Association between circulating leukocytes and arrhythmias: Mendelian randomization analysis in immuno-cardiac electrophysiology

Frontiers in Immunology

Immunology

Fen Zhang¹  Lele Chen²  Lian Lou²  Xuan Zhang²  Yuxiao Chen²  Yao Chen²  Zhihang Li²  Shenjiang Hu²  Jian Yang²  Ting Fu³  Luyang Jin⁴ 

[1] Department of Cardiology, Jinhua People’s Hospital, Jinhua, China;Department of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China;Department of Cardiology, Yiwu Central Hospital, Jinhua, China;Department of Gynecology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China;

关键词: leukocyte;    lymphocyte;    arrhythmia;    atrioventricular block;    Mendelian randomization;   

DOI  :  10.3389/fimmu.2023.1041591

 received in 2022-09-11, accepted in 2023-03-24,  发布年份 2023

来源: Frontiers

【 摘 要 】

BackgroundCardiac arrhythmia is a common disease associated with high mortality and morbidity. Circulating leukocyte counts, which serve as a biomarker for assessing systemic immune status, have been linked to arrhythmias in observational studies. However, observational studies are plagued by confounding factors and reverse causality, whether alterations in circulating leukocyte components are causally associated with arrhythmias remains uncertain. The present study explored this question based on genetic evidence.Methods and findingsWe performed Mendelian randomization (MR) analysis to evaluate whether alterations in leukocyte counts affect aggregated risk of all types of arrhythmia or risk of five specific types of arrhythmia. Single-nucleotide polymorphisms serving as proxies for leukocyte differential counts were retrieved from the Blood Cell Consortium, and statistical data on arrhythmias were obtained from the UK Biobank), FinnGenand a meta-analysis of genome-wide association studies for atrial fibrillation. We applied inverse variance-weighted method as the primary analysis, complemented by a series of sensitivity analyses. Bidirectional analyses were conducted to assess reverse causality. Finally, multivariable MR was performed to study the joint effects of multiple risk factors. We found that genetically predicted differential leukocyte counts were not significantly associated with aggregated occurrence of all types of arrhythmia. In contrast, each 1-standard deviation increase in lymphocyte count was associated with 46% higher risk of atrioventricular block (OR 1.46, 95% CI 1.11–1.93, p=0.0065). A similar effect size was observed across all MR sensitivity analyses, with no evidence of horizontal pleiotropy. Reverse MR analysis suggested that atrioventricular block was unlikely to cause changes in lymphocyte count. Primary MR analysis based on the inverse-variance weighted method suggested that changes in neutrophil count alter risk of right bundle branch block, and changes in basophil count alter risk of atrial fibrillation. However, these causal relationships were not robust in sensitivity analyses. We found no compelling evidence that neutrophil or lymphocyte counts cause atrial fibrillation.ConclusionOur data support higher lymphocyte count as a causal risk factor for atrioventricular block. These results highlight the importance of immune cells in the pathogenesis of specific cardiac conduction disorders.

【 授权许可】

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Copyright © 2023 Chen, Lou, Zhang, Jin, Chen, Chen, Li, Zhang, Fu, Hu and Yang