HLA and CTLA4 polymorphisms may confer a synergistic risk in the susceptibility to Graves’ disease

Abstract

Graves' disease (GD) is an autoimmune disease characterized by hyperthyroidism due to the presence of autoantibodies against thyroid-stimulating hormone receptor, which is measured as thyroid-stimulating hormone-binding inhibitory immunoglobulin (TBII). Most of the GD patients are TBII-positive, but TBII is undetectable in a proportion of GD patients. We previously reported the association of HLA-A*02 and -DPB1*0501 with TBII-positive GD, whereas TBII-negative GD showed association with HLA-A*02 and DPB1*0202. Recently, polymorphisms of cytotoxic T-lymphocyte-associated antigen-4 (CTLA4) gene are reported to be associated with GD. In this study, we investigated 329 (240 TBII-positive and 89 TBII-negative) GD patients and 378 controls for the polymorphisms in HLA-A, -DPB1 and CTLA4 (CT60, rs3087243, A/G) to investigate the contribution of these factors in the susceptibility to GD. A significant association with CTLA4 was found for the TBII-positive GD (G carriers in patients vs controls, 97.1 vs 91.8%; odds ratio (OR)¼2.97, 95% confidence interval¼1.29-6.87, P¼0.008), but the association was weak and not significant for the TBII-negative GD (94.4 vs 91.8%; OR¼1.50, 95% confidence interval¼0.57-3.98, P¼0.41). Stratification analyses suggested a possible synergistic interaction of CTLA4 with HLA-A*02 and -DPB1*0501 in the susceptibility to TBII-positive GD. INTRODUCTIONGraves' disease (GD) is a typical organ-specific autoimmune disease affecting thyroid gland, in which autoantibodies against the receptors for thyroid-stimulating hormone induce hyperthyroidism. The autoantibodies has been measured as thyroid-stimulating antibodies (TSAb) by a biological assay or as thyroid-stimulating hormonebinding inhibitory immunoglobulins (TBII) by a solid phase assay. 1 Although most of the GD patients are positive for both TBII and TSAb, a proportion of the patients carry low or undetectable level of TBII (TBII-negative GD). 2 However, TSAb can be detected in the TBII-negative GD, and it was reported that the TBII-negative patients exhibited mild goiter and followed benign prognosis, implying that the TBII-negative GD might be a clinical subtype different from the ordinary TBII-positive GD. 3 Etiological mechanisms of GD are not fully understood, but certain genetic factors should be involved in the pathogenesis because of familial aggregation of the disease. 4 To decipher the genetic factors candidate gene approaches have been used, and it is well documented that human leukocyte antigen (HLA) polymorphisms are associated with GD, such that HLA-B*08-DRB1*03-DQA1*05-DQB1*02 haplotype showed strong association in European populations. 5,6 However, the distribution of HLA alleles and haplotypes are quite different in different ethnic groups, and the European GD-associated HLA haplotype is virtually absent in Japanese. 7 We previously reported that HLA-A*02 and DPB1*0501 are associated with Japanese GD. 8 In addition, we demonstrated that HLA-A*02 and DPB1*0202 showed association with TBII-negative GD, indicating that the T...

Selective IgA Deficiency in Autoimmune Diseases

“…A number of studies have addressed this question, and Hodge et al (207) and Jacobson et al (25) showed that interaction between HLA-DRB1*03 and different thyroglobulin variants conferred an increased risk for GD. A subsequent study in Japanese subjects (208) suggested that there was also an interaction between selected HLA-A and DP alleles and CTLA4 in a subgroup of GD patients, although Kula et al (209) suggested that the interaction with CTLA4 was due to HLA-DR encoding genes.…”

Correlation between CTLA-4 and CD40 gene polymorphisms and their interaction in graves’ disease in a Chinese Han population

“…Other studies have shown that interactions between CTLA-4 and other genes also increased the risk of GD. For example, interactions between HLA -DPB1*0501 and the CTLA4 -CT60 polymorphism conferred a 9.99 fold GD risk [24] and synergistic interactions may exist between SNP rs231779 in CTLA-4 and rs2069550 in TG [5]. We therefore infer that the mechanisms of CTLA-4 participating in GD pathogenesis are more complicated than we had originally appreciated, and might involve mechanisms of both intra- and extragenic interactions.…”

Synergistic combined effect between CD40-1C>T and CTLA-4+6230G>A polymorphisms in Graves' disease

“…For example, previous studies suggested that the presence of both HLA-DPB1*0501 and CTLA4-CT60-G conferred an OR of 9.99 to GD, which was much higher than that for either of these genes alone (Takahashi and Kimura, 2010). CD40-1C NT (rs1883832) and CTLA-4 + 6230G N A polymorphisms (rs3087243, CT60) were functionally well studied in previous studies.…”