Abstract
Background: While the multigene predisposition to Graves disease (GD) is well known, although not well defined, the genetic susceptibility to Graves ophtalmopathy (GO) remains questionable as a one player in the complex interactions between environmental, endogenous and local factors. The goal of the present study was to analyze the impact of genetic and environmental factors in the GO development by multivariate regression analysis.
Material and Methods: 336 patients diagnosed with Graves disease (criterion: hyperthyroidism + TRAb or ophtalmopathy) and treated by radioiodine and 200 control subjects were included. In the first step, single studies of association with GO were performed for the following genes: HLA-DR3, CTLA4, TNF, LTA, CD40, PTPN22, NFKB, OAS, IL-4, IL-10 (immune response related genes) and TG (thyroid specific gene). Two polymorphisms, NFKB (-94ins/del ATTG) and TG exon 33 SNP (T/C) appeared significant at uncorrected p < 0.05 level (but not after Bonferroni correction) and were included into the second step of analysis, based on multiple logistic regression, together with smoking, TRAb level, duration of the disease, number of pharmacoterapies, 131I treatment courses or operations. All data were available for 183 patients, 101 with GO. RESULTS: Smoking appeared as the strongest risk factor for GO (p = 0.005), followed by the influence of disease duration (p = 0.007). Considering the influence of exogenous and endogenous factors, both analyzed genes appeared significant: the presence of TG polymorphism increased the GO risk by 3.7 x, p = 0.01, NKFB by 2.3x, p=0,02.
Conclusions: We showed by multiple regression analysis that NFKB and TG polymorphisms are associated with Graves ophtalmopathy risk, in interaction with other exogenous (smoking) and endogenous factors. Supported by Ministry of Science and Higher Education grant nr 3T11F 010 29.