Positional Cloning Of A Diabetes Gene On Chromosome 11

Diabetes, Digestive, Kidney Diseases

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Abstract

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.