NIDDM Susceptibility Genes in Mexican Americans

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。包括墨西哥裔美国人在内的某些族群的人患2型糖尿病的倾向增加。2型糖尿病的规模越来越大，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。遗传学研究一直表明T2 DM在本质上是家族性的，从20多个全基因组扫描中有越来越多的证据表明T2 DM的连锁易感基因。然而，影响常见形式T2 DM易感性的基因在很大程度上仍不清楚。1999年，我们在圣安东尼奥家族糖尿病研究(SAFADS)中公布了为定位这些基因而进行的全基因组连锁扫描的结果，这是一项由墨西哥裔美国人组成的扩展家系研究。这项分析首次显示出糖尿病和糖尿病发病年龄特征与染色体10q上的遗传区域有关的重要证据。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10q可能包含一个影响这些特征易感性的基因(S)。我们最近通过扩展的数据集和新的CIDR标记基因组扫描证实了SAFADS中的连锁。我们在确定一个位置候选基因的变异方面取得了令人兴奋的进展，该变异在SAFADS中使糖尿病风险增加2倍以上，并解释了10q区域的部分但不是全部连锁。此外，我们最近观察到在该区域发现了一个新的糖尿病易感基因的支持性证据，该基因是最近通过对合成的小鼠QTL进行定位克隆而确定的。本申请旨在进一步检测影响糖尿病易感性和/或糖尿病发病年龄的基因连锁区域(S)。我们提出了一种综合策略，该策略将利用连锁不平衡作图和对位置候选基因的彻底评估的优势。使用这一策略，我们将检查所有202个已被确定位于富含基因的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)的使用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. 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.