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2000
Volume 25, Issue 12
  • ISSN: 1566-5240
  • E-ISSN: 1875-5666
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Abstract

Background

Atrial fibrillation (AF), the most common cardiac arrhythmia, is associated with significant morbidity and mortality. Inflammation has been implicated in the pathogenesis of AF, but the causal relationship between specific inflammatory proteins and AF risk is not well established. This study aims to clarify this relationship using a bidirectional two-sample Mendelian Randomization (TSMR) approach.

Methods

Employing a bidirectional Mendelian Randomization (MR) method, we analyzed genetic variants as instrumental variables (IVs) to investigate the influence of 91 circulating inflammatory proteins on AF risk. This approach allowed us to assess the potential causal effects of inflammatory proteins on AF and vice versa, thus providing a comprehensive understanding of the bidirectional nature of their relationship.

Results

Seven inflammatory proteins were significantly associated with AF risk. Three proteins increased the risk: Fibroblast Growth Factor 5 (FGF-5) with an odds ratio (OR) of 1.0743 (95% CI: 1.0466-1.1027, p=7.41E-08), Tumor Necrosis Factor (TNF) with an OR of 1.0832 (95% CI: 1.0261-1.1434, p=0.0038), and Interleukin-2 Receptor Subunit Beta (IL-2RB) with an OR of 1.0814 (95% CI: 1.0151-1.1519, p=0.0153). Four proteins showed a protective effect: CD40 Ligand Receptor (CD40) with an OR of 0.9671 (95% CI: 0.9392-0.9959, p=0.0254), Fms-related Tyrosine Kinase 3 Ligand (FIt3L) with an OR of 0.9553 (95% CI: 0.9173-0.9949, p=0.0274), Leukemia Inhibitory Factor Receptor (LIF-R) with an OR of 0.9254 (95% CI: 0.8678-0.9868, p=0.0181), and Sulfotransferase 1A1 (ST1A1) with an OR of 0.9461 (95% CI: 0.9097-0.9839, p=0.0056). The reverse MR analysis revealed no significant effects of AF on the levels of these inflammatory proteins, suggesting a unidirectional causality from proteins to AF.

Conclusion

This bidirectional MR study provides robust evidence for a causal relationship between specific inflammatory proteins and AF risk. The identified proteins could serve as potential biomarkers for AF risk stratification and targets for therapeutic intervention, offering new insights into the pathophysiology of AF and avenues for future research.

© 2025 The Author(s). Published by Bentham Science Publishers.
This is an open access article published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode
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References

  1. NsoN. BookaniK.R. MetzlM. RadparvarF. Role of inflammation in atrial fibrillation: A comprehensive review of current knowledge.J. Arrhythm.202137111010.1002/joa3.12473 33664879
     [Google Scholar]
  2. ZhouX. DudleyS.Jr Evidence for inflammation as a driver of atrial fibrillation.Front. Cardiovasc. Med.202076210.3389/fcvm.2020.00062 32411723
     [Google Scholar]
  3. CammC CasadeiB HopewellJ The inflammatory proteome and risk of atrial fibrillation: genetic insights into causal relevance.Europ Heart J202344Suppl 2ehad655.28710.1093/eurheartj/ehad655.287
     [Google Scholar]
  4. KorantzopoulosP. LetsasK.P. TseG. FragakisN. GoudisC.A. LiuT. Inflammation and atrial fibrillation: A comprehensive review.J. Arrhythm.201834439440110.1002/joa3.12077 30167010
     [Google Scholar]
  5. Adamsson ErydS. SmithJ.G. MelanderO. HedbladB. EngströmG. Inflammation-sensitive proteins and risk of atrial fibrillation: a population-based cohort study.Eur. J. Epidemiol.201126644945510.1007/s10654‑011‑9565‑6 21424216
     [Google Scholar]
  6. Van WagonerD.R. ChungM.K. Inflammation, inflammasome activation, and atrial fibrillation: evidence for causation and new therapeutic targets.Circulation2018138202243224610.1161/CIRCULATIONAHA.118.036143 30571523
     [Google Scholar]
  7. LiangY.C. JiaM.J. LiL. LiuD.L. ChuS.F. LiH.L. Association of circulating inflammatory proteins with type 2 diabetes mellitus and its complications: a bidirectional Mendelian randomization study.Front. Endocrinol.202415135831110.3389/fendo.2024.1358311 38606083
     [Google Scholar]
  8. BurgessS. SmithG.D. DaviesN.M. Guidelines for performing Mendelian randomization investigations: update for summer 2023.Wellcome Open Res.2019418610.12688/wellcomeopenres.15555.1 32760811
     [Google Scholar]
  9. ZhaoJ.H. StaceyD. ErikssonN. Genetics of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and therapeutic targets.Nat. Immunol.20232491540155110.1038/s41590‑023‑01588‑w 37563310
     [Google Scholar]
  10. NielsenJ.B. ThorolfsdottirR.B. FritscheL.G. Biobank-driven genomic discovery yields new insight into atrial fibrillation biology.Nat. Genet.20185091234123910.1038/s41588‑018‑0171‑3 30061737
     [Google Scholar]
  11. BurgessS. ThompsonS.G. CollaborationC.C.G. Avoiding bias from weak instruments in Mendelian randomization studies.Int. J. Epidemiol.201140375576410.1093/ije/dyr036 21414999
     [Google Scholar]
  12. BurgessS. BowdenJ. FallT. IngelssonE. ThompsonS.G. Sensitivity analyses for robust causal inference from Mendelian randomization analyses with multiple genetic variants.Epidemiology2017281304210.1097/EDE.0000000000000559 27749700
     [Google Scholar]
  13. BowdenJ. Davey SmithG. HaycockP.C. BurgessS. Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator.Genet. Epidemiol.201640430431410.1002/gepi.21965 27061298
     [Google Scholar]
  14. BowdenJ. Davey SmithG. BurgessS. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression.Int. J. Epidemiol.201544251252510.1093/ije/dyv080 26050253
     [Google Scholar]
  15. VerbanckM. ChenC.Y. NealeB. DoR. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases.Nat. Genet.201850569369810.1038/s41588‑018‑0099‑7 29686387
     [Google Scholar]
  16. GrecoM.F.D. MinelliC. SheehanN.A. ThompsonJ.R. Detecting pleiotropy in Mendelian randomisation studies with summary data and a continuous outcome.Stat. Med.201534212926294010.1002/sim.6522 25950993
     [Google Scholar]
  17. HemaniG. ZhengJ. ElsworthB. The MR-Base platform supports systematic causal inference across the human phenome.eLife20187e3440810.7554/eLife.34408 29846171
     [Google Scholar]
  18. HemaniG. TillingK. Davey SmithG. Orienting the causal relationship between imprecisely measured traits using GWAS summary data.PLoS Genet.20171311e100708110.1371/journal.pgen.1007081 29149188
     [Google Scholar]
  19. LarssonS.C. ButterworthA.S. BurgessS. Mendelian randomization for cardiovascular diseases: principles and applications.Eur. Heart J.202344474913492410.1093/eurheartj/ehad736 37935836
     [Google Scholar]
  20. IharaK. SasanoT. Role of inflammation in the pathogenesis of atrial fibrillation.Front. Physiol.20221386216410.3389/fphys.2022.862164 35492601
     [Google Scholar]
  21. BoosC.J. AndersonR.A. LipG.Y.H. Is atrial fibrillation an inflammatory disorder?Eur. Heart J.200627213614910.1093/eurheartj/ehi645 16278230
     [Google Scholar]
  22. GaleaR. CardilloM.T. CaroliA. Inflammation and C-reactive protein in atrial fibrillation: cause or effect?Tex. Heart Inst. J.201441546146810.14503/THIJ‑13‑3466 25425976
     [Google Scholar]
  23. HaradaM. Van WagonerD.R. NattelS. Role of inflammation in atrial fibrillation pathophysiology and management.Circ. J.201579349550210.1253/circj.CJ‑15‑0138 25746525
     [Google Scholar]
  24. SunC. TianX. JiaY. YangM. LiY. FernigD.G. Functions of exogenous FGF signals in regulation of fibroblast to myofibroblast differentiation and extracellular matrix protein expression.Open Biol.202212921035610.1098/rsob.210356 36102060
     [Google Scholar]
  25. WuN. XuB. XiangY. Association of inflammatory factors with occurrence and recurrence of atrial fibrillation: A meta-analysis.Int. J. Cardiol.20131691627210.1016/j.ijcard.2013.08.078 24095158
     [Google Scholar]
  26. HohmannC. PfisterR. MollenhauerM. Inflammatory cell infiltration in left atrial appendageal tissues of patients with atrial fibrillation and sinus rhythm.Sci. Rep.2020101168510.1038/s41598‑020‑58797‑8 32015492
     [Google Scholar]
  27. RienstraM. SunJ.X. MagnaniJ.W. White blood cell count and risk of incident atrial fibrillation (from the Framingham Heart Study).Am. J. Cardiol.2012109453353710.1016/j.amjcard.2011.09.049 22100030
     [Google Scholar]
  28. ZhouJ. ZhangY. ZhuangQ. IL2RB affects Th1/Th2 and Th17 responses of peripheral blood mononuclear cells from septic patients.Allergol. Immunopathol. (Madr.)20235131710.15586/aei.v51i3.757 37169553
     [Google Scholar]
  29. LazzeriniP.E. Laghi-PasiniF. AcampaM. Systemic inflammation rapidly induces reversible atrial electrical remodeling: the role of interleukin‐6–mediated changes in connexin expression.J. Am. Heart Assoc.2019816e01100610.1161/JAHA.118.011006 31423933
     [Google Scholar]
  30. CohenY. FischmanM. WatermanM. DolnikovK. AzzamZ.S. GhersinI. P552 Anti-TNF treatment and risk of atrial fibrillation in inflammatory bowel disease patients.J. Crohn’s Colitis202317Suppl. 1i681i110.1093/ecco‑jcc/jjac190.0682
     [Google Scholar]
  31. Schjerning OlsenA.M. FosbølE.L. PallisgaardJ. NSAIDs are associated with increased risk of atrial fibrillation in patients with prior myocardial infarction: a nationwide study.Eur. Heart J. Cardiovasc. Pharmacother.20151210711410.1093/ehjcvp/pvv004 27533979
     [Google Scholar]
  32. NikooM.H. TaghavianS.R. GolmoghaddamH. ArandiN. Abdi ArdakaniA. DoroudchiM. Increased IL-17A in atrial fibrillation correlates with neutrophil to lymphocyte ratio.Iran. J. Immunol.2014114246258 25549592
     [Google Scholar]
  33. Del GiudiceM. GangestadS.W. Rethinking IL-6 and CRP: Why they are more than inflammatory biomarkers, and why it matters.Brain Behav. Immun.201870617510.1016/j.bbi.2018.02.013 29499302
     [Google Scholar]
  34. RosiakM. DziubaM. ChudzikM. Risk factors for atrial fibrillation: Not always severe heart disease, not always so ‘lonely’.Cardiol. J.2010175437442 20865672
     [Google Scholar]
  35. ClanchyF.I.L. BorgheseF. BystromJ. Inflammatory disease status and response to TNF blockade are associated with mechanisms of endotoxin tolerance.J. Autoimmun.202414810330010.1016/j.jaut.2024.103300 39116634
     [Google Scholar]
  36. HeijmanJ. VoigtN. NattelS. DobrevD. Cellular and molecular electrophysiology of atrial fibrillation initiation, maintenance, and progression.Circ. Res.201411491483149910.1161/CIRCRESAHA.114.302226 24763466
     [Google Scholar]
  37. EngelmannM.D.M. SvendsenJ.H. Inflammation in the genesis and perpetuation of atrial fibrillation.Eur. Heart J.200526202083209210.1093/eurheartj/ehi350 15975993
     [Google Scholar]
  38. ReitingerC. BeckmannK. CarleA. Fcγ-receptor-independent controlled activation of CD40 canonical signaling by novel therapeutic antibodies for cancer therapy.Antibodies20241323110.3390/antib13020031
     [Google Scholar]
  39. StrohmL. UbbensH. MünzelT. DaiberA. DaubS. Role of CD40(L)-TRAF signaling in inflammation and resolution—a double-edged sword.Front. Pharmacol.20221399506110.3389/fphar.2022.995061 36267276
     [Google Scholar]
  40. BosmansL.A. BoschL. KustersP.J.H. LutgensE. SeijkensT.T.P. The CD40-CD40L dyad as immunotherapeutic target in cardiovascular disease.J. Cardiovasc. Transl. Res.2021141132210.1007/s12265‑020‑09994‑3 32222950
     [Google Scholar]
  41. RuanW. ZhouX. LiuH. WangT. ZhangG. LinK. Causal role of circulating inflammatory cytokines in cardiac diseases, structure and function, Heart & lung.J. Crit. Care202467707910.1016/j.hrtlng.2024.04.018 38714139
     [Google Scholar]
  42. QuQ. SunJ.Y. ZhangZ.Y. Hub microRNAs and genes in the development of atrial fibrillation identified by weighted gene co-expression network analysis.BMC Med. Genomics202114127110.1186/s12920‑021‑01124‑5 34781940
     [Google Scholar]
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Elucidating the Causal Dynamics between Inflammatory Proteins and Atrial Fibrillation Risk Through Bidirectional Mendelian Randomization
Current Molecular Medicine 25, 1547 (2025); https://doi.org/10.2174/0115665240347233250119190837
/content/journals/cmm/10.2174/0115665240347233250119190837
/content/journals/cmm/10.2174/0115665240347233250119190837
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  • Article Type:     Research Article
Keyword(s): Atrial fibrillation; cardiac arrhythmia; cardiovascular genetics; genetic epidemiology; inflammatory proteins; mendelian randomization

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