Positional Cloning Of A Diabetes Gene On Chromosome 11

先前对居住在美国的皮马印第安人进行的基因组扫描表明，染色体11 q23 -24（LOD=3.6）上存在肥胖易感基因座。还有证据表明，相同的基因组区域包含2型糖尿病（T2 DM）的易感基因座（LOD=1.7）。双变量连锁分析的组合表型糖尿病的易感位点（LOD= 5.2）的最强有力的证据。在这个精确的基因组区域（D11 S4464）与体重指数（BMI）的联系已经在来自心脏病研究的高加索人和来自犹他州（Myriad Genetics）的家系中的病态肥胖男性中得到了复制。皮马印第安人的连锁区域跨越约24 Mb。我们目前的目标是定位克隆负责连锁的基因。正在对整个连锁区域的位置候选基因进行测序，以确定遗传变异。此外，连锁不平衡（LD）定位被用来缩小易感区域。对于LD作图，单核苷酸多态性（SNP）被系统地鉴定，并在整个连锁区域以25 kB的间隔进行基因分型。迄今为止，在1229个DNA样本中，已经对跨越我们连锁区域的大约1070个SNP进行了单独的基因分型，并测试了与BMI或T2 DM的关联。已经初步鉴定了两个独立的区域（BIG 1和BIG 2），其含有与BMI和糖尿病显著相关的多个SNP。为了确定这些区域是否真正定义了一个易感性基因座，或者它们是否代表假阳性结果，来自这两个区域的SNP正在其他人群中复制。到目前为止，已经在Fractionary家族DNA收集、FUSION DNA收集、英国家族收集、来自斯塔尔县的墨西哥裔美国人和犹他州高加索人中测试了多个SNP。从这个广泛的种族群体的关联结果表明，确实有两个独立的肥胖易感基因座。其中一个基因座是皮马印第安人、墨西哥裔美国人、芬兰人（FUSION）和高加索人共有的。第二个基因座在皮马印第安人和犹他州高加索人中很常见。这些结果目前正在通过额外的合作努力来扩展，以在来自圣安东尼奥的墨西哥裔美国人和来自Botnia的芬兰人中进行基因型变异。

A prior genomic scan in Pima Indians living in the United States indicated an obesity susceptibility locus on chromosome 11q23-24 (LOD=3.6). There was also evidence that the same genomic region contained a susceptibility locus for type 2 diabetes mellitus (T2DM)(LOD=1.7). Bivariate linkage analysis for the combined phenotype diabesity gave the strongest evidence for a susceptibility locus (LOD= 5.2). Linkage to body mass index (BMI) at this precise genomic region (D11S4464) has been replicated in Caucasians from the Framingham Heart Study and in morbidly obese males in pedigrees from Utah (Myriad Genetics). The region of linkage in Pima Indians spans approximately 24 Mb. Our current goal is to positionally clone the gene(s) responsible for the linkage. Positional candidate genes across the region of linkage are being sequenced to identify genetic variants. In addition, linkage disequilibrium (LD) mapping is being used to narrow the susceptibility region. For LD mapping, single nucleotide polymorphisms (SNPs) are being systematically identified and genotyped at 25 kB intervals across the region of linkage. To date, approximately 1070 SNPs that span our region of linkage have been individually genotyped in 1229 DNA samples, and tested for association with either BMI or T2DM. Two separate regions (BIG1 and BIG2) have been preliminarily identified that contain multiple SNPs significantly associated with BMI and diabetes. To determine whether these regions truly define a susceptibilty locus or whether they represent false positive results, SNPs from both regions are being replicated in other populations. To date, multiple SNPs have been tested in the Framingham Family DNA collection, the FUSION DNA collection, the UK family collection, Mexican Americans from Starr County, and Utah Caucasians. Association results from this wide range of ethnic groups suggests that there are indeed two separate obesity susceptibility loci. One loci is common to Pima Indians, Mexican Americans, Finns (FUSION) and Framingham Caucasians. The second loci is common to Pima Indians and Utah Caucasians. These results are currently being extended by additional collaborative efforts to genotype variants in Mexican Americans from San Antonio and Finns from Botnia.