Genotypes in relation to phenotypic appearance and exposure to environmental factors in Graves' hyperthyroidism

Abstract

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.

Paediatric‐onset and adult‐onset Graves' disease share multiple genetic risk factors

“…While we have managed to extend the list of POGD risk loci , we also confirmed the previously reported association between the CTLA4 polymorphism and POGD . In general, the results of our study suggest that POGD and AOGD share multiple common genetic risk variants, which is also in line with most findings from studies comparing adults with early‐ and late‐onset GD . Moreover, we showed that the effect sizes for the identified risk variants are similar in POGD and AOGD.…”

“…The PTPN22 gene encodes a lymphoid‐specific protein tyrosine phosphatase (LYP), which is a negative regulator of T cell activation, while the analysed missense variant (rs2476601) confers an increased susceptibility to a number of autoimmune disorders . For both loci , MAGI3 and PTPN22 , an association with age of GD onset has been already shown in our previous studies, while these findings were not replicated in other cohorts . Here, we confirmed our previous results.…”

“…[47][48][49] For both loci, MAGI3 and PTPN22, an association with age of GD onset has been already shown in our previous studies, 16,40 while these findings were not replicated in other cohorts. 13 Here, we confirmed our previous results.…”

“…20,21 In general, the results of our study suggest that POGD and AOGD share multiple common genetic risk variants, which is also in line with most findings from studies comparing adults with early-and late-onset GD. [12][13][14] Moreover, we showed that the effect sizes for the identified risk variants are similar in POGD and AOGD. Although we did not find any variants specifically associated with POGD, we demonstrated that the HCP5 polymorphism was significantly associated with an earlier age of GD onset in a dose-dependent manner while several other variants also showed a nominal association.…”

“…Importantly, Brown et al showed also that both age‐of‐onset‐specific and ‐nonspecific risk variants may be associated with early‐onset GD. Several other studies have investigated the genetic background of GD in young adults (defined as age of GD onset lower than 30‐45 years), showing that certain genetic variants, such as HLA‐DRB1 , CTLA4 and PTPN22 polymorphisms, may be associated with age of GD onset . Most recently, based on the results of an analysis performed in a large cohort of GD patients, Yuan et al reported significant genetic heterogeneity between subjects with age of GD onset ≤20 and >20 years, suggesting it is reasonable to reduce the cut‐off value for the definition of early‐onset GD.…”