Multigenic Basis for Type I Diabetes: Association of HRAS1 Polymorphism With HLA-DR3,DQw2/DR4,DQw8

David Owerbach; Sheila Gunn; Kenneth H Gabbay

doi:10.2337/diab.39.12.1504

Original Articles

Multigenic Basis for Type I Diabetes: Association of HRAS1 Polymorphism With HLA-DR3,DQw2/DR4,DQw8

David Owerbach,
Sheila Gunn and
Kenneth H Gabbay

Endocrinology and Metabolism Section, Department of Pediatrics, Baylor College of Medicine Houston, Texas

Address correspondence and reprint requests to Dr. David Owerbach, Department of Pediatrics, Baylor College of Medicine, 8080 North Stadium Drive, Suite 1225, Houston, TX 77054.

Diabetes 1990 Dec; 39(12): 1504-1509. https://doi.org/10.2337/diab.39.12.1504

Abstract

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-Tag 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 HLAsusceptibility haplotypes compared with other type I patients or healthy control blood donors (P < 0.010 and P < 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 HLADR3/4 type I diabetes mellitus.