Association between Polymorphisms in the TSHR Gene and Graves' Orbitopathy

Abstract

BackgroundGraves' orbitopathy (GO) as well as Graves' disease (GD) hyperthyroidism originate from an autoimmune reaction against the common auto-antigen, thyroid-stimulating hormone receptor (TSHR). GO phenotype is associated with environmental risk factors, mainly nicotinism, as well as genetic risk factors which initiate an immunologic reaction. In some patients GO is observed before diagnosis of GD hyperthyroidism, while it can also be observed far after diagnosis. The intensity of GO symptoms varies greatly in these patients. Thus, the pathogenesis of GD and GO may correlate with different genetic backgrounds, which has been confirmed by studies of correlations between GO and polymorphisms in cytokines involved in orbit inflammation. The aim of our analysis was to assess genetic predisposition to GO in young patients (age of diagnosis ≤30 years of age), for whom environmental effects had less time to influence outcomes than in adults.Methods768 GD patients were included in the study. 359 of them had clinically evident orbitopathy (NOSPECS ≥2). Patients were stratified by age at diagnosis. Association analyses were performed for genes with a known influence on development of GD - TSHR, HLA-DRB1, cytotoxic T-lymphocyte antigen 4 (CTLA4) and lymphoid protein tyrosine phosphatase (PTPN22).ResultsThe rs179247 TSHR polymorphism was associated with GO in young patients only. In young GO-free patients, allele A was statistically more frequent and homozygous carriers had a considerable lower risk of disease incidence than patients with AG or GG genotypes. Those differences were not found in either elderly patients or the group analyzed as a whole.ConclusionsAllele A of the rs179247 polymorphism in the TSHR gene is associated with lower risk of GO in young GD patients.

TSHR intronic polymorphisms (rs179247 and rs12885526) and their role in the susceptibility of the Brazilian population to Graves’ disease and Graves’ ophthalmopathy

“…A series of reports have been confirming that the inheritance of AA genotype for TSHR rs179247 increases the risk for GD [29,30,47,48]. However, contradicting our results, Lui et al [47] suggested that the A allele in rs179247 was highly increased in Chinese patients with GO only, whereas Jurecka-Lubieniecka et al [49] demonstrated that younger patients without GO, in whom GD was diagnosed before 30 years of age, the A allele was more frequent. In this study, the presence of AA genotype was associated with a significant reduction in the risk of GO.…”

Genetic associations of the thyroid stimulating hormone receptor gene with Graves diseases and Graves ophthalmopathy: A meta-analysis

“…Additionally, 1 study did not have sufficient data, and 28 studies did not study the three SNPs. In the end, we selected 8 studies that met the inclusion criteria, including 5 studies that involved 4821 GD patients and 4846 healthy controls 12 19 20 21 22 and 5 studies that involved 904 GO patients and 924 GD patients 20 22 23 24 25 . Importantly, the study by Ploski included 3 different groups of cases and controls 12 .…”

Nicotinamide phosphoribosyltransferase leukocyte overexpression in Graves’ opthalmopathy

“…About 25–50 % of these patients develop Graves’ orbitopathy that might lead to irreversible ocular changes resulting in disturbed vision, changed facial appearance, and a significantly decreased quality of life [ 20 ]. The pathogenesis of Graves’ orbitopathy is unresolved so far, and many distinct factors are postulated to be involved (endogenous, genetic, environmental) [ 21 – 23 ]. Recently published study suggested the association between Graves’ orbitopathy prevalence and severity and diabetes mellitus type 2 with accompanying overweight [ 24 ].…”