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，同一基因组区域包含一个2型糖尿病(T2 DM)的易感基因(LOD=1.7)。对合并表型糖尿病的双变量连锁分析为易感基因提供了最有力的证据(LOD=5.2)。在弗雷明翰心脏研究的高加索人和犹他州(Myriad Genetics)家系的病态肥胖男性中，已经复制了与这个精确基因组区域(D11S4464)的身体质量指数(BMI)的关联。皮马印第安人的连锁区域跨度约为24Mb。我们目前的目标是定位克隆负责连锁的基因(S)。正在对连锁区域的位置候选基因进行测序，以确定遗传变异。此外，还使用了连锁不平衡(LD)作图来缩小易感区域。在LD作图中，单核苷酸多态(SNPs)正在以25kB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，大约700个跨越我们连锁区域的SNPs已经在1229个DNA样本中单独进行了基因分型，并进行了与BMI或T2 DM相关的测试。已经初步确定了两个独立的区域，它们包含与BMI和糖尿病显著相关的多个SNP。对我们目前的L.D.定位数据的初步解释是，在染色体11q23-24上，不止一个基因与糖尿病和BMI有关。

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 700 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 have been preliminarily identified that contain multiple SNPs significantly associated with BMI and diabetes. A preliminary interpretation of our current L.D. mapping data is that more than one gene is responsible for the linkage to diabetes and BMI on chromosome 11q23-24.