Cytotoxic T lymphocyte antigen 4 gene polymorphism confers susceptibility to Type 1 diabetes in Japanese children: analysis of association with HLA genotypes and autoantibodies
N. Kikuoka et al., Cytotoxic T lymphocyte antigen 4 gene polymorphism confers susceptibility to Type 1 diabetes in Japanese children: analysis of association with HLA genotypes and autoantibodies, CLIN ENDOCR, 55(5), 2001, pp. 597-603
Objective Although the polymorphisms of the cytotoxic T lymphocyte antigen
4 (CTLA4) gene have been shown to be associated with Type 1 diabetes in Cau
casians, some conflicting results have been reported among subjects of diff
erent ethnic backgrounds. We examined a CTLA4 polymorphism and its relation
ship to human leucocyte antigen (HLA) genotypes and autoantibodies for glut
amic acid decarboxylase 65 (GAD65) and IA-2 in Japanese children with Type
1 diabetes.
Subjects and measurements The study group consisted of 125 childhood-onset
Japanese subjects (50 males, 76 females) with Type 1 diabetes. The CTLA4 A/
G polymorphism at position 49 was analysed using a PCR-restriction fragment
length polymorphism (PCR-RFLP) method. The HLA-DRB1 and DQB1 genotypes wer
e defined by DNA analysis using PCR-sequence-specific oligonucleotide (PCR-
SSO) probes. The GAD65 autoantibody (GAD65Ab) and IA-2 autoantibody (IA-2Ab
) titres were measured using radioimmunoassay.
Results The distribution of genotype frequencies differs between subjects w
ith Type 1 diabetes (GG: 46%, AG: 50%, AA: 5%) and controls (GG: 39%, AG: 4
4%, AA: 17%) (P<0.01). The frequency of the G allele is higher in the diabe
tes group than in the controls (P<0.05). When the subjects were subdivided
according to HLA genotype, the two major HLA high-risk groups, with DR9-DQ9
and DR4-DQ4, that are unique to Japanese populations showed no difference
in their CTLA4 polymorphism frequencies. Although no association between th
e CTLA4 polymorphism and the prevalence of GAD65Ab was found, CTLA4 GG subj
ects that had been newly diagnosed (<9 months) had significantly higher lev
els of autoantibodies than AG subjects (P<0.01). The prevalence and titres
of IA-2Ab were not associated with the CTLA4 polymorphism.
Conclusions The CTLA4 gene might confer a susceptibility to childhood-onset
Type 1 diabetes in the Japanese population. The association between this C
TLA4 polymorphism and the HLA genotype was similar for both major groups wi
th HLA high-risk alleles. CTLA4 might contribute to the humoral immune resp
onse to GAD in newly diagnosed subjects.