Genome-wide association study in Hashimoto’s thyroiditis

Abstract

Background. The purpose of the study was to identify new genetic loci associated with Hashimoto’s thyroiditis (HT) by performing genome-wide association analysis and to determine their possible functional significance in the pathogenesis of the disease. Materials and methods. A genome-wide association study was performed using a case-control design, which included 200 patients with clinically confirmed HT and 600 control subjects without thyroid diseases. The diagnosis of HT was verified by the presence of antithyroid antibodies and a characteristic ultrasound pattern. Patients with type 1 diabetes were excluded to prevent cross-phenotypic overlap. Statistical analysis was performed using Firth logistic regression after standard quality control of genetic data. To evaluate the results, Manhattan plot, QQ plot, and candidate loci analysis that reached the threshold of suggestive statistical signi­ficance (–log10(P) > 4.5) were used. Results. The analysis revealed seven single-nucleotide polymorphisms associated with HT, localized near the TMEM215, EDIL3, NR5A2, PRR16, AGMO, ADAMTSL1 and GLRA1 genes. The most pronounced association signal was obtained for the rs77684994 variant near the TMEM215 gene (–log10(P) = 4.804). QQ plot analysis (λ = 0.912) did not reveal significant genomic inflation, which confirms the adequacy of the statistical model and the high reliability of the obtained results. Functional analysis showed that the identified genes are involved in the processes of extracellular matrix remodeling, angiogenesis, regu­lation of lipid metabolism, cellular transport, organellar stress and glycosylation, which indicates their potential role in the formation of local vulnerability of thyroid tissue to the development of the di­sease. Conclusions. Genome-wide association analysis has identified new candidate genetic loci potentially involved in the development of HT. The results obtained expand the current understanding of the molecular mechanisms of the disease and indicate that, along with classical immunogenetic factors, local mechanisms of regulation of the thyroid tissue structure and function may play an important role. Functional validation of the identified loci and independent replication of the results in larger samples are promising areas of further research.