Yanagawa T, Hidaka Y, Guimaraes V, Soliman M, DeGroot L J
Department of Medicine, University of Chicago, Illinois 60637.
J Clin Endocrinol Metab. 1995 Jan;80(1):41-5. doi: 10.1210/jcem.80.1.7829637.
Graves' disease (GD) is an autoimmune thyroid disease. Multiple genetic factors are believed to be involved in its pathogenesis, but the factors are largely unknown, except for sex (female disease preponderance) and the role of human leukocyte antigen (HLA) genes on chromosome 6. To understand the mechanisms underlying the development of GD, a search for non-HLA-linked genes is crucial, and we tested several candidate genes, including the CTLA-4 gene on chromosome 2q33. CTLA-4 molecules may either facilitate or down-regulate the second signal to T-cells, which is provided by the interaction between the two accessory molecules CD28 and B7. One hundred and thirty-three Caucasian patients (26 males) with GD and 85 local controls were included in this study. Polymerase chain reaction was used to amplify DNA containing the (AT)n repeat within the 3'-untranslated region of exon 3 of the CTLA-4 gene. The 5'-forward primer was radiolabeled, and amplified products were resolved on 5-7% sequencing gels. All subjects were previously typed for HLA class II alleles. Twenty-one alleles were observed with sizes ranging from 88-134 basepairs. In the association analysis, the genotype frequencies between GD patients and controls differed significantly (P = 0.012), and the difference was attributable to a higher frequency of the 106-basepair allele among patients (relative risk, 2.82). When the patients were subdivided with respect to sex and HLA, the phenotype frequencies of allele 106 was higher in the female patients with protective HLA specificities (DQA10201 positive/DQA10501 negative) than in those with susceptible HLA specificities (DQA10201 negative/DQA10501 positive; 81.8% vs. 45.5%; P = 0.026). The CTLA-4 gene or a closely associated gene (including CD28) confers susceptibility to GD. This association may be more important in female patients with protective HLA specificities, who otherwise would be at low risk of developing the disease.
格雷夫斯病（GD）是一种自身免疫性甲状腺疾病。多种遗传因素被认为参与其发病机制，但除了性别（女性疾病患病率高）和6号染色体上人类白细胞抗原（HLA）基因的作用外，这些因素大多未知。为了了解GD发生发展的潜在机制，寻找非HLA连锁基因至关重要，我们检测了几个候选基因，包括位于2q33染色体上的CTLA-4基因。CTLA-4分子可能促进或下调T细胞的第二信号，该信号由两个辅助分子CD28和B7之间的相互作用提供。本研究纳入了133例高加索GD患者（26例男性）和85名当地对照。采用聚合酶链反应扩增CTLA-4基因外显子3的3'-非翻译区内含（AT）n重复序列的DNA。5'-正向引物进行放射性标记，扩增产物在5-7%测序胶上进行分离。所有受试者之前均已进行HLA II类等位基因分型。观察到21个等位基因，大小范围为88-134个碱基对。在关联分析中，GD患者和对照之间的基因型频率存在显著差异（P = 0.012），差异归因于患者中106碱基对等位基因的频率较高（相对风险，2.82）。当根据性别和HLA对患者进行细分时，具有保护性HLA特异性（DQA10201阳性/DQA10501阴性）的女性患者中106等位基因的表型频率高于具有易感性HLA特异性（DQA10201阴性/DQA10501阳性）的女性患者（81.8%对45.5%；P = 0.026）。CTLA-4基因或紧密相关基因（包括CD28）赋予了对GD的易感性。这种关联在具有保护性HLA特异性的女性患者中可能更为重要，否则她们患该病的风险较低。
