全基因组关联研究显示自身免疫性甲状腺疾病中 MDC1、KLF9 和 CUTA 的 DNA 甲基化存在差异。
Epigenome-wide Association Study Shows Differential DNA Methylation of MDC1, KLF9, and CUTA in Autoimmune Thyroid Disease.
机构信息
Department of Endocrinology & Diabetes, Sir Charles Gairdner Hospital, Nedlands, WA, 6009, Australia.
Medical School, University of Western Australia, Crawley, WA, 6009, Australia.
出版信息
J Clin Endocrinol Metab. 2024 Mar 15;109(4):992-999. doi: 10.1210/clinem/dgad659.
CONTEXT
Autoimmune thyroid disease (AITD) includes Graves disease (GD) and Hashimoto 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 (eg, why some individuals develop GD and others HD).
OBJECTIVE
This work aimed to identify differentially methylated positions (DMPs) and differentially methylated regions (DMRs) comparing GD to HD.
METHODS
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 β 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 < .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.
背景
自身免疫性甲状腺疾病（AITD）包括格雷夫斯病（GD）和桥本甲状腺炎（HD），这两种疾病常发生于同一家庭。AITD 的病因尚不完全清楚：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]）可能导致其余的变异（例如，为什么有些人会患上 GD，而有些人会患上 HD）。
目的
本研究旨在比较 GD 与 HD 患者，确定差异甲基化位置（DMPs）和差异甲基化区域（DMRs）。
方法
采用 Infinium MethylationEPIC 芯片对 32 例澳大利亚 GD 患者和 30 例 HD 患者（发现队列）以及 32 例丹麦 GD 患者和 32 例 HD 患者（复制队列）的全血 DNAm 进行了全基因组检测。采用线性混合模型对 GD 和 HD 患者的 DNAm 定量归一化β值差异进行检验，并对数据进行了meta 分析。使用 Comb-p 软件识别 DMRs。
结果
我们发现了 GD 和 HD 之间存在全基因组显著差异（P < 9E-8）并复制了（P <.05）的 2 个 DMPs（cg06315208 在 MDC1 内和 cg00049440 在 KLF9 内）。我们还鉴定并复制了 CUTA 内的一个 DMR（6p21.32 上的 5 个 CpG）。在 meta 分析中，我们还鉴定了 64 个 DMPs 和 137 个 DMRs。
结论
本研究揭示了 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，而有些人会患上 HD，并为环境危险因素提供了联系。需要进一步研究以深入了解 DNAm 在 AITD 中的作用，并研究其预后和治疗潜力。
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