engleski

A genome-wide association analysis of Hashimoto’s thyroiditis

Background: Hashimoto’s thyroiditis (HT) is the most common autoimmune thyroid disease characterized by chronic inflammation and reduced function of the thyroid gland. HT is the major cause of hypothyroidism in iodine- sufficient areas and it is highly prevalent in women. Although strong genetic susceptibility to HT has been proposed, underlying genetic factors are poorly known. Moreover, HT has never been analyzed on the genome-wide level. The aim of our study was to identify genetic variants associated with HT by performing the first genome-wide association analysis of this disease. Methods: A total of 869 individuals from Croatia, comprising of 430 HT cases and 439 controls, were included in this study. All HT cases met ETA recommendations and guidelines for Management of Subclinical Hypothyroidism. Control individuals were derived from the population-based “10, 001 Dalmatians project” of which 349 individuals already had genome- wide data scanned by Illumina HumanOmniExpressExome array whereas additional 90 controls and HT cases were typed using Illumina Infinium HumanCoreExome array. Following quality control, two datasets were merged on an overlapping set of variants and imputed using 1000 Genomes reference panel. Association analysis was performed on 8, 633, 733 genetic variants under the univariate linear mixed model using GEMMA software. Binary disease status was treated as quantitative trait, and model was adjusted for age, sex, population stratification and relatedness. Reported investigations have been carried out following the principles of the Declaration of Helsinki. Results: We identified a missense variant inside TET1 gene at the genome-wide significance level (β=0.365, se=0.066, p=4.21x10 -8) and a missense variant inside UGT8 gene just below genome-wide significance (β=0, 365, se=0, 072, p=5.25x10 -7). Replication of these two signals along with 10 other suggestively associated variants (p<10 -5) is currently underway in an independent dataset of 303 HT cases and 302 controls. Discussion: TET1 is a methylcytosine dioxygenase that is involved in DNA demethylation and gene activation indicating a role of epigenetic events in HT susceptibility. UGT8 is an UDP- glycosyltransferase that has a role in the biosynthesis of galactocerebrosides of the nervous systems. Conclusion: In this first genome-wide analysis of HT to date, we have identified promising associations of biologically interesting genes pointing to a novel mechanisms underlying HT development.

Hashimoto’s thyroiditis, genome-wide association analysis

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