Association between polymorphisms in the TSHR gene and Graves' orbitopathy.

Beata Jurecka-Lubieniecka,Rafal Ploski,Tomasz Bednarczuk,Urszula Ambroziak,Kornelia Hasse-Lazar,Dorota Kula,Andrzej Tukiendorf,Zofia Kolosza,Konrad Szymanski,Barbara Jarzab,Lidia Hyla-Klekot,Güher Saruhan-Direskeneli

doi:10.1371/journal.pone.0102653

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.

Highlights

Orbitopathy is an inflammatory autoimmune reaction involving the orbit [1,2]
Graves’ disease (GD) hyperthyroidism may coexist with Graves’ orbitopathy (GO), most typically GO precedes or follows GD hyperthyroidism at intervals ranging from a few months to a few years [6]
When the group was analyzed as a whole, as well as when older patients were analyzed alone, there was no difference found in allele frequency or distribution of genotypes for any of the analyzed polymorphisms

Summary

Introduction

Orbitopathy is an inflammatory autoimmune reaction involving the orbit [1,2]. Autoimmune reactions against TSHR located on fibroblasts prompt changes in the orbit connective tissue, which create fundamental clinical signs of disease [1,2], [4]. Clinical symptoms of orbitopathy are diverse, starting from minimal symptoms to severe sight-threatening forms. Graves’ orbitopathy (GO) as well as Graves’ disease (GD) hyperthyroidism originate from an autoimmune reaction against the common auto-antigen, thyroid-stimulating hormone receptor (TSHR). 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

Methods

Results

Conclusion