Positional Cloning Of A Diabetes Gene On Chromosome 11

Diabetes, Digestive, Kidney Diseases

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Abstract

A prior genomic linkage 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). Bivariate linkage analysis for the combined phenotype ?diabesity? gave the strongest evidence for a disease locus (LOD= 5.2). The region of linkage spans 24 Mb. To narrow this region, single nucleotide polymorphisms (SNPs) are being genotyped at a 10 kb density, across the entire 24 Mb, for linkage disequilibrium (LD) mapping. To date, more than 2500 SNPs have been individually genotyped and tested for association with either BMI or T2DM in 1229 Pima Indians. LD mapping using this genotypic data shows three distinct regions (Regions 1-3), each spanning approximately 500 kb, that contain multiple SNPs significantly associated with BMI in Pima Indians. SNPs within two of these regions have been further genotyped in other, ethnically diverse populations. SNPs in Region 1 are modestly associated with BMI in two groups of Finns (FUSION study and Malmo), USA Caucasians (Framingham) and German Caucasians (Leipzig School Children) (all p<0.05 after adjusting for age and sex). SNPs in Region 1 are also associated with T2DM in Pima Indians (p<0.001), Mexican Americans (Starr County; p<0.05) and Finns (Helsinki; p<0.02). SNPs in Region 2 are associated with BMI in two Caucasian populations (Framingham and Utah; p<0.001 and p<0.05, respectively, after adjusting for age and sex) and are also associated with T2DM in Utah Caucasians. In contrast, none of the SNPs that were tested from either region were associated with BMI or T2DM in Caucasians from the UK. We are currently attempting to replicate associations in Region 3.