Association between inflammatory cytokines and arrhythmias: a bidirectional Mendelian randomization study
TONG Tong1,2, ZHANG Xiaoxiao2, YANG Yuhan1,2, YAO Kuiwu3
1. Graduate School, Beijing University of Chinese Medicine, Beijing 100029, China; 2. Department of Cardiology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China; 3. China Academy of Chinese Medical Sciences, Beijing 100700, China
Abstract：Objective To examine the association between inflammatory cytokines and arrhythmias using two-sample bidirectional Mendelian randomization (MR) approach, so as to provide the basis for the prevention and treatment of arrhythmias. Methods Data of 91 types of inflammatory cytokines were collected from a meta-analysis of genome-wide association studies (GWAS), and data of 7 types of arrhythmia were collected from GWAS database of susceptibility genes. A forward MR analysis was performed using the inverse variance weighted method with inflammatory cytokines as exposure and arrhythmias as the outcome, and a reverse MR analysis was performed with arrhythmias as exposure and inflammatory cytokines as the outcome. The positive and negative direction of association was evaluated using MR Steiger test. The sensitivity analysis were assessed using the Cochran's Q test, MR-PRESSO test and MR-Egger regression. Results Forward MR analysis results showed that fractalkine (OR=1.231), fibroblast growth factor 5 (OR=1.105) and tumor necrosis factor (TNF)-related activation cytokine (OR=0.848) were statistically associated with ventricular arrhythmias (all P<0.05). CD40L receptor (OR=0.970), fibroblast growth factor 5 (OR=1.071), FMS-related tyrosine kinase 3 ligand (OR=0.958), and monocyte chemotactic protein-2 (OR=1.020) were statistically associated with atrial fibrillation (all P<0.05). TNF-related activation cytokine (OR=1.125) was statistically associated with paroxysmal tachycardia (P<0.05). Interleukin-15 receptor subunit α (OR=1.001) was statistically associated with bradycardia (P<0.05). C-C motif chemokine ligand 28 (OR=1.974) and interleukin-7 (OR=1.738) were statistically associated with right bundle branch block (both P<0.05). TNF superfamily member 14 (OR=0.784) was statistically associated with left bundle branch block (P<0.05). CXC motif chemokine ligand 11 (OR=1.277), interleukin-12B (OR=1.127), matrix metalloproteinase-1 (OR=1.333), stem cell factor (OR=0.874), and TNF-β (OR=1.152) were statistically associated with atrioventricular block (all P<0.05). Cochran's Q test detected no heterogeneity, and neither the MR-Egger regression nor the MR-PRESSO test revealed horizontal pleiotropy of instrumental variables (all P>0.05). Reverse MR analysis showed no association between gut microbiota and constipation (all P>0.05). Conclusion Among the 91 types of inflammatory cytokines, 12 types were associated with increased risk of arrhythmias and 5 types were associated with decreased risk of arrhythmias.
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