孟德尔随机化探究类风湿性关节炎与冠状动脉疾病因果关系以及步行速度的介导作用

目的类风湿性关节炎(rheumatoid arthritis, RA)患者的冠状动脉疾病(coronary artery disease, CAD)发生风险会升高。由于关节疼痛/僵硬或其他关节问题, RA患者的身体素质通常会有所降低,比如步行速度下降。但是,RA、步行速度和CAD这3者之间的因果关联目前尚不清楚。本研究旨在采用网络孟德尔随机化方法研究RA与CAD因果关系及步行速度在该因果关系中的介导作用。方法公共数据库下载RA、CAD和步行速度的全基因组关联研究(genomewide association study, GWAS)统计结果数据,进行两样本的孟德尔随机化分析。RA数据共有103 688例样本,CAD数据有547 261例样本,步行速度有452 264例样本。选取与RA和步行速度相关的独立SNP作为工具变量。使用逆方差加权法与加权中值法进行因果关系分析,并采用MR-Egger和留一法进行模型评价。结果分析结果显示,RA与CAD的总体因果效应是正相关(OR=1.03, 95%CI:1.01～1.04, P=3.90×10-5),RA与正常步行速度负相关(β=-0.02, 9...

Using Mendelian randomization to assess the causal association between rheumatoid arthritis and coronary artery disease and the mediation effect of usual walking pace

It is believed that patients with rheumatoid arthritis (RA) have an increased risk of developing coronary artery disease (CAD). Due to joint pain/stiffness or other joint problems, physical fitness (e.g. walking speed) is often reduced in RA patients. However, the causal link between RA, usual walking pace, and CAD remains unclear. Here we aimed to examine the causal association between RA and CAD by using Mendelian randomization (MR). Whether usual walking pacemediates the causal pathway from RA to CAD was also assessed. Methods Summary statistics from genome-wide association studies (GWASs) were used for 2-sample MR analyses. There were 103688 samples in RA data, 547261 samples in CAD data and 452264 samples in usual walking pace data. MR analysis was performed using inverse variance weighting method and weighted median method. The final estimation was evaluated by MR-Egger and leave-one-out analyses. Results MR analyses showed that RA was positively associated with the risk of CAD (OR = 1.03, 95% CI:1.01~1.04, P = 3.90×10-5) and negatively associated with usual walking pace (β = -0.02，95% CI: -0.04 ~ -0.01, P = 3.15 × 10 -4). Significant negative causal effect of usual walking pace on CAD was also observed (OR = 0.841, 95% CI: 0.81~0.88, P = 3.43×10-15). Mediation analysis showed that usual walking pace might account for about 15.8% of the association between RA and incident CAD.Conclusion In conclusion, our results indicate that RA may be causally associated with increased risk of CAD and usual walking pace might mediate a significant proportion of the relationship between RA and CAD.