β-2-Adrenergic receptor gene polymorphism confers susceptibility to Graves disease

Abstract

Graves disease (GD) is an autoimmune disorder with genetic predisposition. The polymorphisms 47A-->G (Arg16Gly) and 79C-->G (Gln27Glu) of the adrenergic beta-2 receptor (ADRB2) gene in the 5q32 region affect the functional reaction to adrenergic stimulation, which contributes to the regulation of immunological response. The -367T-->C polymorphism within the 5'-leading regulatory sequence affects ADRB2 transcriptional activity. The aim of the present study was to investigate whether ADRB2 gene variants are associated with susceptibility to GD. All polymorphisms were studied in Polish GD patients (n=300) and healthy control subjects without a family history of autoimmune disorders (n=301). Genotypes were determined by the MassARRAY system (Sequenom, San Diego, CA). Gly16 and Gln27 allele frequencies were 61.4% and 55.2% among healthy controls, almost the same as previously reported in 4441 white participants of a cardiovascular health study. We found a higher risk of GD in Gln27 carriers (CC or CG genotypes) than in Glu27 homozygous (GG genotype) participants (OR=1.99, 95% CI: 1.27-3.12, p=0.003, pcorr=0.03). The frequency of the 79GG protective genotype was significantly smaller in the GD patients without symptoms of Graves ophthalmopathy compared to controls (10% vs 22%, OR=0.41, 95% CI: 0.234-0.706, p=0.0017, pcorr=0.015). We didn't find any association of -367T--> or 47A-->G genotypes/alleles with Graves disease, however, haplotype analysis has shown a significant difference in haplotype distribution between patients and controls (the global p=0.001) with increased -367T/47A/79C haplotype frequency in GD patients compared to controls (34% vs 25%, p=0.00073, pcorr=0.0044). In conclusion, Gln27 carriers (79CC or 79GC genotypes) have increased risk of Graves disease. Our results suggest that ADRB2 plays a role in susceptibility to Graves disease in humans.