Genetics of Type 2 Diabetes

描述（由申请人提供）：这个正在进行的项目先前证明了2型糖尿病（T2DM）与高加索人染色体1q21-q24之间的联系，最近在非裔美国人受试者中也证实了这一点。上一个资助期的数据令人信服地表明，尽管在不同种族群体中复制良好，但1q连锁区域包含多个易感位点，并且这些位点与高加索人的其他染色体区域相互作用。此外，来自我们实验室和其他实验室的数据表明，大多数易感性变异将是非编码的。基于这些发现，我们提出了几个假设。1)多个效应大小不同的1q基因座对连锁信号有贡献；2)每个群体至少有一些基因座是独特的。3)这些易感性变异会改变关键生理通路中的基因表达或非编码RNA； 4)这些基因座的一些亚群可以通过在可用组织（脂肪、淋巴细胞和肌肉）中基因表达的改变来检测。5) 1号染色体位点相互作用，并与非1号染色体易感位点相互作用，增加T2DM易感性。我们提出5个目标来检验这些假设。我们的研究旨在补充NIH资助的国际高通量工作，通过为我们人群中的重要区域提供生理和低通量方法来定位1q易感位点。在目标1和目标2中，我们将使用密集图谱、等位基因关联、家族研究和中间性状研究来扩展我们实验室和联盟在高加索和非裔美国人样本中的初步发现。目标3将测试1号染色体位点之间的相互作用，以及最强1q位点与其他染色体上区域之间的相互作用，特别是在其他人群中具有关联证据的非1q位点。Aim 4将使用新的方法来测试广泛定义的候选基因中的等位基因失衡，表明在白种人和非裔美国人受试者中获得的脂肪细胞、肌肉和转化淋巴细胞中存在邻近的顺式作用调节变异。Aim 5将启动研究，以确定最强烈相关变异的生理后果，包括脂肪细胞和肌肉中的基因表达。在联盟和其他实验室的持续努力下，我们期望这些研究将定位并开始描述两种人群中增加T2DM易感性的特定变异，并将导致更多的研究来确定T2DM发病机制中涉及的生物学途径。

DESCRIPTION (provided by applicant): This ongoing project previously demonstrated linkage of type 2 diabetes (T2DM) to chromosome 1q21-q24 in Caucasians, and more recently in African American subjects. Data from the last funding period show convincingly that although replicating well across ethnic groups, the 1q linkage region encompasses multiple susceptibility loci, and that these loci interact with other chromosomal regions in Caucasians. Furthermore, data from our laboratory and others suggest that most susceptibility variants will be noncoding. Based on these findings, we propose several hypotheses. 1) Multiple 1q loci of varying effect size contribute to the linkage signal, and 2) at least some loci will be unique to each population. 3) These susceptibility variants will alter gene expression or noncoding RNA in key physiologic pathways, and 4) some subset of these loci can be detected by alteration of gene expression in available tissues (fat, lymphocytes, and muscle). 5) Chromosome 1 loci will interact with each other and with non-chromosome 1 susceptibility loci to increase T2DM susceptibility. We propose 5 aims to test these hypotheses. Our studies are designed to complement NIH funded international, high throughput efforts to localize 1q susceptibility loci by providing physiologic and lower throughput approaches for regions of significance in our populations. In Aims 1 and 2, we will use dense maps, allelic association, family studies, and intermediate trait studies to extend initial findings from our laboratory and the Consortium in Caucasian and African American samples. Aim 3 will test for interactions both among chromosome 1 loci and between the strongest 1q loci and regions on other chromosomes, particularly non-1 q loci with evidence for association in other populations. Aim 4 will use novel methods to test for allelic imbalance in broadly defined candidate genes, suggesting nearby cis-acting regulatory variants, in adipocytes, muscle, and transformed lymphocytes obtained from Caucasian and African American human subjects. Aim 5 will initiate studies to identify the physiologic consequences of the most strongly associated variants, including gene expression in adipocytes and muscle. Together with ongoing efforts from the Consortium and other laboratories, we expect these studies will localize and begin to characterize the specific variants that increase susceptibiltiy to T2DM in two populations, and will lead to additional studies to identify the biological pathways involved in T2DM pathogenesis.