Department of Clinical and Experimental Medicine, Endocrinology Units, University of Pisa and University Hospital of Pisa, Pisa, Italy.
Department of Surgical, Medical and Molecular Pathology, Ophthalmopathy Unit I, University of Pisa and University Hospital of Pisa, Pisa, Italy.
Eur Thyroid J. 2024 Nov 6;13(6). doi: 10.1530/ETJ-24-0179. Print 2024 Dec 1.
The pathogenesis of Graves' orbitopathy (GO) remains to be fully elucidated. Here, we reviewed the role of genetics and epigenetics.
We conducted a PubMed search with the following keywords: GO, thyroid eye disease; or Graves' ophthalmopathy; or thyroid-associated ophthalmopathy; and: genetic, or epigenetic, or gene expression, or gene mutation, or gene variant, or gene polymorphism, or DNA methylation, or DNA acetylation. Articles in which whole DNA and/or RNA sequencing, proteome, and methylome analyses were performed were chosen.
The different prevalence of GO in the two sexes, as well as racial differences, suggest that genetics play a role in GO pathogenesis. In addition, the long-lasting phenotype of GO and patient-derived orbital fibroblasts suggests a genetic or epigenetic mechanism. Although no genes have been found to confer a specific risk for GO, differential gene expression has been reported in orbital fibroblasts from GO patients vs control fibroblasts, suggesting that an epigenetic mechanism may be involved. In this regard, a different degree of DNA methylation, which affects gene expression, has been found between GO and control fibroblasts, which was confirmed by whole methylome analysis. Histone acetylation and deacetylation, which also affect gene expression, remain to be investigated.
Although no pathogenic gene variants have been reported, epigenetic mechanisms elicited by an initial autoimmune insult seem to be needed for differential gene expression to occur and, thus, for GO to develop and persist over time.
格雷夫斯眼病（GO）的发病机制仍未完全阐明。在这里，我们回顾了遗传学和表观遗传学的作用。
我们使用以下关键词在 PubMed 上进行了搜索：GO、甲状腺眼病；或格雷夫斯眼病；或甲状腺相关眼病；和：遗传、或表观遗传、或基因表达、或基因突变、或基因变异、或基因多态性、或 DNA 甲基化、或 DNA 乙酰化。选择了进行全 DNA 和/或 RNA 测序、蛋白质组学和甲基组学分析的文章。
GO 在两性中的不同患病率，以及种族差异，表明遗传在 GO 发病机制中起作用。此外，GO 的持久表型和患者来源的眼眶成纤维细胞表明存在遗传或表观遗传机制。尽管尚未发现赋予 GO 特定风险的基因，但已在 GO 患者和对照成纤维细胞的眼眶成纤维细胞中报告了差异基因表达，表明可能涉及表观遗传机制。在这方面，GO 和对照成纤维细胞之间发现了不同程度的 DNA 甲基化，这影响了基因表达，这通过全甲基组分析得到了证实。组蛋白乙酰化和去乙酰化，也影响基因表达，仍有待研究。
尽管尚未报道致病基因变异，但最初的自身免疫攻击引发的表观遗传机制似乎需要发生差异基因表达，从而使 GO 随着时间的推移发展和持续存在。
