Positional Cloning Of A Diabetes Gene On Chromosome 11

Diabetes, Digestive, Kidney Diseases

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Abstract

We have previously identified a region of linkage to both body mass index (LOD=3.6), age-adjusted diabetes (LOD=1.7) and the combined phenotype of "diabesity" (LOD=5.2)on chrom 11q23-24. In our efforts to positionally clone the diabetes/BMI susceptibility gene(s) on chromosome 11q23-24, we are identifying and genotyping single nucleotide polymorphisms (SNPs) in all physiologic candidate genes mapped to chromosome 11q23-24. To date, 14 genes within this region have been thoroughly analyzed as candidates based on a perceivable function in glucose metabolism/insulin. Multiple SNPs were identified in all of these genes, but none appear to be the underlying cause of the linkage to BMI observed in this region. We are also using linkage disequilibrium mapping to refine our region of focus on 11q23-24. SNPs are being systematically identified and genotyped at 50 kB intervals across the entire 40 cM region of linkage. To date, 350 SNPs were genotyped at Sequenom, Inc, using their mass-array technology for pooled DNA. This is the most cost-effective method for genotyping large numbers of subjects. Each verified SNP was genotyped in pools of DNA representing the 1348 individuals from our initial linkage studies. SNPs deemed as "high priority" due to their position within a gene mapped to our peak of linkage, or their position adjacent to another SNP shown to be associated with a phenotype, were individually genotyped in the 1348 DNA samples in our laboratory using the technology of Pyrosequencing or Allelic Discrimination. To date we have individually genotyped more than 100 high priority SNPs in the 1348 subjects for haplotype/ subphenotype analysis.