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

Diabetes. 1990 Dec;39(12):1504-9. doi: 10.2337/diab.39.12.1504.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Base Sequence
  • Chromosome Mapping
  • Chromosomes, Human, Pair 11
  • DNA / genetics
  • Diabetes Mellitus, Type 1 / etiology
  • Diabetes Mellitus, Type 1 / genetics*
  • Enhancer Elements, Genetic / genetics
  • Female
  • HLA-DQ Antigens / genetics
  • HLA-DR3 Antigen / genetics
  • HLA-DR4 Antigen / genetics
  • Humans
  • Insulin / genetics
  • Male
  • Molecular Sequence Data
  • Pedigree
  • Polymorphism, Genetic / genetics
  • Polymorphism, Restriction Fragment Length
  • Promoter Regions, Genetic / genetics
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Tyrosine 3-Monooxygenase / genetics


  • HLA-DQ Antigens
  • HLA-DQ2 antigen
  • HLA-DQ8 antigen
  • HLA-DR3 Antigen
  • HLA-DR4 Antigen
  • Insulin
  • MAS1 protein, human
  • Proto-Oncogene Mas
  • DNA
  • Tyrosine 3-Monooxygenase
  • HRAS protein, human
  • Proto-Oncogene Proteins p21(ras)