Type 2 Diabetes Gene Discovery Linked to 3p in Hispanics

描述(申请人提供)：2型糖尿病(T2 DM)的发病率持续上升，并日益影响所有种族的所有年龄段的个人；然而，包括墨西哥裔美国人在内的某些种族群体的个人患T2 DM的倾向增加。墨西哥裔美国人患T2 DM的风险增加可能表明遗传易感性增加。因此，我们进行了全基因组连锁扫描，以定位圣安东尼奥家族糖尿病/胆囊症研究(SAFDGS)中的这些基因，这是一项扩展的家系研究，包括39个墨西哥裔美国家庭，906个个体。使用每个受试者最近的糖尿病状态的随访数据，我们观察到显著的证据表明糖尿病特征和糖尿病发病年龄与3p染色体上的一个遗传区域有关(经验多点LOD值为3.76p=0.000016)。此前，许多独立研究表明，这一区域与糖尿病及相关特征有关。此外，在一项对墨西哥裔美国人的独立大型研究中，我们最近观察到该地区已知和新的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。峰值附近的1.5-LOD支持区间跨越大约15Mb的区域，包含大约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，但许多基因的功能仍不清楚。这项建议旨在通过识别与糖尿病相关的DNA序列变异并解释观察到的连锁信号，来识别该区域影响糖尿病易感性和/或糖尿病发病年龄的基因(S)。为了有效和彻底地研究这个基因座，我们将以大约每1.6千碱基1个碱基的间隔进行变异的关联测试(具体目标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，在本提案的第三个具体目标中使用一种新的统计功能基因组分析(BQTN)应该会加强识别所涉及的特定变种的最后阶段。

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.