NIDDM Susceptibility Genes in Mexican Americans

描述（由申请人提供）：2型糖尿病（T2 DM）的发病率持续上升，并日益影响所有种族所有年龄段的个体。来自某些种族群体（包括墨西哥裔美国人）的个体发生T2 DM的倾向增加。T2 DM的规模不断扩大，其巨大的货币和社会成本要求需要新的方法来提供早期风险估计以及新的干预途径。遗传学研究一致表明，T2 DM在本质上是家族性的，并且有越来越多的证据表明，来自20多个全基因组扫描的易感基因座与T2 DM连锁。然而，影响T2 DM常见形式易感性的基因在很大程度上仍然未知。1999年，我们发表了一项全基因组连锁扫描的结果，该扫描旨在定位圣安东尼奥家族糖尿病研究（SAFADS）中的这些基因，SAFADS是一项由墨西哥裔美国人组成的扩展系谱研究。该分析首次显示了糖尿病和糖尿病发病年龄与染色体10 q上的遗传区域之间存在联系的重要证据。从那时起，在其他人群中进行的大量T2 DM基因组扫描和相关定量测量的结果也表明，染色体10 q是可能含有影响这些性状易感性的基因的区域。我们最近已经证实了SAFADS与扩展数据集和新的CIDR标记基因组扫描的联系。我们已经取得了令人兴奋的进展，确定了一个位置候选基因的变异，该变异使SAFADS中糖尿病的风险增加了2倍以上，并解释了10 q区域的部分但不是全部连锁。此外，我们最近观察到的支持性证据，一个新的糖尿病易感基因的区域，最近确定通过定位克隆的合成小鼠QTL。本申请旨在进一步检查影响糖尿病易感性和/或糖尿病发病年龄的基因的连锁区域。我们提出了一个组合策略，将利用连锁不平衡作图和位置候选基因的彻底评估的优势。使用这种策略，我们将检查所有202个已被确定为位于基因丰富的26 Mb 1.5 LOD支持区间内的基因。此外，一种新的统计功能基因组分析（贝叶斯数量性状核苷酸分析）的利用，应提高识别所涉及的特定变异的最后阶段。

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. Individuals from certain ethnic groups including Mexican Americans have an increased propensity towards developing T2DM. The growing magnitude of T2DM and its huge monetary and social costs mandate a need for new methods to provide early risk estimates as well as novel avenues of intervention. Genetic studies consistently indicate that T2DM is familial in nature, and there is mounting evidence for susceptibility loci from over 20 genome-wide scans for linkage of T2DM. However, the genes influencing susceptibility to the common forms of T2DM remain largely unknown. In 1999, we published the results of a genome-wide linkage scan conducted to localize those genes in the San Antonio Family Diabetes Study (SAFADS), an extended pedigree study comprised of Mexican Americans. The analysis was the first to show significant evidence for linkage of the traits diabetes and diabetes age-of-onset to a genetic region on chromosome 10q. Since then, results from a number of genome scans for T2DM and related quantitative measures in other populations have also implicated chromosome 10q as a region which might harbor a gene(s) influencing susceptibility to these traits. We have recently confirmed linkage in SAFADS with an expanded dataset and a new CIDR marker genome scan. We have made exciting progress toward identifying a variant in a positional candidate gene that increases risk for diabetes more than 2-fold in SAFADS and accounts for part but not all of the linkage in the 10q region. Additionally, we have recently observed supportive evidence of a novel diabetes susceptibility gene in the region that was recently identified through positional cloning of a synthetic mouse QTL. This application aims to further examine the linked region for gene(s) that influence diabetes susceptibility and/or diabetes age-of-onset. We are proposing a combined strategy that will exploit the strengths of linkage disequilibrium mapping and thorough evaluation of positional candidate genes. Using this strategy, we will examine all 202 genes that have been identified to be located within the gene-rich 26 Mb 1.5 LOD support interval. Furthermore, the utilization of a novel statistical functional genomic analysis (Bayesian quantitative trait nucleotide analysis) should enhance the final stage of identifying the specific variants involved.