Villanueva R, Inzerillo A M, Tomer Y, Barbesino G, Meltzer M, Concepcion E S, Greenberg D A, MacLaren N, Sun Z S, Zhang D M, Tucci S, Davies T F
Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA.
Thyroid. 2000 Sep;10(9):791-8. doi: 10.1089/thy.2000.10.791.
Graves' disease (GD) is an autoimmune thyroid disease (AITD) characterized by hyperthyroidism and by the occurrence of a distinctive ophthalmopathy (orbitopathy), which presents with varying degrees of severity. Graves' disease clusters in families but the importance of heredity in the pathogenesis of the associated ophthalmopathy is unclear. We have studied the family history of 114 consecutive, ethnically mixed patients with severe Graves' ophthalmopathy (GO). Patients were selected by unambiguous single ascertainment. Seventy-seven percent of patients were female and 59% smoked. The mean age at onset of their GD was 43 years (range 17-78 years). Forty-one patients (36%) had a family history of AITD, defined as a first- and/or a second-degree relative affected with either Graves' disease (GD) or Hashimoto's thyroiditis (HT). The segregation ratio for AITD in nuclear families in our ascertained Graves' ophthalmopathy families was 0.07 (0.12 in Caucasians only). Hence, the higher prevalence of AITD among relatives of Graves' ophthalmopathy patients agreed with the known genetic predisposition to AITD and this predisposition was stronger in women than in men. However, only 3 of the 114 patients had a family history of severe Graves' ophthalmopathy (all second-degree relatives) and the segregation ratio for GO was 0. These data did not support a major role for familial factors in the development of severe Graves' ophthalmopathy distinct from Graves' disease itself. In addition, we tested 4 candidate genes, human leukocyte antigen (HLA), tumor necrosis factor-beta (TNF-beta), CTLA-4 and the thyrotropin receptor (TSHR), for association with Graves' ophthalmopathy. These were negative except for the HLA and CTLA-4 genes, which were found to be weakly associated with GO giving similar relative risk (RR) as in GD patients without ophthalmopathy. These data suggested that environmental factors, rather than major genes, were likely to predispose certain individuals with AITD to severe Graves' ophthalmopathy. Smoking remains one example of such potential external insults.
格雷夫斯病（GD）是一种自身免疫性甲状腺疾病（AITD），其特征为甲状腺功能亢进以及出现一种独特的眼病（眼眶病），病情严重程度各异。格雷夫斯病在家族中呈聚集性，但遗传因素在相关眼病发病机制中的重要性尚不清楚。我们研究了114例连续的、种族混合的重度格雷夫斯眼病（GO）患者的家族史。患者通过明确的单一确诊法选取。77%的患者为女性，59%的患者吸烟。他们患GD的平均发病年龄为43岁（范围17 - 78岁）。41例患者（36%）有AITD家族史，定义为一级和/或二级亲属患有格雷夫斯病（GD）或桥本甲状腺炎（HT）。在我们确诊的格雷夫斯眼病家族的核心家庭中，AITD的分离比为0.07（仅白种人为0.12）。因此，格雷夫斯眼病患者亲属中AITD的较高患病率与已知的AITD遗传易感性相符，且这种易感性在女性中比男性更强。然而，114例患者中只有3例有重度格雷夫斯眼病家族史（均为二级亲属），GO的分离比为0。这些数据不支持家族因素在与格雷夫斯病本身不同的重度格雷夫斯眼病发展中起主要作用。此外，我们检测了4个候选基因，即人类白细胞抗原（HLA）、肿瘤坏死因子-β（TNF-β）、细胞毒性T淋巴细胞相关蛋白4（CTLA-4）和促甲状腺激素受体（TSHR）与格雷夫斯眼病的关联性。除HLA和CTLA-4基因外，其他均为阴性，这两个基因被发现与GO弱相关，相对风险（RR）与无眼病的GD患者相似。这些数据表明，环境因素而非主要基因可能使某些AITD个体易患重度格雷夫斯眼病。吸烟仍是此类潜在外部刺激因素的一个例子。
