Association between circulating leukocytes and arrhythmias: Mendelian randomization analysis in immuno-cardiac electrophysiology
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 confou...
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Frontiers Media S.A.
2023-04-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1041591/full |
| _version_ | 1797852195252600832 |
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| author | Yuxiao Chen Lian Lou Xuan Zhang Luyang Jin Yao Chen Lele Chen Zhihang Li Fen Zhang Ting Fu Shenjiang Hu Jian Yang |
| author_facet | Yuxiao Chen Lian Lou Xuan Zhang Luyang Jin Yao Chen Lele Chen Zhihang Li Fen Zhang Ting Fu Shenjiang Hu Jian Yang |
| author_sort | Yuxiao Chen |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-09T19:29:49Z |
| format | Article |
| id | doaj.art-4e8e303c2b9c4555a030a75e15ee9aa0 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-09T19:29:49Z |
| publishDate | 2023-04-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Immunology |
| spelling | doaj.art-4e8e303c2b9c4555a030a75e15ee9aa02023-04-05T04:26:06ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-04-011410.3389/fimmu.2023.10415911041591Association between circulating leukocytes and arrhythmias: Mendelian randomization analysis in immuno-cardiac electrophysiologyYuxiao Chen0Lian Lou1Xuan Zhang2Luyang Jin3Yao Chen4Lele Chen5Zhihang Li6Fen Zhang7Ting Fu8Shenjiang Hu9Jian Yang10Department of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, ChinaDepartment of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, ChinaDepartment of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, ChinaDepartment of Gynecology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, ChinaDepartment of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, ChinaDepartment of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, ChinaDepartment of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, ChinaDepartment of Cardiology, Jinhua People’s Hospital, Jinhua, ChinaDepartment of Cardiology, Yiwu Central Hospital, Jinhua, ChinaDepartment of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, ChinaDepartment of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, ChinaBackgroundCardiac 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.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1041591/fullleukocytelymphocytearrhythmiaatrioventricular blockMendelian randomization |
| spellingShingle | Yuxiao Chen Lian Lou Xuan Zhang Luyang Jin Yao Chen Lele Chen Zhihang Li Fen Zhang Ting Fu Shenjiang Hu Jian Yang Association between circulating leukocytes and arrhythmias: Mendelian randomization analysis in immuno-cardiac electrophysiology Frontiers in Immunology leukocyte lymphocyte arrhythmia atrioventricular block Mendelian randomization |
| title | Association between circulating leukocytes and arrhythmias: Mendelian randomization analysis in immuno-cardiac electrophysiology |
| title_full | Association between circulating leukocytes and arrhythmias: Mendelian randomization analysis in immuno-cardiac electrophysiology |
| title_fullStr | Association between circulating leukocytes and arrhythmias: Mendelian randomization analysis in immuno-cardiac electrophysiology |
| title_full_unstemmed | Association between circulating leukocytes and arrhythmias: Mendelian randomization analysis in immuno-cardiac electrophysiology |
| title_short | Association between circulating leukocytes and arrhythmias: Mendelian randomization analysis in immuno-cardiac electrophysiology |
| title_sort | association between circulating leukocytes and arrhythmias mendelian randomization analysis in immuno cardiac electrophysiology |
| topic | leukocyte lymphocyte arrhythmia atrioventricular block Mendelian randomization |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1041591/full |
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