Follow-Up Studies of a Genome-Wide Association Analysis in Pima Indians

我们一直在跟踪来自我们之前的全基因组关联(GWA)研究(100k)的PIMA印第安人的关联信号。到目前为止，已经对超过4035个SNPs进行了基因分型，以便在几个基因组区域进行精细定位。我们还在测试最好的SNPs在人群水平上的意义，到目前为止，我们已经在3500名全血统的皮马印第安人中对1703多个SNPs进行了基因分型。来自强心脏研究的另外4100名皮马印第安人和3000名美洲原住民正在进一步测试选定的SNPs是否可以复制。我们已经确定了Nell-1基因附近与糖尿病密切相关的变异，目前我们正在努力建立功能变异。此外，我们已经在A2BP1基因中发现了与体重指数高度相关的变异，目前我们正在试图确定受该基因影响的代谢途径。另一个SNP是通过GWA定位于编码甘露糖结合凝集素蛋白的MBL2基因。这种蛋白质是先天免疫系统中的关键角色，最近被发现在胰岛素抵抗以及1型糖尿病和妊娠期糖尿病的发展中发挥作用。在两组独立的皮马印第安人和阿米什人群中，先前已被证明影响血清MBL2蛋白水平的变异与2型糖尿病有关。

We have been following-up association signals from our prior genome-wide association (GWA) study (100k) in Pima Indians. To date, have genotyped more than 4035 SNPs for fine-mapping in several genomic regions. We are also testing the population-level significance of the best SNPs and, to date, have genotyped more than 1703 SNPs in a population-based sample of 3500 full-heritage Pima Indians. Selected SNPs are being further tested for replication in an additional 4100 Pima Indians as well as 3000 Native Americans from the Strong Heart study. We have identified variants near the NELL-1 gene that are strongly associated with diabetes and we are currently trying to establish the functional variant. In addition, we have identified variation within the A2BP1 gene that is highly associated with body mass index and we are currently trying to determine the metabolic pathway that is affected by this gene. Another SNP that was identified via the GWA mapped within the MBL2 gene that encodes the mannose-binding lectin protein. This protein is a key player in the innate immune system, and has recently been found to play a role in insulin resistance and development of type 1 diabetes and gestational diabetes. Variants which have previosuly been shown to influence serum MBL2 protein levels were associated with type 2 diabetes in two independent groups of Pima Indians as well as an Amish population.