Previous observational studies have suggested that gastroesophageal reflux disease (GERD) increases the risk of stroke, but the specific underlying mechanisms are unclear. We investigated the causal associations of GERD with stroke and its subtypes using Mendelian randomization (MR), and evaluated the potential mediating effects of modifiable stroke risk factors in the causal pathway. Genetic instrumental variables for GERD were extracted from the latest genome-wide association study (GWAS) summary level data. We initially performed two-sample MR to examine the association of GERD with stroke and its subtypes, including ischemic stroke, intracranial hemorrhage, and the major subtypes of ischemic stroke. Two-step MR was further employed to investigate the mediating effect of 15 risk factors in the causal pathway. We found significant causal associations of genetically predicted GERD with increased risk of stroke (OR: 1.22 95% CI: 1.126–1.322), ischemic stroke (OR: 1.19 95% CI: 1.098–1.299), and large-artery stroke (OR: 1.49 95% CI: 1.214–1.836). Replication and sensitivity analyses yielded consistent effect directions and similar estimates. Further mediation analyses indicated that hypertension (HTN), systolic blood pressure (SBP), and type 2 diabetes (T2D) mediated 36.0%, 9.0%, and 15.8% of the effect of GERD on stroke; 42.9%, 10.8%, and 21.4% for ischemic stroke, and 23.3%; 7.9%, and 18.7% for large-artery stroke, respectively. This study supports that GERD increases susceptibility to stroke, ischemic stroke, and large-artery stroke, and is partially mediated by HTN, SBP, and T2D.

中文翻译：

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可改变的危险因素介导胃食管反流病对卒中和亚型的影响：孟德尔随机研究

此前的观察性研究表明，胃食管反流病（GERD）会增加中风的风险，但具体的潜在机制尚不清楚。我们使用孟德尔随机化 (MR) 研究了 GERD 与中风及其亚型的因果关系，并评估了因果路径中可改变的中风危险因素的潜在中介作用。GERD 的遗传工具变量是从最新的全基因组关联研究 (GWAS) 汇总级数据中提取的。我们最初进行了两样本磁共振检查，以检查 GERD 与中风及其亚型（包括缺血性中风、颅内出血和缺血性中风的主要亚型）的关联。进一步采用两步MR研究15个危险因素在因果路径中的中介作用。我们发现基因预测的 GERD 与中风（OR：1.22 95% CI：1.126–1.322）、缺血性中风（OR：1.19 95% CI：1.098–1.299）和大动脉中风（OR： 1.49 95% CI：1.214–1.836）。复制和敏感性分析得出了一致的效果方向和相似的估计。进一步的中介分析表明，高血压 (HTN)、收缩压 (SBP) 和 2 型糖尿病 (T2D) 介导了 GERD 对卒中影响的 36.0%、9.0% 和 15.8%；缺血性中风分别为 42.9%、10.8% 和 21.4%，以及 23.3%；大动脉卒中的发生率分别为 7.9% 和 18.7%。这项研究支持 GERD 增加中风、缺血性中风和大动脉中风的易感性，并且部分由 HTN、SBP 和 T2D 介导。