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| Association between inflammatory cytokines and arrhythmias: a bidirectional Mendelian randomization study |
| TONG Tong1,2, ZHANG Xiaoxiao2, YANG Yuhan1,2, YAO Kuiwu3
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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 |
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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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Received: 17 April 2024
Revised: 21 August 2024
Published: 14 November 2024
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[1] LIPPI G,SANCHIS-GOMAR F,CERVELLIN G.Global epidemiology of atrial fibrillation:an increasing epidemic and public health challenge[J].Int J Stroke,2021,16(2):217-221.
[2] DAI W J,ZHANG J,WANG Y,et al.The balance between CD4+ T helper 17 and T-cell immunoglobulin and mucin domain 3 is involved in the pathogenesis and development of atrial fibrillation[J].Afr Health Sci,2023,23(3):607-615.
[3] CHENG T Y,CHEN Y C,LI S J,et al.Interleukin-33/ST2 axis involvement in atrial remodeling and arrhythmogenesis[J].Transl Res,2024,268:1-12.
[4] LAZZERINI P E,CUPELLI M,CARTOCCI A,et al.Elevated interleukin-6 levels are associated with an increased risk of QTc interval prolongation in a large cohort of US Veterans[J/OL].J Am Heart Assoc,2024,13(4)[2024-08-21].https://doi.org/10.1161/JAHA.123.032071.
[5] 于天琦,徐文涛,苏雅娜,等.孟德尔随机化研究基本原理、方法和局限性[J].中国循证医学杂志,2021,21(10):1227-1234.
[6] ZHAO J H,STACEY D,ERIKSSON N,et al.Genetics of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and therapeutic targets[J].Nat Immunol,2023,24(9):1540-1551.
[7] SAKAUE S,KANAI M,TANIGAWA Y,et al.A cross-population atlas of genetic associations for 220 human phenotypes[J].Nat Genet,2021,53(10):1415-1424.
[8] NIELSEN J B,THOROLFSFOTTIR R B,FRITSCHE L G,et al.Biobank-driven genomic discovery yields new insight into atrial fibrillation biology[J].Nat Genet,2018,50(9):1234-1239.
[9] STAERK L,SHERER J A,KO D,et al.Atrial fibrillation:epidemiology,pathophysiology,and clinical outcomes[J].Circ Res,2017,120(9):1501-1517.
[10] LUBOS N,VAN DER GAAG S,GERÇEK M,et al.Inflammation shapes pathogenesis of murine arrhythmogenic cardiomyopathy[J/OL].Basic Res Cardiol,2020[2024-08-21].https://doi.org/10.1007/s00395-020-0803-5.
[11] JOHNSON C N.Calcium modulation of cardiac sodium channels[J].J Physiol,2020,598(14):2835-2846.
[12] KOWALEWSKI M,URBAN M,MROCZKO B.Proinflammatory cytokines (IL-6,TNF-alpha) and cardiac troponin Ⅰ (cTnI) in serum of young people with ventricular arrhythmias[J].Pol Arch Med Wewn,2002,108(1):647-651.
[13] LI G,SANDERS J M,BEVARD M H,et al.CD40 ligand promotes Mac-1 expression,leukocyte recruitment,and neointima formation after vascular injury[J].Am J Pathol,2008,172(4):1141-1152.
[14] ZHANG K N,ZHENG Y Q,BAO G W,et al.Flt3 activation mitigates mitochondrial fragmentation and heart dysfunction through rebalanced L-OPA1 processing by hindering the interaction between acetylated p53 and PHB2 in cardiac remodeling[J/OL].Antioxidants(Basel),2023,12(9)[2024-08-21].https://doi.org/10.3390/antiox12091657.
[15] MA W Z,LIANG F F,ZHAN H Q,et al.Activated FMS-like tyrosine kinase 3 ameliorates angiotensin Ⅱ-induced cardiac remodelling[J/OL].Acta Physiol(Oxf),2020,230(2)[2024-08-21].https://doi.org/10.1111/apha.13519.
[16] BRAUNERSREUTHER V,MACH F,STEFFENS S.The specific role of chemokines in atherosclerosis[J].Thromb Haemost,2007,97(5):714-721.
[17] ZHANG H,DHALLA N S.The role of pro-inflammatory cytokines in the pathogenesis of cardiovascular disease[J/OL].Int J Mol Sci,2024,25(2)[2024-08-21].https://doi.org/10.3390/ijms25021082.
[18] KORBECKI J,KOJDER K,BARCZAK K,et al.Hypoxia alters the expression of CC chemokines and CC chemokine receptors in a tumor:a literature review[J/OL].Int J Mol Sci,2020,21(16)[2024-08-21].https://doi.org/10.3390/ijms21165647.
[19] IKEDA T.Right bundle branch block:current considerations[J].Curr Cardiol Rev,2021,17(1):24-30.
[20] LAZZERI E,ROMAGNANI P.CXCR3-binding chemokines:novel multifunctional therapeutic targets[J].Curr Drug Targets Immune Endocr Metabol Disord,2005,5(1):109-118.
[21] YOUN J C,YU H T,LIM B J,et al.Immunosenescent CD8+ T cells and C-X-C chemokine receptor type 3 chemokines are increased in human hypertension[J].Hypertension,2013,62(1):126-133.
[22] YONG K,DOGRA G,BOUDVILLE N,et al.Interleukin-12 is associated with arterial stiffness in healthy individuals[J].Am J Hypertens,2013,26(2):159-162.
[23] CHEN J Y,CHANG K C,LIOU Y M.Matrix metalloproteinase 1 1G/2G gene polymorphism is associated with acquired atrioventricular block via linking a higher serum protein level[J/OL].Sci Rep,2020,10(1)[2024-08-21].https://doi.org/10.1038/s41598-020-66896-9.
[24] KOSTOV K,BLAZHEV A.Changes in serum levels of matrix metalloproteinase-1 and tissue inhibitor of metalloproteinases-1 in patients with essential hypertension[J/OL].Bioengineering(Basel),2022[2024-08-21].https://doi.org/10.3390/bioengineering9030119.
[25] BJORKBACKA H,YAO MATTISSON I,WIGREN M,et al.Plasma stem cell factor levels are associated with risk of cardiovascular disease and death[J].J Intern Med,2017,282(6):508-521.
[26] XIANG F L,LU X,HAMMOUD L,et al.Cardiomyocyte-specific overexpression of human stem cell factor improves cardiac function and survival after myocardial infarction in mice[J].Circulation,2009,120(12):1065-1074. |
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