Department of Medical Biology, University of Split, School of Medicine, Split, Croatia.
Department of Nuclear Medicine, University Hospital of Split, Split, Croatia.
Sci Rep. 2020 Feb 4;10(1):1754. doi: 10.1038/s41598-020-58457-x.
Thyroid volume of Hashimoto's thyroiditis (HT) patients varies in size over the course of disease and it may reflect changes in biological function of thyroid gland. Patients with subclinical hypothyroidism predominantly have increased thyroid volume whereas patients with more pronounced hypothyroidism have smaller thyroid volumes. Suggested mechanism for thyroid atrophy is thyrocyte death due to apoptosis. We performed the first genome-wide association study (GWAS) of thyroid volume in two groups of HT patients, depending on levothyroxine (LT4) therapy, and then meta-analysed across. Study included 345 HT patients in total and 6 007 322 common autosomal genetic variants. Underlying hypothesis was that genetic components that are involved in regulation of thyroid volume display their effect in specific pathophysiologic conditions of thyroid gland of HT patients. We additionally performed immunohistochemical analysis using thyroid tissues and analysed differences in expression levels of identified proteins and apoptotic marker between HT patients and controls. We found genome-wide significant association of two loci, both involved in apoptosis, with thyroid volume of HT patients: rs7212416 inside apoptosis-antagonizing transcription factor AATF (P = 8.95 × 10) and rs10738556 near chromatin-remodeling SMARCA2 (P = 2.83 × 10). In immunohistochemical analysis we observed that HT patients with homozygous AATF risk genotypes have decreased AATF expression (0.46-fold, P < 0.0001) and increased apoptosis (3.99-fold, P = 0.0001) in comparison to controls. HT patients with heterozygous SMARCA2 genotypes have decreased SMARCA2 expression, albeit without reaching statistical significance (1.07-fold, P = 0.5876), and significantly increased apoptosis (4.11-fold, P < 0.0001). By two lines of evidence we show that two highly plausible genetic loci, AATF and SMARCA2, may be involved in determining the thyroid volume of HT patients. The results of our study significantly add to the current knowledge of disturbed biological mechanisms in thyroid gland of HT patients.
桥本甲状腺炎（HT）患者的甲状腺体积在疾病过程中会发生变化，这可能反映了甲状腺生物功能的变化。亚临床甲状腺功能减退症患者的甲状腺体积主要增大，而更明显的甲状腺功能减退症患者的甲状腺体积较小。甲状腺萎缩的机制是由于细胞凋亡导致甲状腺细胞死亡。我们对两组 HT 患者的甲状腺体积进行了首次全基因组关联研究（GWAS），这两组患者分别依赖于左旋甲状腺素（LT4）治疗，然后进行了荟萃分析。研究共纳入 345 名 HT 患者和 6007322 个常见常染色体遗传变异。基本假设是，参与调节甲状腺体积的遗传成分在 HT 患者甲状腺的特定病理生理条件下发挥作用。我们还使用甲状腺组织进行了免疫组织化学分析，并分析了 HT 患者和对照组之间鉴定蛋白和凋亡标志物表达水平的差异。我们发现两个与凋亡相关的基因座与 HT 患者的甲状腺体积呈全基因组显著关联：凋亡拮抗转录因子 AATF 内的 rs7212416（P=8.95×10）和染色质重塑 SMARCA2 附近的 rs10738556（P=2.83×10）。在免疫组织化学分析中，我们观察到 HT 患者中具有 AATF 风险基因型的纯合子的 AATF 表达减少（0.46 倍，P<0.0001）和凋亡增加（3.99 倍，P=0.0001）与对照组相比。具有杂合性 SMARCA2 基因型的 HT 患者的 SMARCA2 表达减少，尽管没有达到统计学意义（1.07 倍，P=0.5876），但凋亡显著增加（4.11 倍，P<0.0001）。我们通过两条证据表明，两个高度合理的遗传基因座 AATF 和 SMARCA2 可能参与决定 HT 患者的甲状腺体积。我们的研究结果显著增加了对 HT 患者甲状腺中失调的生物学机制的现有认识。
