CTLA4 gene polymorphism contributes to the mode of onset of diabetes with antiglutamic acid decarboxylase antibody in Japanese patients: genetic analysis of diabetic patients with antiglutamic acid decarboxylase antibody

Diabet Med. 2001 Sep;18(9):726-31. doi: 10.1046/j.0742-3071.2001.00551.x.


Aim: The mode of onset is occasionally similar in Type 1 and Type 2 diabetes mellitus, and some patients with Type 2 diabetes are positive for antiglutamic acid decarboxylase antibody (GAD Ab). We investigated the contribution of Type 1 diabetes susceptibility genes to the progression of the insulin-deficient state and mode of onset of Type 2 diabetes in GAD Ab-positive (GAD-Ab+) patients. We examined the variable number of tandem repeats in the promoter region of the insulin gene (INS-VNTR, insulin-dependent diabetes mellitus (IDDM) 2) and cytotoxic T lymphocyte antigen 4 (CTLA4, IDDM12) as representative of Type 1 diabetes susceptibility genes.

Methods: Patients with Type 2 diabetes who were GAD-Ab+ (n = 51) were selected for this study. In INS-VNTR, the class I allele was classified according to length (1S, 25-38 repeat units; 1M, 39-41 repeat units; 1L, 42-44 repeat units) and the exact class I allele length was analysed by specific polymerase chain reaction (PCR) amplifications. Analyses of classes II and III were performed by Southern blot. CTLA4 gene polymorphism (exon 1 position 49, G/A) was analysed by PCR-restriction fragment length polymorphism.

Results: The distribution of INS-VNTR was no different between Type 1 diabetes and Type 2 diabetes with GAD Ab. The allele frequencies of CTLA4 gene polymorphism G and A in Type 2 diabetes/GAD-Ab+ were significantly different from those of Type 1 diabetes/GAD-Ab+ (G: 53%, A: 47% vs. G: 84%, A: 16%; P < 0.0001).

Conclusions: Our data showed that GAD-Ab+ Japanese patients presenting with Type 2 diabetes have shifted A allele while patients with abrupt onset have shifted G allele of CTLA4 gene polymorphism. Our results suggest that immunological function and polymorphism of the CTLA4 gene may contribute to the pathogenesis and progression of Type 1 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abatacept
  • Adult
  • Alleles
  • Antigens, CD
  • Antigens, Differentiation / genetics*
  • Autoantibodies / blood*
  • CTLA-4 Antigen
  • Diabetes Mellitus, Type 1 / genetics*
  • Diabetes Mellitus, Type 1 / immunology
  • Diabetes Mellitus, Type 2 / genetics*
  • Diabetes Mellitus, Type 2 / immunology
  • Female
  • Gene Frequency
  • Genetic Predisposition to Disease
  • Genotype
  • Glutamate Decarboxylase / immunology*
  • Humans
  • Immunoconjugates*
  • Insulin / genetics
  • Japan
  • Male
  • Middle Aged
  • Minisatellite Repeats
  • Polymorphism, Genetic*
  • Polymorphism, Restriction Fragment Length


  • Antigens, CD
  • Antigens, Differentiation
  • Autoantibodies
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • Immunoconjugates
  • Insulin
  • Abatacept
  • Glutamate Decarboxylase