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

Abstract

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 autoimmune 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.319COT, c.49AOG, 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, PZ0.000001). This level was higher in severe than in nonsevere GO (median: 10.3 vs 5.6 ng/ml, PZ0.01). 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 GGCGT) as compared with subjects with an absence of the [G] allele (TT genotype; median: 9.18 vs 4.0 ng/ml, PZ0.02). Also patients possessing CT60[G] allele (genotype GGCGA) had higher serum sCTLA-4 levels than subjects who lack the [G] allele (AA genotype; median: 8.73 vs 2.28 ng/ml, PZ0.03). 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.

Ctla-4 Gene Polymorphism in Relation to Thyroid Disorders in Patients With Chronic Hepatitis C Under Interferon Alpha Therapy

“…Our results are in agreement with those of Oaks and Hallet (2000); Saverino et al (2007) and Daroszewski et al (2009).…”

“…The CT60 in the 3'UTR region of CTLA4 gene is the most promising locus for the autoimmune thyroid disease (Ban et al, 2005;Daroszewski et al, 2009). The meta-analysis study of Kavvoura et al (2007), shows consistent associations between Graves' disease and Hashimoto thyroiditis with CT60.…”

The soluble CTLA-4 receptor and its role in autoimmune diseases: an update

“…Thus, sCTLA-4 production does not seem to be affected by disease evolution over time [49]. However, a recent study has shown that increased sCTLA-4 serum levels correlate with the severity of Graves' ophthalmopathy [33]. The discrepancy in these finding may be related to the greater number of GD patients enrolled in the later study (93 vs. 31).…”

“…Linkage and association of the CTLA-4 exon 1 polymorphism with GD, and to lesser extent with HT, has been found in several populations, although there seems to be some inconsistency, probably due to population heterogeneity [11,17,27,[30][31][32][33] (Table 1).…”

“…Increased serum levels of sCTLA-4 have been reported in patients with several autoimmune diseases significantly more often than in healthy individuals [20, 33, 49-51, 60, 62]. Patients with GD [20,33,49], HT [20,49], MG [50], systemic lupus erythematosus [55], systemic sclerosis (SSc) [54], CD [51], autoimmune pancreatitis (AIP) [62] and spondyloarthropathies and RA [60] have been investigated. The first studies on sCTLA-4 serum levels in autoimmune disease were performed 10 years ago [20] in 17 patients with GD and 3 patients with HT.…”