Introduction: Both genetic and environmental factors contribute to clinical manifestation of Graves disease including the response to medical therapy. CTLA-4 gene is an important inhibitor of T-cell activation and its polymorphisms may influence the course of the disease.
Goal: We investigated the association between CTLA−4 gene polymorphisms: c.49A>G, g.319C>T, g.*642AT(8_33), CT60, and Jo31 and the response to pharmacological therapy.
Materials: One hundred and seventy-two unrelated GD patients were genotyped and categorized into two groups: 96 patients responded to medical treatment and 76 subjects required surgical or I131 therapy because of a relapse.
Methods: The polymorphisms g.319C>T (rs5742909) in the promoter region, c.49A>G (rs231775) in exon 1, and CT60 (g.*6230G>A, rs3087243) in the 3′UTR of the CTLA-4 gene were examined by PCR-restriction fragment length polymorphism (PCR-RFLP) using TruI, BseXI, and TailI enzymes. The Jo31 (g.*10223G>T; rs11571302) polymorphism in the 3′UTR region of the CTLA-4 gene was genotyped using PCR amplification followed by minisequencing using the commercial kit SNapShot. The CTLA-4 3′UTR containing an (AT)n repeat was studied by PCR and fluorescence based technique.
Results: CT60[G] allele (genotype [GG] or [GT]) carriers were 4.51-fold more prone to disease progression (P=0.01, 95% CI: 1.2516.20). CT60[G] allele and [GG] genotype increased risk of disease progression (P=0.002, OR=2.05, 95% CI: 1.293.27 and P=0.01, OR=2.24, 95% CI: 1.214.15, respectively).
Also presence of one or two Jo31[G] allele was associated with relapse ([G] allele: P=0.008, OR=1.82, 95% CI: 1.172.83 and [GG] genotype: P=0.02, OR=2.07, 95%CI: 1.103.89, respectively). The CT60 and Jo31 markers were subjected to multivariate analysis. It appeared that only the CT60 polymorphic marker is an independent risk factor for disease progression (P=0.02, OR=4.51, 95% CI: 1.2416.30).
Conclusion: These data suggest that the variation within CTLA-4 gene may discriminate Graves disease patients with different clinical manifestation and help to identify subjects at risk of a relapse.