Skip to content
2000
  1. Home
  2. A-Z Publications
  3. Current Molecular Medicine
  4. Fast Track Articles
  5. Fast Track Article
image of Elucidating the Causal Dynamics between Inflammatory Proteins and Atrial Fibrillation Risk Through Bidirectional Mendelian Randomization

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 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/cmm/10.2174/0115665240347233250119190837
2025-01-20
2025-03-15

  • From This Site

    /content/journals/cmm/10.2174/0115665240347233250119190837
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. Nso N. Bookani K.R. Metzl M. Radparvar F. Role of inflammation in atrial fibrillation: A comprehensive review of current knowledge. J. Arrhythm. 2021 37 1 1 10 10.1002/joa3.12473 33664879
    [Google Scholar]
  2. Zhou X. Dudley S. Jr Evidence for inflammation as a driver of atrial fibrillation. Front Cardiovasc. Med. 2020 7 62 10.3389/fcvm.2020.00062 32411723
    [Google Scholar]
  3. Camm C. Casadei B. Hopewell J. The inflammatory proteome and risk of atrial fibrillation: genetic insights into causal relevance. Europ. Heart J. 2023 44 Suppl 2 ehad655.287 10.1093/eurheartj/ehad655.287
    [Google Scholar]
  4. Korantzopoulos P. Letsas K.P. Tse G. Fragakis N. Goudis C.A. Liu T. Inflammation and atrial fibrillation: A comprehensive review. J. Arrhythm. 2018 34 4 394 401 10.1002/joa3.12077 30167010
    [Google Scholar]
  5. Adamsson Eryd S. Smith J.G. Melander O. Hedblad B. Engström G. Inflammation-sensitive proteins and risk of atrial fibrillation: a population-based cohort study. Eur. J. Epidemiol. 2011 26 6 449 455 10.1007/s10654‑011‑9565‑6 21424216
    [Google Scholar]
  6. Van Wagoner D.R. Chung M.K. Inflammation, inflammasome activation, and atrial fibrillation: evidence for causation and new therapeutic targets. Circulation. 2018 138 20 2243 2246 10.1161/CIRCULATIONAHA.118.036143 30571523
    [Google Scholar]
  7. Liang Y.C. Jia M.J. Li L. Liu D.L. Chu S.F. Li H.L. Association of circulating inflammatory proteins with type 2 diabetes mellitus and its complications: a bidirectional Mendelian randomization study. Front. Endocrinol. 2024 15 1358311 10.3389/fendo.2024.1358311 38606083
    [Google Scholar]
  8. Burgess S. Smith G.D. Davies N.M. Dudbridge F. Gill D. Glymour M.M. Hartwig F.P. Kutalik Z. Holmes M.V. Minelli C. Guidelines for performing Mendelian randomization investigations: update for summer 2023 Wellcome Open Res. 2019 4 186 10.12688/wellcomeopenres.15555.1 32760811
    [Google Scholar]
  9. Zhao J.H. Stacey D. Eriksson N. Macdonald-Dunlop E. Hedman Å.K. Kalnapenkis A. Enroth S. Cozzetto D. Digby-Bell J. Marten J. Folkersen L. Herder C. Jonsson L. Bergen S.E. Gieger C. Needham E.J. Surendran P. Metspalu A. Milani L. Mägi R. Nelis M. Hudjašov G. Paul D.S. Polasek O. Thorand B. Grallert H. Roden M. Võsa U. Esko T. Hayward C. Johansson Å. Gyllensten U. Powell N. Hansson O. Mattsson-Carlgren N. Joshi P.K. Danesh J. Padyukov L. Klareskog L. Landén M. Wilson J.F. Siegbahn A. Wallentin L. Mälarstig A. Butterworth A.S. Peters J.E. Genetics of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and therapeutic targets. Nat. Immunol. 2023 24 9 1540 1551 10.1038/s41590‑023‑01588‑w 37563310
    [Google Scholar]
  10. Nielsen J.B. Thorolfsdottir R.B. Fritsche L.G. Zhou W. Skov M.W. Graham S.E. Herron T.J. McCarthy S. Schmidt E.M. Sveinbjornsson G. Surakka I. Mathis M.R. Yamazaki M. Crawford R.D. Gabrielsen M.E. Skogholt A.H. Holmen O.L. Lin M. Wolford B.N. Dey R. Dalen H. Sulem P. Chung J.H. Backman J.D. Arnar D.O. Thorsteinsdottir U. Baras A. O’Dushlaine C. Holst A.G. Wen X. Hornsby W. Dewey F.E. Boehnke M. Kheterpal S. Mukherjee B. Lee S. Kang H.M. Holm H. Kitzman J. Shavit J.A. Jalife J. Brummett C.M. Teslovich T.M. Carey D.J. Gudbjartsson D.F. Stefansson K. Abecasis G.R. Hveem K. Willer C.J. Biobank-driven genomic discovery yields new insight into atrial fibrillation biology. Nat. Genet. 2018 50 9 1234 1239 10.1038/s41588‑018‑0171‑3 30061737
    [Google Scholar]
  11. Burgess S. Thompson S.G. Collaboration C.C.G. Avoiding bias from weak instruments in Mendelian randomization studies. Int. J. Epidemiol. 2011 40 3 755 764 10.1093/ije/dyr036 21414999
    [Google Scholar]
  12. Burgess S. Bowden J. Fall T. Ingelsson E. Thompson S.G. Sensitivity analyses for robust causal inference from Mendelian randomization analyses with multiple genetic variants. Epidemiology 2017 28 1 30 42 10.1097/EDE.0000000000000559 27749700
    [Google Scholar]
  13. Bowden J. Davey Smith G. Haycock P.C. Burgess S. Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator. Genet. Epidemiol. 2016 40 4 304 314 10.1002/gepi.21965 27061298
    [Google Scholar]
  14. Bowden J. Davey Smith G. Burgess S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int. J. Epidemiol. 2015 44 2 512 525 10.1093/ije/dyv080 26050253
    [Google Scholar]
  15. Verbanck M. Chen C.Y. Neale B. Do R. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat. Genet. 2018 50 5 693 698 10.1038/s41588‑018‑0099‑7 29686387
    [Google Scholar]
  16. Greco M F.D. Minelli C. Sheehan N.A. Thompson J.R. Detecting pleiotropy in Mendelian randomisation studies with summary data and a continuous outcome. Stat. Med. 2015 34 21 2926 2940 10.1002/sim.6522 25950993
    [Google Scholar]
  17. Hemani G. Zheng J. Elsworth B. Wade K.H. Haberland V. Baird D. Laurin C. Burgess S. Bowden J. Langdon R. Tan V.Y. Yarmolinsky J. Shihab H.A. Timpson N.J. Evans D.M. Relton C. Martin R.M. Davey Smith G. Gaunt T.R. Haycock P.C. The MR-Base platform supports systematic causal inference across the human phenome. eLife 2018 7 e34408 10.7554/eLife.34408 29846171
    [Google Scholar]
  18. Hemani G. Tilling K. Davey Smith G. Orienting the causal relationship between imprecisely measured traits using GWAS summary data. PLoS Genet. 2017 13 11 e1007081 10.1371/journal.pgen.1007081 29149188
    [Google Scholar]
  19. Larsson S.C. Butterworth A.S. Burgess S. Mendelian randomization for cardiovascular diseases: principles and applications. Eur. Heart J. 2023 44 47 4913 4924 10.1093/eurheartj/ehad736 37935836
    [Google Scholar]
  20. Ihara K. Sasano T. Role of inflammation in the pathogenesis of atrial fibrillation. Front. Physiol. 2022 13 862164 10.3389/fphys.2022.862164 35492601
    [Google Scholar]
  21. Boos C.J. Anderson R.A. Lip G.Y.H. Is atrial fibrillation an inflammatory disorder? Eur. Heart J. 2006 27 2 136 149 10.1093/eurheartj/ehi645 16278230
    [Google Scholar]
  22. Galea R. Cardillo M.T. Caroli A. Marini M.G. Sonnino C. Narducci M.L. Biasucci L.M. Inflammation and C-reactive protein in atrial fibrillation: cause or effect? Tex. Heart Inst. J. 2014 41 5 461 468 10.14503/THIJ‑13‑3466 25425976
    [Google Scholar]
  23. Harada M. Van Wagoner D.R. Nattel S. Role of inflammation in atrial fibrillation pathophysiology and management. Circ. J. 2015 79 3 495 502 10.1253/circj.CJ‑15‑0138 25746525
    [Google Scholar]
  24. Sun C. Tian X. Jia Y. Yang M. Li Y. Fernig D.G. Functions of exogenous FGF signals in regulation of fibroblast to myofibroblast differentiation and extracellular matrix protein expression. Open Biol. 2022 12 9 210356 10.1098/rsob.210356 36102060
    [Google Scholar]
  25. Wu N. Xu B. Xiang Y. Wu L. Zhang Y. Ma X. Tong S. Shu M. Song Z. Li Y. Zhong L. Association of inflammatory factors with occurrence and recurrence of atrial fibrillation: A meta-analysis. Int. J. Cardiol. 2013 169 1 62 72 10.1016/j.ijcard.2013.08.078 24095158
    [Google Scholar]
  26. Hohmann C. Pfister R. Mollenhauer M. Adler C. Kozlowski J. Wodarz A. Drebber U. Wippermann J. Michels G. Inflammatory cell infiltration in left atrial appendageal tissues of patients with atrial fibrillation and sinus rhythm. Sci. Rep. 2020 10 1 1685 10.1038/s41598‑020‑58797‑8 32015492
    [Google Scholar]
  27. Rienstra M. Sun J.X. Magnani J.W. Sinner M.F. Lubitz S.A. Sullivan L.M. Ellinor P.T. Benjamin E.J. White blood cell count and risk of incident atrial fibrillation (from the Framingham Heart Study). Am. J. Cardiol. 2012 109 4 533 537 10.1016/j.amjcard.2011.09.049 22100030
    [Google Scholar]
  28. Zhou J. Zhang Y. Zhuang Q. IL2RB affects Th1/Th2 and Th17 responses of peripheral blood mononuclear cells from septic patients. Allergol. Immunopathol. (Madr.) 2023 51 3 1 7 10.15586/aei.v51i3.757 37169553
    [Google Scholar]
  29. Lazzerini P.E. Laghi-Pasini F. Acampa M. Srivastava U. Bertolozzi I. Giabbani B. Finizola F. Vanni F. Dokollari A. Natale M. Cevenini G. Selvi E. Migliacci N. Maccherini M. Boutjdir M. Capecchi P.L. Systemic inflammation rapidly induces reversible atrial electrical remodeling: the role of interleukin‐6–mediated changes in connexin expression. J. Am. Heart Assoc. 2019 8 16 e011006 10.1161/JAHA.118.011006 31423933
    [Google Scholar]
  30. Cohen Y. Fischman M. Waterman M. Dolnikov K. Azzam Z.S. Ghersin I. P552 Anti-TNF treatment and risk of atrial fibrillation in inflammatory bowel disease patients. J. Crohn’s Colitis 2023 17 Suppl. 1 i681 i681 10.1093/ecco‑jcc/jjac190.0682
    [Google Scholar]
  31. Schjerning Olsen A.M. Fosbøl E.L. Pallisgaard J. Lindhardsen J. Lock Hansen M. Køber L. Hansen P.R. Torp-Pedersen C. Gislason G.H. NSAIDs are associated with increased risk of atrial fibrillation in patients with prior myocardial infarction: a nationwide study. Eur. Heart J. Cardiovasc. Pharmacother. 2015 1 2 107 114 10.1093/ehjcvp/pvv004 27533979
    [Google Scholar]
  32. Nikoo M.H. Taghavian S.R. Golmoghaddam H. Arandi N. Abdi Ardakani A. Doroudchi M. Increased IL-17A in atrial fibrillation correlates with neutrophil to lymphocyte ratio. Iran. J. Immunol. 2014 11 4 246 258 25549592
    [Google Scholar]
  33. Del Giudice M. Gangestad S.W. Rethinking IL-6 and CRP: Why they are more than inflammatory biomarkers, and why it matters. Brain Behav. Immun. 2018 70 61 75 10.1016/j.bbi.2018.02.013 29499302
    [Google Scholar]
  34. Rosiak M. Dziuba M. Chudzik M. Cygankiewicz I. Bartczak K. Drozdz J. Wranicz J.K. Risk factors for atrial fibrillation: Not always severe heart disease, not always so ‘lonely’. Cardiol. J. 2010 17 5 437 442 20865672
    [Google Scholar]
  35. Clanchy F.I.L. Borghese F. Bystrom J. Balog A. Penn H. Hull D.N. Mageed R.A. Taylor P.C. Williams R.O. Inflammatory disease status and response to TNF blockade are associated with mechanisms of endotoxin tolerance. J. Autoimmun. 2024 148 103300 10.1016/j.jaut.2024.103300 39116634
    [Google Scholar]
  36. Heijman J. Voigt N. Nattel S. Dobrev D. Cellular and molecular electrophysiology of atrial fibrillation initiation, maintenance, and progression. Circ. Res. 2014 114 9 1483 1499 10.1161/CIRCRESAHA.114.302226 24763466
    [Google Scholar]
  37. Engelmann M.D.M. Svendsen J.H. Inflammation in the genesis and perpetuation of atrial fibrillation. Eur. Heart J. 2005 26 20 2083 2092 10.1093/eurheartj/ehi350 15975993
    [Google Scholar]
  38. Reitinger C. Beckmann K. Carle A. Blümle E. Jurkschat N. Paulmann C. Prassl S. Kazandijan L.V. Nimmerjahn F. Fischer S. Fcγ-receptor-independent controlled activation of CD40 canonical signaling by novel therapeutic antibodies for cancer therapy. Antibodies 2024 13 2 31 10.3390/antib13020031
    [Google Scholar]
  39. Strohm L. Ubbens H. Münzel T. Daiber A. Daub S. Role of CD40(L)-TRAF signaling in inflammation and resolution—a double-edged sword. Front. Pharmacol. 2022 13 995061 10.3389/fphar.2022.995061 36267276
    [Google Scholar]
  40. Bosmans L.A. Bosch L. Kusters P.J.H. Lutgens E. Seijkens T.T.P. The CD40-CD40L dyad as immunotherapeutic target in cardiovascular disease. J. Cardiovasc. Transl. Res. 2021 14 1 13 22 10.1007/s12265‑020‑09994‑3 32222950
    [Google Scholar]
  41. Ruan W. Zhou X. Liu H. Wang T. Zhang G. Lin K. Causal role of circulating inflammatory cytokines in cardiac diseases, structure and function, Heart & lung. J. Crit. Care 2024 67 70 79 10.1016/j.hrtlng.2024.04.018 38714139
    [Google Scholar]
  42. Qu Q. Sun J.Y. Zhang Z.Y. Su Y. Li S.S. Li F. Wang R.X. Hub microRNAs and genes in the development of atrial fibrillation identified by weighted gene co-expression network analysis. BMC Med. Genomics 2021 14 1 271 10.1186/s12920‑021‑01124‑5 34781940
    [Google Scholar]
/content/journals/cmm/10.2174/0115665240347233250119190837
Loading
Elucidating the Causal Dynamics between Inflammatory Proteins and Atrial Fibrillation Risk Through Bidirectional Mendelian Randomization
Bentham Science Publishers ; https://doi.org/10.2174/0115665240347233250119190837
/content/journals/cmm/10.2174/0115665240347233250119190837
/content/journals/cmm/10.2174/0115665240347233250119190837
Loading

Data & Media loading...


  • Article Type:     Research Article
Keywords: inflammatory proteins ; mendelian randomization ; cardiovascular genetics ; genetic epidemiology ; Atrial fibrillation

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test