Positional Cloning Of A Diabetes Gene On Chromosome 11

我们先前对皮马印第安人的基因组扫描显示，肥胖易感基因位于染色体11q23-24(LOD=3.6)。也有证据表明，同一基因组区域含有2型糖尿病(T2 DM)的易感基因(LOD=1.7)，并对其联合表型、肥胖、肥胖进行了双变量连锁分析。为易感基因座提供了最有力的证据(LOD=5.2)。我们目前的目标是定位克隆负责连锁的基因(S)。整个连锁区域的位置候选基因正在进行变异测序，到目前为止，已经分析了29个基因。此外，还使用了连锁不平衡(LD)作图来缩小易感区域。对于LD作图，单核苷酸多态(SNPs)正在以50kB的间隔在整个连锁区域被系统地识别和基因分型。到目前为止，在1229名PIMA患者中，大约有200个SNPs被单独进行了基因分型，并进行了与体重指数(BMI)或T2 DM相关的测试。已经初步确定了三个不同的狭窄区域，它们包含与BMI显著相关的多个SNP。已经确定了一个包含与糖尿病显著相关的SNPs簇的单一区域。

Our prior genomic scan in Pima Indians 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) and a bivariate linkage analysis for the combined phenotype ?diabesity? gave the strongest evidence for a susceptibility locus (LOD= 5.2). Our current goal is to positionally clone the gene(s) responsible for the linkages. Positional candidate genes across the region of linkage are being sequenced for variants, and to date, 29 genes have been analyzed. 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 50 kB intervals across the region of linkage. To date, approximately 200 SNPs have been individually genotyped and tested for association with either body mass index (BMI) or T2DM in 1229 Pimas. Three distinct, narrow regions have been preliminarily identified that contain multiple SNPs significantly associated with BMI. A single region has been identified that contains a cluster of SNPs significantly associated with diabetes.