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Meta-Analysis
. 2023 Apr 5:14:1041591.
doi: 10.3389/fimmu.2023.1041591. eCollection 2023.

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

Affiliations
Meta-Analysis

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

Yuxiao Chen et al. Front Immunol. .

Abstract

Background: Cardiac 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 findings: We 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.

Conclusion: Our 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.

Keywords: Mendelian randomization; arrhythmia; atrioventricular block; leukocyte; lymphocyte.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Mendelian randomization (MR) estimates derived from the inverse-variance weighted (IVW) method to assess the causal effect of genetically predicted differential leukocyte counts on arrhythmias. Statistical significance was defined as p<0.05. LBBB, left bundle-branch block; RBBB, right bundle-branch block; OR, odds ratio; CI, confidence interval.
Figure 2
Figure 2
Sensitivity analyses of the causal association between lymphocyte count and risk of atrioventricular block using MR-Egger, weighted median, MR-PRESSO and multivariable MR (MVMR) analyses. *No outlier was detected. Statistical significance was defined as p<0.05.
Figure 3
Figure 3
Sensitivity analyses of the causal association between neutrophil count and risk of RBBB using MR-Egger, weighted median, MR-PRESSO and MVMR analyses. *No outlier was detected. Statistical significance was defined as p<0.05.
Figure 4
Figure 4
Sensitivity MR analyses of the causal association between basophil count and risk of atrial fibrillation using MR-Egger, weighted median, MR-PRESSO and MVMR analyses. Statistical significance was defined as p<0.05.

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