Ao Xiang, Parisien Marc, Fillingim Roger B, Ohrbach Richard, Slade Gary D, Diatchenko Luda, Smith Shad B
Faculty of Dental Medicine and Oral Health Sciences, Department of Anesthesia, Faculty of Medicine and Health Sciences, Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada.
Department of Community Dentistry and Behavioral Science, University of Florida, Gainesville, FL, United States.
Pain. 2024 May 1;165(5):1060-1073. doi: 10.1097/j.pain.0000000000003104. Epub 2023 Nov 28.
Temporomandibular disorders (TMDs), collectively representing one of the most common chronic pain conditions, have a substantial genetic component, but genetic variation alone has not fully explained the heritability of TMD risk. Reasoning that the unexplained heritability may be because of DNA methylation, an epigenetic phenomenon, we measured genome-wide DNA methylation using the Illumina MethylationEPIC platform with blood samples from participants in the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) study. Associations with chronic TMD used methylation data from 496 chronic painful TMD cases and 452 TMD-free controls. Changes in methylation between enrollment and a 6-month follow-up visit were determined for a separate sample of 62 people with recent-onset painful TMD. More than 750,000 individual CpG sites were examined for association with chronic painful TMD. Six differentially methylated regions were significantly ( P < 5 × 10 -8 ) associated with chronic painful TMD, including loci near genes involved in the regulation of inflammatory and neuronal response. A majority of loci were similarly differentially methylated in acute TMD consistent with observed transience or persistence of symptoms at follow-up. Functional characterization of the identified regions found relationships between methylation at these loci and nearby genetic variation contributing to chronic painful TMD and with gene expression of proximal genes. These findings reveal epigenetic contributions to chronic painful TMD through methylation of the genes FMOD , PM20D1 , ZNF718 , ZFP57 , and RNF39 , following the development of acute painful TMD. Epigenetic regulation of these genes likely contributes to the trajectory of transcriptional events in affected tissues leading to resolution or chronicity of pain.
颞下颌关节紊乱病（TMDs）是最常见的慢性疼痛病症之一，具有重要的遗传成分，但仅基因变异并不能完全解释TMD风险的遗传性。鉴于无法解释的遗传性可能是由于DNA甲基化这一表观遗传现象，我们使用Illumina MethylationEPIC平台，对来自口面部疼痛：前瞻性评估与风险评估（OPPERA）研究参与者的血液样本进行全基因组DNA甲基化测量。与慢性TMD的关联分析使用了496例慢性疼痛性TMD病例和452例无TMD对照的甲基化数据。对于另外62例近期发作的疼痛性TMD患者样本，确定了入组时和6个月随访之间的甲基化变化。检查了超过75万个个体CpG位点与慢性疼痛性TMD的关联。六个差异甲基化区域与慢性疼痛性TMD显著相关（P < 5×10 -8），包括参与炎症和神经元反应调节的基因附近的位点。大多数位点在急性TMD中也有类似的差异甲基化，这与随访中观察到的症状短暂性或持续性一致。对已识别区域的功能特征分析发现，这些位点的甲基化与附近导致慢性疼痛性TMD的基因变异以及近端基因的表达之间存在关联。这些发现揭示了在急性疼痛性TMD发生后，通过FMOD、PM20D1、ZNF718、ZFP57和RNF39基因的甲基化对慢性疼痛性TMD的表观遗传贡献。这些基因的表观遗传调控可能有助于受影响组织中转录事件的发展轨迹，从而导致疼痛的缓解或慢性化。
