LOCALIZATION OF A TYPE-I DIABETES SUSCEPTIBILITY LOCUS TO THE VARIABLE TANDEM REPEAT REGION FLANKING THE INSULIN GENE

A susceptibility gene for type I diabetes is present on chromosome 11p 15.5, but its location, identity, and mechanism of action are unknown. We have sequenced 14 kilobases of DNA flanking the human insulin gene and found new DNA polymorphisms and determined their frequencies in t he general population and in families of type I diabetic subjects. A D NA polymorphism located 3123 base pairs downstream from the initiation site of transcription of the insulin gene, when present in the homozy gous state, provides a relative risk for type I diabetes of 5.2 (P = 0 .006). However, theis DNA polymorphism as well as other diabetes-assoc iated 3' markers are in linkage-disequilibrium with the actual suscept ibility region, because these polymorphisms are found on haplotypes bo th positively and negatively associated with type I diabetes susceptib ility. Nucleotide sequence analysis of the variable tandem repeat regi on flanking the 5' end of the insulin gene shows variable tandem repea t elements associated with these haplotypes to differ greatly in compo sition, i.e., an ATAGGGGTGTGGGG repeat element is absent on a haplotyp e associated with type I diabetes susceptibility, but is found in 6-10 copies on two haplotypes negatively associated with the disease. Thes e findings suggest that the type I diabetes susceptibility locus on ch romosome 11p15.5 is probably located in the 5' variable tandem repeat region rather than in the 3' region of the insulin gene.