Yanagawa T, Mangklabruks A, Chang Y B, Okamoto Y, Fisfalen M E, Curran P G, DeGroot L J
Department of Medicine, University of Chicago, Illinois 60637.
J Clin Endocrinol Metab. 1993 Jun;76(6):1569-74. doi: 10.1210/jcem.76.6.8501164.
Graves' disease (GD) is an autoimmune disease of the thyroid gland. Genes of, or closely associated to, the HLA complex are assumed to contribute to the genetic predisposition to GD. We have previously reported an increased frequency of HLA-DR3/DQ2 in Caucasian patients with GD, and recently the importance of Dw24 encoded by DRB3 gene has been suggested. To further investigate the associations of GD and these genes, 94 unrelated patients with GD and 75 control subjects were typed for HLA-DRB3, -DRB1, -DQA1, and -DQB1, using sequence-specific oligonucleotide probes to analyze polymerase chain reaction amplified DNA (PCR-SSO). Three findings emerged from these studies. 1) The frequency of subjects positive for DQA10501 (GD, 73.4% vs. control 42.7%, P = 0.0001, Pc < 0.001, RR = 3.71) was significantly increased among patients. The frequency of DR3 (GD, 34.0% vs. control 17.3%, P = 0.0146, RR = 2.46), which is in tight linkage disequilibrium with DQA10501, was also increased; however, it was not significant when the P value was corrected for the number of antigens tested. Neither DQB1 nor DRB3 alleles were significantly increased in frequency. 2) After exclusion of DR3-positive subjects, DQA10501 was still significantly increased (GD, 59.7% vs. control 30.6%, P = 0.0012, Pc < 0.01, RR = 3.35) among patients. 3) The distributions of Dw24 and Dw25,26 (Dw25 or Dw26) did not differ between patients and controls on either DR3 positive or negative groups. These findings suggest that DQA10501, or a closely associated unknown gene, confers susceptibility to GD, while Dw24 is not directly involved. The importance of DR3, however, remains to be elucidated, because of the fixed linkage with DQA1*0501.
格雷夫斯病（GD）是一种甲状腺自身免疫性疾病。假定HLA复合体的基因或与之紧密相关的基因会导致GD的遗传易感性。我们之前报道过，白种人GD患者中HLA - DR3/DQ2的频率增加，并且最近有人提出DRB3基因编码的Dw24的重要性。为了进一步研究GD与这些基因的关联，我们使用序列特异性寡核苷酸探针分析聚合酶链反应扩增的DNA（PCR - SSO），对94例无亲缘关系的GD患者和75例对照者进行了HLA - DRB3、- DRB1、- DQA1和- DQB1分型。这些研究得出了三个结果。1）患者中DQA10501阳性的频率显著增加（GD患者为73.4%，对照者为42.7%，P = 0.0001，Pc < 0.001，RR = 3.71）。与DQA10501紧密连锁不平衡的DR3的频率（GD患者为34.0%，对照者为17.3%，P = 0.0146，RR = 2.46）也增加；然而，当对检测的抗原数量进行P值校正时，该差异不显著。DQB1和DRB3等位基因的频率均未显著增加。2）排除DR3阳性的受试者后，患者中DQA10501的频率仍显著增加（GD患者为59.7%，对照者为30.6%，P = 0.0012，Pc < 0.01，RR = 3.35）。3）在DR3阳性或阴性组中，患者与对照者之间Dw24和Dw25,26（Dw25或Dw26）的分布没有差异。这些结果表明，DQA10501或与之紧密相关的未知基因赋予了对GD的易感性，而Dw24并不直接参与。然而，由于与DQA1*0501的固定连锁，DR3的重要性仍有待阐明。
