Hayashi H, Kusaka I, Nagasaka S, Kawakami A, Rokkaku K, Nakamura T, Saito T, Higashiyama M, Honda K, Ishikawa S E
Division of Endocrinology and Metabolism, Department of Medicine, Jichi Medical School, Tochigi, Japan.
Clin Endocrinol (Oxf). 1999 Dec;51(6):793-9. doi: 10.1046/j.1365-2265.1999.00890.x.
CTLA-4, expressed on activated T cells, is thought to be a negative regulator of T cell function. Its gene (2q33) may confer genetic susceptibility to type 1 diabetes mellitus (IDDM12). The present study was undertaken to clarify the role of CTLA-4 gene polymorphism in Japanese subjects with type 1 diabetes and its effect on their clinical features.
In 117 Japanese subjects with type 1 diabetes, the CTLA-4 exon 1 polymorphism (49 A/G) was defined by PCR-RFLP analysis. Anti-GAD antibodies (GAD-Ab) and fasting serum C-peptide were also determined. 141 healthy age- and sex-matched subjects served as controls.
The frequency of each polymorphism was not different between the type 1 diabetic subjects and the controls; AA 21, AG 42 and GG 54 for the diabetic subjects, and AA 22, AG 47 and GG 72 for the controls. The frequency of the GG genotype was higher in the diabetic subjects with positive GAD-Ab (greater than 8 U/ml) (67%) than in the GAD-Ab negative subjects (39%) (P < 0.05). The prevalence of positive GAD-Ab declined with the duration of diabetes. In the diabetic subjects with disease duration of less than 5 years (n = 40), the frequency of the GG genotype was also higher in the GAD-Ab positive subjects (71%) (P < 0.05). In the analysis of all the diabetic subjects, there was a strong association between positive GAD-Ab and beta cell function (P < 0.0001).
There was no evidence that the CTLA-4 exon 1 polymorphism (49 A/G) confers genetic susceptibility to type 1 diabetes mellitus in our case-control study in Japanese subjects. However, the frequency of positive GAD-Ab was higher in the GG subjects. CTLA-4 polymorphism might contribute to the clinical heterogeneity of type 1 diabetes mellitus in Japanese subjects.
细胞毒性T淋巴细胞相关抗原4（CTLA-4）表达于活化的T细胞，被认为是T细胞功能的负调节因子。其基因（2q33）可能赋予1型糖尿病（IDDM12）遗传易感性。本研究旨在阐明CTLA-4基因多态性在日本1型糖尿病患者中的作用及其对临床特征的影响。
对117例日本1型糖尿病患者，采用聚合酶链反应-限制性片段长度多态性分析（PCR-RFLP）确定CTLA-4外显子1多态性（49 A/G）。同时检测抗谷氨酸脱羧酶抗体（GAD-Ab）和空腹血清C肽。141例年龄和性别匹配的健康受试者作为对照。
1型糖尿病患者与对照组各多态性频率无差异；糖尿病患者中AA型21例、AG型42例、GG型54例，对照组中AA型22例、AG型47例、GG型72例。GAD-Ab阳性（大于8 U/ml）的糖尿病患者中GG基因型频率（67%）高于GAD-Ab阴性患者（39%）（P<0.05）。GAD-Ab阳性率随糖尿病病程延长而下降。病程小于5年的糖尿病患者（n = 40）中，GAD-Ab阳性患者的GG基因型频率也较高（71%）（P<0.05）。在所有糖尿病患者的分析中，GAD-Ab阳性与β细胞功能之间存在强相关性（P<0.0001）。
在我们对日本受试者的病例对照研究中，没有证据表明CTLA-4外显子1多态性（49 A/G）赋予1型糖尿病遗传易感性。然而，GG基因型受试者中GAD-Ab阳性频率较高。CTLA-4多态性可能导致日本1型糖尿病患者的临床异质性。
