CONTEXT Autoimmune thyroid disease (AITD) includes Graves' disease (GD) and Hashimoto's disease (HD), which often run in the same family. AITD etiology is incompletely understood: genetic factors may account for up to 75% of phenotypic variance, whereas epigenetic effects (including DNA methylation (DNAm)) may contribute to the remaining variance (e.g. why some individuals develop GD and others HD). OBJECTIVE To identify differentially methylated positions (DMPs) and differentially methylated regions (DMRs) comparing GD to HD. METHOD Whole blood DNAm was measured across the genome using the Infinium MethylationEPIC array in 32 Australian patients with GD and 30 with HD (discovery cohort) and 32 Danish patients with GD and 32 with HD (replication cohort). Linear mixed models were used to test for differences in quantile-normalized beta values of DNAm between GD and HD and data were later meta-analyzed. Comb-p software was used to identify DMRs. RESULTS We identified epigenome-wide significant differences (p<9E-8) and replicated (p<0.05) 2 DMPs between GD and HD (cg06315208 within MDC1 and cg00049440 within KLF9). We identified and replicated a DMR within CUTA (5 CpGs at 6p21.32). We also identified 64 DMPs and 137 DMRs in the meta-analysis. CONCLUSION Our study reveals differences in DNAm between GD and HD, which may help explain why some people develop GD and others HD and provide a link to environmental risk factors. Additional research is needed to advance understanding of the role of DNAm in AITD and investigate its prognostic and therapeutic potential.

中文翻译：

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全表观基因组关联研究表明，MDC1、KLF9 和 CUTA 在自身免疫性甲状腺疾病中存在差异 DNA 甲基化。

背景自身免疫性甲状腺疾病（AITD）包括格雷夫斯病（GD）和桥本病（HD），它们通常在同一家族中发生。AITD 病因尚不完全清楚：遗传因素可能占表型变异的 75%，而表观遗传效应（包括 DNA 甲基化 (DNAm)）可能会导致剩余的变异（例如，为什么有些人患有 GD，而另一些人则患有 HD）。目的 比较 GD 和 HD 以确定差异甲基化位置 (DMP) 和差异甲基化区域 (DMR)。方法 使用 Infinium MmethylationEPIC 阵列对 32 名澳大利亚 GD 患者和 30 名 HD 患者（发现队列）以及 32 名丹麦 GD 患者和 32 名 HD 患者（复制队列）进行全基因组全血 DNAm 测量。使用线性混合模型来测试 GD 和 HD 之间 DNAm 分位数归一化 β 值的差异，随后对数据进行荟萃分析。Comb-p 软件用于识别 DMR。结果我们确定了 GD 和 HD 之间表观基因组范围内的显着差异 (p<9E-8) 和重复 (p<0.05) 2 个 DMP（MDC1 内的 cg06315208 和 KLF9 内的 cg00049440）。我们在 CUTA 内识别并复制了 DMR（6p21.32 处的 5 个 CpG）。我们还在荟萃分析中确定了 64 个 DMP 和 137 个 DMR。结论 我们的研究揭示了 GD 和 HD 之间 DNAm 的差异，这可能有助于解释为什么有些人会患上 GD，而另一些人会患上 HD，并提供与环境风险因素的联系。需要进行更多研究来加深对 DNAm 在 AITD 中的作用的理解，并调查其预后和治疗潜力。