Polymorphisms of endothelin 1 (G5665T and T-1370G) and endothelin receptor type A (C+70G and G-231A) in Graves' disease

Abstract

Purpose: Endothelin 1 (EDN1) is a strong angiogenic and mitogenic factor, playing a key role in hypervascularization, thyroid follicle cell hyperplasia, and lymphocyte infiltration in the thyroid gland of patients with Graves' disease (GD). EDN1 induces angiogenesis and mitogenesis via endothelin receptor type A (EDNRA). This study examined the possible association of EDN1 (G5665T and T-1370G) and EDNRA (C+70G and G-231A) single nucleotide polymorphisms (SNPs) with the occurrence of GD, and evaluates the relationship between genotypes and clinical/laboratory manifestations of GD.

Materials and methods: We analyzed genotype and allele distributions of EDN1 and EDNRA polymorphisms in 165 patients with GD and 181 healthy controls by real-time PCR combined with melting curve analysis.

Results: No significant associations between GD and variant alleles of the studied polymorphisms were observed. However, the anti-thyroid peroxidase (anti-TPO) and anti-thyroglobulin (anti-TG) levels in EDN1 G5665T GG genotype were higher than those in T allele carriers (GT+TT) (p=0.001 and p=0.026, respectively). In addition, anti-TPO levels in EDN1 T-1370G wild-type homozygous patients were found to be higher than in mutant gene carrying patients (GT+GG) (p=0.006). The presence of EDNRA+70G allele was associated with 3.37-fold increased risk for development of ophthalmopathy in GD patients (p=0.009).

Conclusion: Although there were no associations between EDN1 (G5665T and T-1370G) and EDNRA (C+70G and G-231A) SNPs and susceptibility to GD, EDN1 G5665T and T-1370G polymorphisms were related to alterations of autoantibody production and EDNRA C+70G polymorphism is related with increased risk for ophthalmopathy in GD patients.

Keywords: AT; Angiogenesis; Anti-TPO; Anti-Tg; Autoantibody; CI; EDN1; EDNRA; Endothelin 1; Endothelin family; Endothelin receptor type A; GD; Graves' disease; HWE; Hardy–Weinberg Equilibrium; ICAM1; Intercellular adhesion molecule 1; MMI; OR; Odds ratio; Ophthalmopathy; PTU; Polymorphism; SNPs; TNFα; TRAb; TSH; TSH receptor antibody; Tumor necrosis factor α; UTR; Untranslated region; VEGF; anti-thyroglobulin; anti-thyroid; anti-thyroid peroxidase; confidence interval; methimazole; propylthiouracil; single nucleotide polymorphisms; thyroid-stimulating hormone; vascular endothelial growth factor.