Background: Genetic polymorphisms and environmental factors are both involved in the pathogenesis of Graves' disease, but their interaction and effect on Graves' phenotypes have scarcely been investigated.
Objective: To test the hypothesis that subjects with susceptibility genotypes develop more severe Graves' hyperthyroidism at a younger age and after less exposure to environmental factors, with attention to gender differences.
Study design: A prospective observational multicenter study in 205 adult Caucasian patients with untreated first episode of Graves' hyperthyroidism.
Methods: Evaluation of genotypes (HLA DRB1*03, DQA1*05, DQB1*02; CTLA4 49A/G, CT60 A/G; PTPN22 C/T) in relation to phenotypes (age, sex, severity (clinical, biochemical, and immunological)) of hyperthyroidism and environmental factors (smoking, stress questionnaires).
Results: G-alleles in CTLA4 single nucleotide polymorphisms were dose-dependently associated with younger age at the time of diagnosis and less exposure to daily hassles. In gender-specific analysis, this association is enhanced in men and attenuated in women. Males (but not females) in HLA linkage disequilibrium had more severe (biochemical and immunological) hyperthyroidism and a tendency to younger age at diagnosis, compared with those not in linkage disequilibrium.
Conclusion: Graves' hyperthyroidism occurs at a younger age with less exposure to environmental factors in subjects carrying susceptibility genotypes. The impact of genotypes seems to be greater in males than in females.