Association between polymorphisms in the TSHR gene and Graves' orbitopathy

Area of Science:

• Endocrinology
• Immunogenetics
• Ophthalmology

Background:

• Graves' disease (GD) and Graves' orbitopathy (GO) stem from an autoimmune response targeting the thyroid-stimulating hormone receptor (TSHR).
• GO development is influenced by environmental factors like smoking and genetic predispositions, with varying onset relative to GD diagnosis.
• Pathogenesis may differ between GD and GO, potentially linked to distinct genetic backgrounds, especially concerning inflammatory cytokines.

Purpose of the Study:

• To investigate the genetic predisposition to Graves' orbitopathy (GO) specifically in young patients (≤30 years old) with Graves' disease (GD).
• To assess the influence of genetic factors on GO development, considering that environmental impacts are minimized in younger individuals.

Main Methods:

• Analyzed 768 Graves' disease (GD) patients, with 359 exhibiting clinically evident orbitopathy (NOSPECS ≥2).
• Stratified patients by age at diagnosis and performed association analyses for key genes: TSHR, HLA-DRB1, CTLA4, and PTPN22.
• Focused on the rs179247 polymorphism within the TSHR gene.

Main Results:

• The rs179247 TSHR polymorphism showed a significant association with Graves' orbitopathy (GO) exclusively in young GD patients.
• In young GO-free patients, allele A of rs179247 was more frequent; homozygous carriers (AA) had a substantially lower risk of GO incidence compared to AG or GG genotypes.
• These specific associations were not observed in elderly patients or the overall patient cohort.

Conclusions:

• The A allele of the rs179247 polymorphism in the TSHR gene confers a lower risk of developing Graves' orbitopathy (GO) in young patients diagnosed with Graves' disease (GD).
• This finding highlights a potential genetic protective factor against GO in a specific young demographic within the GD population.