CT60 Single Nucleotide Polymorphisms of the Cytotoxic T-Lymphocyte–Associated Antigen-4 Gene Region is Associated with Graves' Disease in an Italian Population

Abstract

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](n)-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-DRB1*03 allele to be associated with GD; interestingly, the association of the CTLA-4 markers was independent from the HLA DRB1*03 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.

Genetic Profiling in Graves' Disease: Further Evidence for Lack of a Distinct Genetic Contribution to Graves' Ophthalmopathy

“…CTLA4 gene polymorphisms have been shown to confer susceptibility to several autoimmune diseases, including AITD. However, CTLA4 was not demonstrated as a specific GO-associated gene in the present study in keeping with our previous observations (27) and those of others (45,46). The IL-23R is a type I transmembrane protein that binds with the IL-23 cytokine to activate Janus kinases.…”

Soluble CTLA-4 receptor an immunological marker of Graves' disease and severity of ophthalmopathy is associated with CTLA-4 Jo31 and CT60 gene polymorphisms

“…The influence of the polymorphisms within CTLA-4 gene on the GD (31,(34)(35)(36)(37)(38)(39)(40)(41)(42) as well as on GO (43)(44)(45) has been widely studied. The CT60 in the 3 0 UTR region of this gene was the most promising locus for the autoimmune thyroid disease (31,(40)(41)(42).…”

“…The CT60 in the 3 0 UTR region of this gene was the most promising locus for the autoimmune thyroid disease (31,(40)(41)(42). Notwithstanding, the present study has been focused on the possible influence of tested polymorphic sites on the serum sCTLA-4 concentration.…”

New HLA DRB1 and DQB1 Haplotypes in a Pedigree of Familial Graves' Disease in Japan

“…Both genetic and environmental factors may affect the development of Graves' disease. Such an autoimmune mechanism could be associated with HLA on chromosome 6p [5][6][7][8][9][10][11][12][13][24][25][26][27][28][29][30][31][32][33] and CTLA-4 on chromosome 2q33 [14][15][16][17][18]. There are several different results regarding HLA haplotypes associated with Graves' disease in Japan [13,28,29,32,33].…”