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

我们一直在跟踪我们之前在皮马印第安人中进行的全基因组关联（GWA）研究（100k）的关联信号。迄今为止，已经在几个基因组区域对4035多个snp进行了基因分型，用于精细定位。我们还测试了最佳snp的种群水平显著性，迄今为止，在3500名全血统皮马印第安人的种群样本中，我们已经对超过1703个snp进行了基因分型。选定的snp正在进一步测试，以在另外4100名皮马印第安人和3000名来自强心脏研究的美洲原住民中复制。我们已经确定了与糖尿病密切相关的NELL-1基因附近的变异，我们目前正试图确定功能性变异。此外，我们已经确定了与体重指数高度相关的A2BP1基因的变异，我们目前正试图确定受该基因影响的代谢途径。通过GWA鉴定的另一个SNP位于编码甘露糖结合凝集素蛋白的MBL2基因内。这种蛋白在先天免疫系统中起关键作用，最近发现它在胰岛素抵抗和1型糖尿病和妊娠糖尿病的发展中起作用。先前已被证明影响血清MBL2蛋白水平的变异与两个独立的皮马印第安人和阿米什人群体中的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.