Association between G protein polymorphisms (GNAS1 T393C and GNB3 C825T) and course of Graves’ disease and Graves’ orbitopathy

Summary The biology of initiation and progression of Graves’ hyperthyroidism and Graves’ orbitopathy is complex. For the individually tailored therapy of the diseases it is very important to identify the risk factors. Research of the last century revealed that measuring the thyrotropin receptor antibody levels enables the prognostic statements at certain points in the course of hyperthyroidism and orbitopathy. Signal transduction of the thyrotropin receptor is coupled with G protein. The aim of the present study was to find out if two single nucleotide polymorphisms that encode the Gαs and Gβ3 subunits of G protein were related to the course of Graves’ disease. In a series of 359 patients, the genotype and allele frequencies of the GNAS1 T393C and GNB3 C825T single nucleotide polymorphisms were determined. They did not contribute to the individual susceptibility to Graves’ hyperthyroidism and orbitopathy. However, the TT genotype of the GNAS1 T393C gene was associated with a significantly increased risk of relapse of hyperthyroidism (odds ratio 2,5; 95% confidence interval 1,1-5,5; p=0,025). The underlying molecular mechanisms are not easy to explain. According to one of the hypotheses, changing a secondary structure of the mRNA influences its stability. Clinically, the thyrotropin receptor antibody levels are the highest in patients with the TT genotype. The question whether only the elevated antibody levels are responsible for the more severe course of hyperthyroidism or if this relation is supported by the TT genotype cannot be answered based on our study group. The studied cohort should be extended in order to find out if genotyping the T393C single nucleotide polymorphism of the GNAS1 gene is relevant for clinical decisions in the treatment of Graves’ hyperthyroidism