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.
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.
Abe
T
T
First Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan.
Yamaguchi
Y
Y
Takino
H
H
Fujita
N
N
Yamauchi-Degawa
M
M
Ozaki
M
M
Yamakawa
K
K
Sera
Y
Y
Sakamaki
H
H
Uotani
S
S
Kawasaki
E
E
Awata
T
T
Yamasaki
H
H
Eguchi
K
K
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
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