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

Objective: Graves' disease (GD) is an autoimmune disorder with genetic and environmental background. CTLA-4 is a candidate gene for thyroid autoimmunity Increased serum levels of soluble CTLA-4 (sCTLA-4) were found in Some autoimmunity diseases. Aim: The aim of the Study was to evaluate the relation between sCTLA-4 level and clinical manifestation of Graves' ophthalmopathy (GO). thyroid status. and CTLA-4 gene polymorphisms. Design: Serum sCTLA-4 concentrations were determined in 93 GO patients and 93 healthy controls. In the GO group. CTLA-4 gene was genotyped in five polymorphic sites: g.319C>T. c.49A>G. CT60 by means of PRC-RFLP. Jo31. and g.*642AT(8_33) by means of minisequencing assay. Results: Serum sCTLA-4 level was significantly higher in the GO group than in controls (median: 7.94 vs 0.00 ng/ml. P=0.000001). This level was higher in severe than in nonsevere GO (median: 10.3 vs 5.6 ng/ml. P=0.0.1). sCTLA-4 concentration was related neither to the activity of GO nor to thyroid function. Elevated sCTLA-4 levels were observed in carriers Jo31[G] allele (genotype GG+GT) as compared With Subjects with an absence of the [G] allele (TT genotype; median: 9.18 vs 4.0 ng/ml, P=0.02). Also patients possessing CT60[G] allele (genotype GG+GA) had higher serum sCTLA-4 levels than subjects who lack the [G] allele (AA genotype: median: 8.73 vs 2.28 ng/ml. P=0.03). Conclusions: It was shown for the first time that increased serum concentration of sCTLA-4 correlate with the severity of GO. Genetic variation in the CTLA-4 gene region in GD patients at least partially determines the level of sCTLA-4.