Li Peng, Zhang Wei, Guo Xin, Yuan Jiang
Department of Thoracic Surgery, Binzhou People's Hospital, Binzhou, China.
Department of Thoracic Surgery, Ganzhou Cancer Hospital, Ganzhou, China.
Medicine (Baltimore). 2025 Jun 6;104(23):e42761. doi: 10.1097/MD.0000000000042761.
Emerging evidence suggests a potential link between gastroesophageal reflux disease (GERD) and autoimmune disorders, yet the causal effect of GERD on myasthenia gravis (MG) remains unclear. Psychological factors, particularly negative emotions, have been implicated in both GERD and MG pathogenesis, raising the possibility that they may mediate this association. This study aims to elucidate the bidirectional causal relationship between GERD and MG, explore its subtype-specific effects, and investigate the mediating role of negative emotions through Mendelian randomization (MR) approach. Univariate MR (UVMR) was conducted to assess the bidirectional causal association between GERD and MG, with additional stratified analyses for its subtypes. Multivariable MR (MVMR) was then performed to evaluate the independent effect of GERD on MG after adjusting for body mass index. Finally, mediation analysis was employed to determine whether negative emotions mediated the effect of GERD on MG. UVMR analysis demonstrated that GERD significantly increased the risk of MG (ORIVW, 1.47; 95% CI, 1.10-1.97; P = .009), whereas MG had no causal effect on GERD (ORIVW, 1.01; 95% CI, 0.98-1.03; P = .635). Subgroup analysis revealed a significant association between GERD and late-onset MG (ORIVW, 1.47; 95% CI, 1.03-2.08; P = .033) but no evident link with early-onset MG (ORIVW, 0.90; 95% CI, 0.49-1.64; P = .727). MVMR analysis indicated that the causal effect of GERD on MG remained robust after adjusting for body mass index (ORIVW, 1.48; 95% CI, 1.05-2.09; P = .027). Mediation analysis further identified Fed-up feelings as a significant mediator in the GERD-MG pathway (mediation proportion [95% CI]: 49.4% (10.6%-88.2%], P = .012), whereas worrier/anxious feelings (mediation proportion [95% CI]: 7.2% [-6.3% to 20.7%], P = .278) and depression (mediation proportion [95% CI]: -25.0% [-103.2% to 53.1%], P = .530) did not exhibit significant mediation effects. This study provides robust genetic evidence supporting GERD as a potential causal risk factor for MG and, for the first time, highlights Fed-up feelings as a key mediator in this relationship. These findings underscore the importance of psychological factors in the pathogenesis of GERD-associated MG and suggest that targeting emotional well-being may offer novel strategies for disease prevention and management.
新出现的证据表明胃食管反流病（GERD）与自身免疫性疾病之间可能存在联系，但GERD对重症肌无力（MG）的因果效应仍不清楚。心理因素，尤其是负面情绪，已被认为与GERD和MG的发病机制有关，这增加了它们可能介导这种关联的可能性。本研究旨在阐明GERD与MG之间的双向因果关系，探讨其亚型特异性影响，并通过孟德尔随机化（MR）方法研究负面情绪的中介作用。进行单变量MR（UVMR）以评估GERD与MG之间的双向因果关联，并对其亚型进行额外的分层分析。然后进行多变量MR（MVMR）以评估在调整体重指数后GERD对MG的独立影响。最后，采用中介分析来确定负面情绪是否介导了GERD对MG的影响。UVMR分析表明，GERD显著增加了MG的风险（IVW比值比，1.47；95%置信区间，1.10 - 1.97；P = 0.009），而MG对GERD没有因果效应（IVW比值比，1.01；95%置信区间，0.98 - 1.03；P = 0.635）。亚组分析显示GERD与晚发型MG之间存在显著关联（IVW比值比，1.47；95%置信区间，1.03 - 2.08；P = 0.033），但与早发型MG没有明显联系（IVW比值比，0.90；95%置信区间，0.49 - 1.64；P = 0.727）。MVMR分析表明，在调整体重指数后，GERD对MG的因果效应仍然显著（IVW比值比，1.48；95%置信区间，1.05 - 2.09；P = 0.027）。中介分析进一步确定厌烦情绪是GERD - MG途径中的一个重要中介因素（中介比例[95%置信区间]：49.4%（10.6% - 88.2%]，P = 0.012），而担忧/焦虑情绪（中介比例[95%置信区间]：7.2%（-6.3%至20.7%]，P = 0.278）和抑郁（中介比例[95%置信区间]：-25.0%（-103.2%至53.1%]，P = 0.530）没有显著的中介效应。本研究提供了有力的遗传证据，支持GERD作为MG的潜在因果风险因素，并且首次强调厌烦情绪是这种关系中的关键中介因素。这些发现强调了心理因素在GERD相关MG发病机制中的重要性，并表明针对情绪健康可能为疾病预防和管理提供新的策略。
