Kikuoka N, Sugihara S, Yanagawa T, Ikezaki A, Kim H S, Matsuoka H, Kobayashi Y, Wataki K, Konda S, Sato H, Miyamoto S, Sasaki N, Sakamaki T, Niimi H, Murata M
Department of Pediatrics, Tokyo Women's Medical University, Daini Hospital, Japan.
Clin Endocrinol (Oxf). 2001 Nov;55(5):597-603. doi: 10.1046/j.1365-2265.2001.01397.x.
Although the polymorphisms of the cytotoxic T lymphocyte antigen 4 (CTLA4) gene have been shown to be associated with Type 1 diabetes in Caucasians, some conflicting results have been reported among subjects of different ethnic backgrounds. We examined a CTLA4 polymorphism and its relationship to human leucocyte antigen (HLA) genotypes and autoantibodies for glutamic acid decarboxylase 65 (GAD65) and IA-2 in Japanese children with Type 1 diabetes.
The study group consisted of 125 childhood-onset Japanese subjects (50 males, 75 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 were 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.
The distribution of genotype frequencies differs between subjects with Type 1 diabetes (GG: 46%, AG: 50%, AA: 5%) and controls (GG: 39%, AG: 44%, AA: 17%) (P < 0.01). The frequency of the G allele is higher in the diabetes 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 the CTLA4 polymorphism and the prevalence of GAD65Ab was found, CTLA4 GG subjects that had been newly diagnosed (< 9 months) had significantly higher levels of autoantibodies than AG subjects (P < 0.01). The prevalence and titres of IA-2Ab were not associated with the CTLA4 polymorphism.
The CTLA4 gene might confer a susceptibility to childhood-onset Type 1 diabetes in the Japanese population. The association between this CTLA4 polymorphism and the HLA genotype was similar for both major groups with HLA high-risk alleles. CTLA4 might contribute to the humoral immune response to GAD in newly diagnosed subjects.
尽管细胞毒性T淋巴细胞抗原4（CTLA4）基因多态性已被证明与白种人中的1型糖尿病相关，但在不同种族背景的受试者中也有一些相互矛盾的结果报道。我们研究了日本1型糖尿病儿童中CTLA4基因多态性及其与人类白细胞抗原（HLA）基因型以及谷氨酸脱羧酶65（GAD65）和胰岛抗原2（IA-2）自身抗体的关系。
研究组由125名日本1型糖尿病儿童患者（50名男性，75名女性）组成。采用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）方法分析第49位的CTLA4 A/G多态性。使用聚合酶链反应-序列特异性寡核苷酸（PCR-SSO）探针通过DNA分析确定HLA-DRB1和DQB1基因型。采用放射免疫分析法测量GAD65自身抗体（GAD65Ab）和IA-2自身抗体（IA-2Ab）的滴度。
1型糖尿病患者（GG：46%，AG：50%，AA：5%）和对照组（GG：39%，AG：44%，AA：17%）的基因型频率分布不同（P<0.01）。糖尿病组中G等位基因的频率高于对照组（P<0.05）。当根据HLA基因型对受试者进行细分时，日本人群特有的两个主要HLA高风险组，即DR9-DQ9和DR4-DQ4组，其CTLA4多态性频率没有差异。虽然未发现CTLA4多态性与GAD65Ab患病率之间存在关联，但新诊断（<9个月）的CTLA4 GG受试者的自身抗体水平显著高于AG受试者（P<0.01）。IA-2Ab的患病率和滴度与CTLA4多态性无关。
CTLA4基因可能使日本人群易患儿童期1型糖尿病。对于两个具有HLA高风险等位基因的主要组，这种CTLA4多态性与HLA基因型之间的关联相似。CTLA4可能在新诊断的受试者中促进对GAD的体液免疫反应。
