title: 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.
abstract: OBJECTIVE
  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.
authors.affiliation: First Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Abe
authors.forename: Y
authors.initials: Y
authors.lastname: Yamaguchi
authors.forename: H
authors.initials: H
authors.lastname: Takino
authors.forename: N
authors.initials: N
authors.lastname: Fujita
authors.forename: M
authors.initials: M
authors.lastname: Yamauchi-Degawa
authors.forename: M
authors.initials: M
authors.lastname: Ozaki
authors.forename: K
authors.initials: K
authors.lastname: Yamakawa
authors.forename: Y
authors.initials: Y
authors.lastname: Sera
authors.forename: H
authors.initials: H
authors.lastname: Sakamaki
authors.forename: S
authors.initials: S
authors.lastname: Uotani
authors.forename: E
authors.initials: E
authors.lastname: Kawasaki
authors.forename: T
authors.initials: T
authors.lastname: Awata
authors.forename: H
authors.initials: H
authors.lastname: Yamasaki
authors.forename: K
authors.initials: K
authors.lastname: Eguchi
mesh_terms: D000069594:Abatacept; D000328:Adult; D000483:Alleles; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics*; D001323:Autoantibodies / Q000097:blood*; D060908:CTLA-4 Antigen; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000276:immunology; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005968:Glutamate Decarboxylase / Q000276:immunology*; D006801:Humans; D018796:Immunoconjugates; D007328:Insulin / Q000235:genetics; D007564:Japan; D008297:Male; D008875:Middle Aged; D018598:Minisatellite Repeats; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D001323:Autoantibodies; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D018796:Immunoconjugates; D007328:Insulin; D000069594:Abatacept; D005968:Glutamate Decarboxylase