engleski

Genome-Wide Association Analysis of Thyroid Volume and Thyroid Antibodies in Hashimoto’s Thyroiditis

Hashimoto’s thyroiditis (HT) is the most common autoimmune thyroid disorder defined as a chronic inflammation of the thyroid gland. It is characterized by the infiltration of lymphocytes and progressive destruction of thyroid tissue. Another distinguished feature of HT is the presence of elevated thyroid autoantibodies against thyroid peroxidase (TPOAb) and thyroglobulin (TgAb). The aim of this study was to explore the genetic background of HT-associated traits, namely thyroid volume and thyroid antibodies, in HT patients by genome-wide association analysis (GWAS). The study included 430 HT patients recruited at the University Hospital Split (Croatia). Diagnosis of HT patients was based on clinical findings and laboratory parameters according to ETA recommendations and guidelines for Management of Subclinical Hypothyroidism. Participants were genotyped using the Illumina Infinium HumanCoreExome genotyping platform and imputed using the “1000 Genomes” reference panel and IMPUTE2 software. Association analysis of the resulting 8, 592, 875 genetic markers was performed using GEMMA software. Three analyzed traits were adjusted for covariates under standard linear regression model: thyroid volume was adjusted for gender, age, BSA, TSH, and levothyroxine therapy status whereas TPOAb and TgAb levels were adjusted for gender. Derived residuals were further included in the association analysis as a new phenotype for each trait under the linear mixed model, which accounts for population stratification and relatedness. We identified two genome-wide significant associations of intronic variants inside the AATF and CNDP1 genes (p=1.36×10-8, p=3.08×10-8, respectively) with thyroid volume. An additional genetic variant near the MIR8054 gene was suggestively associated with thyroid volume (p=2×10-7). No SNP reached genome-wide significance for thyroid antibodies ; however, we identified two suggestive associations of genetic variants near the FAM13A and TRIM61 genes with TPOAb levels (p=6.30×10-8, p=4.89×10-7, respectively) and two suggestive associations of genetic variants near GTF3AP6 and inside the CA10 gene with TgAb levels (p=2.27×10-7, p=6.48 ×10-7, respectively). Our most interesting signal resides within AATF (apoptosis antagonizing transcription factor), which is involved in the regulation of gene transcription and cell proliferation. Overexpression of this gene interferes with MAP3K12-induced apoptosis, whereas, inhibition of the same MAP3K12 activity is driven by MBIP, a gene that has already been associated with thyroid cancer and TSH level, giving further evidence of the biological relevance of this pathway in thyroid function. The second hit resides inside CNDP1 (carnosine dipeptidase 1), which is a human carnosinase mainly expressed in the central nervous system. In conclusion, our study identified novel, biologically interesting genes associated with thyroid volume and several suggested genes associated with thyroid antibodies in HT patients. These findings represent a good basis for further exploration of underlying genetics of HT determinants.

Hashimoto’s thyroiditis (HT)

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