Petrone Antonio, Giorgi Gabriele, Galgani Andrea, Alemanno Irene, Corsello Salvatore M, Signore Alberto, Di Mario Umberto, Nisticò Lorenza, Cascino Isabella, Buzzetti Raffaella
Department of Clinical Science, University of Rome La Sapienza, 00161 Rome, Italy.
Thyroid. 2005 Mar;15(3):232-8. doi: 10.1089/thy.2005.15.232.
Graves' disease (GD) is an autoimmune and polygenic disorder. Several studies have shown that human leukocyte antigen (HLA) class II and the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) gene are involved in the genetic susceptibility. We performed a case control study on 150 patients with GD and 301 controls, matched for age and gender, to verify the association of three polymorphisms located in CTLA-4 region (A49G, AT-3'UTR, and CT60) and of HLA-DRB1 and DQB1 loci with the disease in an Italian population. The prevalence of patients with GD carrying the G allele of CT60 was significantly higher compared to control subjects (p = 0.02, odds ratio [OR] = 1.82). The allelic frequency of the G allele of CT60 was also significantly higher in patients with GD (p = 0.02). The G allele frequency of A49G in patients was significantly higher compared to control subjects (p = 0.04). The 280 allele phenotype frequency of (AT)(n)-3'UTR was also significantly higher in patients (p = 0.04). The G allele of A49G, the G allele of CT60, and the 280 allele of (AT)(n)-3'UTR microsatellite were significantly increased in patients with GD with thyroid-associated ophthalmopathy (TAO) compared to controls (p = 0.04, p = 0.03, and p = 0.02, respectively), however, we did not find any significant difference between TAO and non-TAO patients. We also found the HLA-DRB103 allele to be associated with GD; interestingly, the association of the CTLA-4 markers was independent from the HLA DRB103 status. These results highlight the role of the CTLA-4 locus, in addition to HLA, in the susceptibility to GD. Inside the CTLA-4 region, CT60 appears to be the most associated polymorphism to GD, however, further studies are needed to identify the etiologic variant.
格雷夫斯病(GD)是一种自身免疫性多基因疾病。多项研究表明,人类白细胞抗原(HLA)II类和细胞毒性T淋巴细胞相关抗原4(CTLA-4)基因与遗传易感性有关。我们对150例GD患者和301例年龄及性别匹配的对照进行了病例对照研究,以验证位于CTLA-4区域的三种多态性(A49G、AT-3'UTR和CT60)以及HLA-DRB1和DQB1基因座与意大利人群中该疾病的关联。携带CT60的G等位基因的GD患者患病率显著高于对照(p = 0.02,比值比[OR] = 1.82)。CT60的G等位基因频率在GD患者中也显著更高(p = 0.02)。患者中A49G的G等位基因频率显著高于对照(p = 0.04)。(AT)(n)-3'UTR的280等位基因表型频率在患者中也显著更高(p = 0.04)。与对照相比,患有甲状腺相关性眼病(TAO)的GD患者中A49G的G等位基因、CT60的G等位基因和(AT)(n)-3'UTR微卫星的280等位基因显著增加(分别为p = 0.04、p = 0.03和p = 0.02),然而,我们未发现TAO患者与非TAO患者之间有任何显著差异。我们还发现HLA-DRB103等位基因与GD相关;有趣的是,CTLA-4标记物的关联独立于HLA DRB103状态。这些结果突出了除HLA外CTLA-4基因座在GD易感性中的作用。在CTLA-4区域内,CT60似乎是与GD最相关的多态性,但需要进一步研究来确定病因变异。