Multigenic basis for type I diabetes. Association of HRAS1 polymorphism with HLA-DR3, DQw2/DR4, DQw8.

We analyzed extended haplotypes composed of DNA loci on the short arm of chromosome 11 for segregation with insulin-dependent (type I) diabetes mellitus. The markers for these loci are tyrosine hydroxylase, insulin, and c-Ha-ras-1 proto-oncogene (HRAS1). We report, in a study of 27 families, that a specific haplotype (H), containing a 3-kilobase (kb) HRAS1-Taq I DNA polymorphism, segregated differentially in diabetic and nondiabetic siblings (P = 0.005). A parallel population study showed that the 3-kb HRAS1-Taq I polymorphism is increased in frequency in type I patients having two strong HLA-susceptibility haplotypes compared with other type I patients or healthy control blood donors (P less than 0.010 and P less than 0.025, respectively). The polymorphic variable, enhancer, and promoter regions flanking the human insulin gene on the H haplotype were not associated with type I diabetes. These results indicate that the HRAS1 locus or genes in linkage disequilibrium with this locus are involved in the pathogenesis of HLA-DR3/4 type I diabetes mellitus.