖尿病和相关特征有关。此外，我们最近在一项独立的墨西哥裔美国人大型研究中观察到该地区已知和新转录本的表达谱与糖尿病风险高度相关。因此，越来越多的证据表明，该区域可能含有影响T2 DM易感性的基因，值得探索。我们的峰值周围的1.5-LOD支持区间跨越约15 Mb的区域，包含约59个已识别的基因和EST。这些基因中的一些似乎与糖尿病的病理生理学具有生物学相关性，而许多基因的功能仍然未知。该提案旨在通过鉴定与糖尿病相关的DNA序列变异并解释观察到的连锁信号来鉴定该区域中影响糖尿病易感性和/或糖尿病发病年龄的基因。为了有效和彻底地研究该基因座，我们将以每1.6个碱基中约1个的间隔对变体进行关联检验（特定目标1）。我们还将对该区域的候选基因进行全面分析（具体目标2）。此外，在该提案的第三个具体目标中利用新的统计功能基因组分析（BQTN）应增强识别所涉及的特定变体的最后阶段。

DESCRIPTION (provided by applicant): The incidence of type 2 diabetes (T2DM) continues to rise and increasingly affects individuals of all ages across all ethnic groups; however, individuals from certain ethnic groups including Mexican Americans have an increased propensity towards developing T2DM. The increased risk of T2DM in Mexican Americans may indicate an increased genetic susceptibility. Hence, we performed a genome-wide linkage scan to localize those genes in the San Antonio Family Diabetes/Gallbladder Study (SAFDGS), an extended pedigree study comprised of 39 Mexican Americans families with 906 individuals. Using follow-up data which used each subject's most recent diabetic status, we observed significant evidence for linkage of the traits diabetes and diabetes age-of-onset to a genetic region on chromosome 3p (empirical multipoint LOD score of 3.76, p=0.000016). This region has previously been implicated by numerous independent studies to be linked to diabetes and related traits. In addition, we have recently observed the expression profiles of known and novel transcripts from this region to be highly correlated with diabetes risk in an independent, large study of Mexican Americans. Therefore, there is growing evidence that this region may harbor a gene influencing susceptibility to T2DM and deserves exploration. The 1.5-LOD support interval around our peak spans an approximately 15 Mb region and harbors approximately 59 identified genes and ESTs. A number of these genes appear to have biologic relevance to the pathophysiology of diabetes, whereas the function of many is still unknown. This proposal aims to identify the gene(s) in this region that influences diabetes susceptibility and/or diabetes age-of-onset by identifying DNA sequence variants that are associated with diabetes and account for the observed linkage signal. In order to efficiently and thoroughly investigate this locus, we will conduct association tests for variants at intervals of approximately 1 per 1.6 kilobases (Specific Aim 1). We will also conduct comprehensive analyses of candidate genes in the region (Specific Aim 2). In addition, the utilization of a novel statistical functional genomic analysis (BQTN) in the 3rd specific aim of this proposal should enhance the final stage of identifying the specific variants involved.