The clinical presentation of Graves disease (GD) depends on the combination of environmental and genetic factors. The CTLA-4 and CD28, ICOS genes encoding negative and positive regulator of the T-lymphocyte immune response, are candidate genes for conferring susceptibility to thyroid autoimmunity.
Polymorphisms in genes: CTLA-4: g.319C>T (rs5742909), c.49A>G (rs231775), g.*642AT(8_33), CT60 (g.*6230G>A, rs3087243), Jo31 (g.*10223G>T, rs11571302), CD28: c.17+3T>C (rs3116496) and ICOS: c.1554_4GT(8_15) were determined in 172 GD patients and 381 healthy persons. Data were analyzed in the context of familial history of thyroid disease, response to the anti-thyroid treatment and severity of Graves orbitopathy (GO).
Carriers of G allele in marker CT60 (genotype GG and/or GA) had increased risk of GD 1.80 (P=0.04, OR=1.80, 95%CI: 1.033.14). Carriers of alleles with 1221 AT repeat at g.*642AT (8_33) were 1.84-more prone to the disease (P=0.001, 95%CI: 1.262.69). The multivariate logistic regression analysis showed that only g.*642AT (8_33) marker is an independent risk factor for disease (χ2=33.3, P=0.0008). Moreover, CT60G allele and presence of G allele significantly reduced the rate of a successful medical anti-thyroid treatment (P=0.002, and P=0.01 respectively). Similar results were observed for marker Jo31. The multivariate logistic regression analysis showed that only the CT60 marker is an independent risk factor of the progression of GD (χ2=114.6, P=0.009). We also observed that carriers of CTLA-4g.319C>T CC genotype were over-represented in a subgroup with familial history of thyroid disease (81.2% vs 47.1%, P=0.00005). Carriers of c.49A>G G allele more often develop severe GO (P=0.02, OR=2.17, 95%CI:1.104.30). Moreover, patients carrying allele of 1221 AT repeat at g.*642AT(8_33) more often develop severe GO (P=0.01, 95%CI: 1.194.53). The multivariate logistic regression analysis pointed that g.*642AT (8_33) marker as well as male gender are independent risk factor for GO (P=0.04, and P=0.00008 respectively).
Our results suggest that polymorphisms within gene encoding the CTLA-4 molecule influence the risk of GD and modifies the clinical course of the disease.