Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Prognostic role of genetic polymorphisms of the interleukin-6 signaling pathway in patients with severe heart failure

The Pharmacogenomics Journal volume 19, pages 428–437 (2019)Cite this article

Subjects

Abstract

Heart failure (HF) is associated with perturbations of the interleukin-6 (IL-6) signaling pathway. A total of 559 Danish subjects with severe chronic HF enrolled in the previously reported Echocardiography and Heart Outcome Study were genotyped for three SNPs in IL6, nine in the IL-6 receptor gene (IL6R), and two in the IL-6 signal transducer gene (IL6ST). After a mean follow-up of 5.0 years, 5 SNPs in IL6R introns (rs12083537, rs6684439, rs4845622, rs4537545, and rs7529229) and a SNP in the IL6R coding region (rs2228145, also known as Asp358Ala) were associated with adverse outcomes, e.g., hazard ratios (HRs) for cardiovascular death and all-cause death 1.38 (CI: 1.09–1.76; P = 0.008) and 1.37 (CI: 1.10–1.70; P = 0.004) for rs6684439 heterozygotes, and 1.39 (CI: 1.09–1.77; P = 0.007) and 1.37 (CI: 1.10–1.70; P = 0.005) for rs4845622 heterozygotes, respectively. We conclude that SNPs in the IL-6 signaling pathway may be independent predictors of fatal outcomes in patients with severe HF.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1

Similar content being viewed by others

References

  1. Heymans S, Hirsch E, Anker SD, Aukrust P, Balligand J-L, Cohen-Tervaert JW, et al. Inflammation as a therapeutic target in heart failure? A scientific statement from the Translational Research Committee of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail. 2009;11:119–29.

    Article  CAS  Google Scholar 

  2. Gullestad L, Ueland T, Vinge LE, Finsen A, Yndestad A, Aukrust P. Inflammatory cytokines in heart failure: mediators and markers. Cardiology. 2012;122:23–35.

    Article  CAS  Google Scholar 

  3. Janssen SPM, Gayan-Ramirez G, Van den Bergh A, Herijgers P, Maes K, Verbeken E, et al. Interleukin-6 causes myocardial failure and skeletal muscle atrophy in rats. Circulation. 2005;111:996–1005.

    Article  CAS  Google Scholar 

  4. Rauchhaus M, Doehner W, Francis DP, Davos C, Kemp M, Liebenthal C, et al. Plasma cytokine parameters and mortality in patients with chronic heart failure. Circulation. 2000;102:3060–7.

    Article  CAS  Google Scholar 

  5. Deswal A, Petersen NJ, Feldman AM, Young JB, White BG, Mann DL. Cytokines and cytokine receptors in advanced heart failure: an analysis of the cytokine database from the Vesnarinone trial (VEST). Circulation. 2001;103:2055–9.

    Article  CAS  Google Scholar 

  6. Chow SL, Maisel AS, Anand I, Bozkurt B, De Boer RA, Felker GM, et al. Role of biomarkers for the prevention, assessment, and management of heart failure: a scientific statement from the American Heart Association. Circulation 2017;135:e1054–91.

  7. Wollert KC, Drexler H. The role of interleukin-6 in the failing heart. Heart Fail Rev. 2001;6:95–103.

    Article  CAS  Google Scholar 

  8. Askevold ET, Gullestad L, Dahl CP, Yndestad A, Ueland T, Aukrust P. Interleukin-6 signaling, soluble glycoprotein 130, and inflammation in heart failure. Curr Heart Fail Rep. 2014;11:146–55.

    Article  CAS  Google Scholar 

  9. Rose-John S, Scheller J, Elson G, Jones SA. Interleukin-6 biology is coordinated by membrane-bound and soluble receptors: role in inflammation and cancer. J Leukoc Biol. 2006;80:227–36.

    Article  CAS  Google Scholar 

  10. Jostock T, Müllberg J, Ozbek S, Atreya R, Blinn G, Voltz N, et al. Soluble gp130 is the natural inhibitor of soluble interleukin-6 receptor transsignaling responses. Eur J Biochem. 2001;268:160–7.

    Article  CAS  Google Scholar 

  11. Guo M, Guo G, Ji X. Genetic polymorphisms associated with heart failure: a literature review. J Int Med Res. 2016;44:15–29.

    Article  CAS  Google Scholar 

  12. Luo R, Li X, Fan X, Yuan W, Wu X. Association of tumor necrosis factor-α gene G-308A polymorphism with dilated cardiomyopathy: a meta-analysis. DNA Cell Biol. 2013;32:130–7.

    Article  CAS  Google Scholar 

  13. Maitra A, Shanker J, Dash D, John S, Sannappa PR, Rao VS, et al. Polymorphisms in the IL6 gene in Asian Indian families with premature coronary artery disease—the Indian Atherosclerosis Research Study. Thromb Haemost. 2008;99:944–50.

    Article  CAS  Google Scholar 

  14. Yang Y, Zhang F, Skrip L, Lei H, Wang Y, Hu D, et al. IL-6 gene polymorphisms and CAD risk: a meta-analysis. Mol Biol Rep. 2013;40:2589–98.

    Article  CAS  Google Scholar 

  15. IL6R Genetics Consortium Emerging Risk Factors Collaboration, Sarwar N, Butterworth AS, Freitag DF, Gregson J, Willeit P, et al. Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies. Lancet. 2012;379:1205–13.

    Article  Google Scholar 

  16. Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium, Swerdlow DI, Holmes MV, Kuchenbaecker KB, Engmann JEL, Shah T, et al. The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis. Lancet. 2012;379:1214–24.

    Article  Google Scholar 

  17. Zhou J, Chen X, Ye H, Peng P, Ba Y, Yang X, et al. An association study between genetic polymorphism in the interleukin-6 receptor gene and coronary heart disease. Biomed Res Int. 2014;2014:504727.

    PubMed  PubMed Central  Google Scholar 

  18. Luchtefeld M, Schunkert H, Stoll M, Selle T, Lorier R, Grote K, et al. Signal transducer of inflammation gp130 modulates atherosclerosis in mice and man. J Exp Med. 2007;204:1935–44.

    Article  CAS  Google Scholar 

  19. Benrick A, Jirholt P, Wernstedt I, Gustafsson M, Scheller J, Eriksson A-L, et al. A non-conservative polymorphism in the IL-6 signal transducer (IL6ST)/gp130 is associated with myocardial infarction in a hypertensive population. Regul Pept. 2008;146:189–96.

    Article  CAS  Google Scholar 

  20. Klein L, Gheorghiade M. Coronary artery disease and prevention of heart failure. Med Clin North Am. 2004;88:1209–35.

    Article  Google Scholar 

  21. Cole W, Brown DW, Giles WH, Stine OC, O’Connell JE, Mitchell BD, et al. Ischemic stroke risk, smoking, and the genetics of inflammation in a biracial population: the stroke prevention in young women study. Thromb J. 2008;6:11.

    Article  Google Scholar 

  22. Akinyemi R, Arnett DK, Tiwari HK, Ovbiagele B, Sarfo F, Srinivasasainagendra V, et al. Interleukin-6 (IL-6) rs1800796 and cyclin dependent kinase inhibitor (CDKN2A/CDKN2B) rs2383207 are associated with ischemic stroke in indigenous West African Men. J Neurol Sci. 2017;379:229–35.

    Article  CAS  Google Scholar 

  23. Adamopoulos S, Kolokathis F, Gkouziouta A, Georgiadou P, Chaidaroglou A, Karavolias GK, et al. Cytokine gene polymorphisms are associated with markers of disease severity and prognosis in patients with idiopathic dilated cardiomyopathy. Cytokine. 2011;54:68–73.

    Article  CAS  Google Scholar 

  24. Miettinen KH, Lassus J, Harjola V-P, Siirilä-Waris K, Melin J, Punnonen KR, et al. Prognostic role of pro- and anti-inflammatory cytokines and their polymorphisms in acute decompensated heart failure. Eur J Heart Fail. 2008;10:396–403.

    Article  CAS  Google Scholar 

  25. Mishra A, Srivastava A, Mittal T, Garg N, Mittal B. Role of inflammatory gene polymorphisms in left ventricular dysfunction (LVD) susceptibility in coronary artery disease (CAD) patients. Cytokine. 2013;61:856–61.

    Article  CAS  Google Scholar 

  26. Torp-Pedersen C, Køber L, Carlsen JE, Akkan D, Bruun NE, Dacoronias D, et al. A randomised trial of a pre-synaptic stimulator of DA 2-dopaminergic and α 2-adrenergic receptors on morbidity and mortality in patients with heart failure. Eur J Heart Fail. 2008;10:89–95.

    Article  CAS  Google Scholar 

  27. Schmidt M, Pedersen L, Sørensen HT. The Danish Civil Registration System as a tool in epidemiology. Eur J Epidemiol. 2014;29:541–9.

    Article  Google Scholar 

  28. Nelveg-Kristensen KE, Busk Madsen M, Torp-Pedersen C, Køber L, Egfjord M, Berg Rasmussen H, et al. Pharmacogenetic risk stratification in angiotensin-converting enzyme inhibitor-treated patients with congestive heart failure: a retrospective cohort study. PLoS ONE. 2015;10:e0144195.

    Article  Google Scholar 

  29. Nelveg-Kristensen KE, Madsen MB, Torp-Pedersen C, Køber L, Egfjord M, Hansen T, et al. Prognostic impact of carboxylesterase 1 gene variants in patients with congestive heart failure treated with angiotensin-converting enzyme inhibitors. Pharm Genom. 2016;26:169–77.

    Article  CAS  Google Scholar 

  30. Enevold C, Oturai AB, Sørensen PS, Ryder LP, Koch-Henriksen N, Bendtzen K. Multiple sclerosis and polymorphisms of innate pattern recognition receptors TLR1-10, NOD1-2, DDX58, and IFIH1. J Neuroimmunol. 2009;212:125–31.

    Article  CAS  Google Scholar 

  31. Petersen M, Andersen JT, Hjelvang BR, Broedbaek K, Afzal S, Nyegaard M, et al. Association of beta-adrenergic receptor polymorphisms and mortality in carvedilol-treated chronic heart-failure patients. Br J Clin Pharmacol. 2011;71:556–65.

    Article  CAS  Google Scholar 

  32. Kathiresan S, Willer CJ, Peloso GM, Demissie S, Musunuru K, Schadt E, et al. Common variants at 30 loci contribute to polygenetic dyslipidemia. Nat Genet. 2009;41:56–65.

    Article  CAS  Google Scholar 

  33. Yates A, Akanni W, Amode MR, Barrell D, Billis K, Carvalho-Silva D, et al. Ensembl 2016. Nucleic Acids Res. 2016;44(D1):D710–6.

    Article  CAS  Google Scholar 

  34. Kleveland O, Kunszt G, Bratlie M, Ueland T, Broch K, Holte E, et al. Effect of a single dose of the interleukin-6 receptor antagonist tocilizumab on inflammation and troponin T release in patients with non-ST-elevation myocardial infarction: a double-blind, randomized, placebo-controlled phase 2 trial. Eur Heart J. 2016;37:2406–13.

    Article  CAS  Google Scholar 

  35. Huang M, Yang D, Xiang M, Wang J. Role of interleukin-6 in regulation of immune responses to remodeling after myocardial infarction. Heart Fail Rev. 2015;20:25–38.

    Article  CAS  Google Scholar 

  36. Ritschel VN, Seljeflot I, Arnesen H, Halvorsen S, Eritsland J, Fagerland MW, et al. Circulating levels of IL-6 receptor and gp130 and long-term clinical outcomes in ST-elevation myocardial infarction. J Am Heart Assoc. 2016;5:e003014.

    Article  Google Scholar 

  37. Sherry ST, Ward MH, Kholodov M, Baker J, Phan L, Smigielski EM, et al. dbSNP: the NCBI database of genetic variation. Nucleic Acids Res. 2001;29:308–11.

    Article  CAS  Google Scholar 

  38. Pendergrass SA, Dudek SM, Crawford DC, Ritchie MD. Synthesis-View: visualization and interpretation of SNP association results for multi-cohort, multi-phenotype data and meta-analysis. BioData Min. 2010;3:10.

    Article  Google Scholar 

  39. Terry CF, Loukaci V, Green FR. Cooperative influence of genetic polymorphisms on interleukin 6 transcriptional regulation. J Biol Chem. 2000;275:18138–44.

    Article  CAS  Google Scholar 

  40. Kämäräinen O-P, Solovieva S, Vehmas T, Luoma K, Riihimäki H, Ala-Kokko L, et al. Common interleukin-6 promoter variants associate with the more severe forms of distal interphalangeal osteoarthritis. Arthritis Res Ther. 2008;10:R21.

    Article  Google Scholar 

  41. Podgoreanu MV, White WD, Morris RW, Mathew JP, Stafford-Smith M, Welsby IJ, et al. Inflammatory gene polymorphisms and risk of postoperative myocardial infarction after cardiac surgery. Circulation. 2006;114(Suppl 1):I275–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Liu Y, Berthier-Schaad Y, Fallin MD, Fink NE, Tracy RP, Klag MJ, et al. IL-6 haplotypes, inflammation, and risk for cardiovascular disease in a multiethnic dialysis cohort. J Am Soc Nephrol. 2006;17:863–70.

    Article  CAS  Google Scholar 

  43. Oh SA, Byun H, Jang E, Jeong S. Identification of cis-regulatory variations in the IL6R gene through the inheritance assessment of allelic transcription. Biochim Biophys Acta. 2014;1840:637–44.

    Article  CAS  Google Scholar 

  44. Revez JA, Bain L, Chapman B, Powell JE, Jansen R, Duffy DL, et al. A new regulatory variant in the interleukin-6 receptor gene associates with asthma risk. Genes Immun. 2013;14:441–6.

    Article  CAS  Google Scholar 

  45. Qi L, Rifai N, Hu FB Interleukin-6 receptor gene, plasma C-reactive protein, and diabetes risk in women. Diabetes. 2009;58(1939-327X (Electronic)):275–8.

    Article  Google Scholar 

  46. Danik JS, Paré G, Chasman DI, Zee RYL, Kwiatkowski DJ, Parker A, et al. Novel loci, including those related to Crohn disease, psoriasis, and inflammation, identified in a genome-wide association study of fibrinogen in 17,686 women: the Women’s Genome Health Study. Circ Cardiovasc Genet. 2009;2:134–41.

    Article  CAS  Google Scholar 

  47. Reich D, Patterson N, Ramesh V, De Jager PL, McDonald GJ, Tandon A, et al. Admixture mapping of an allele affecting interleukin 6 soluble receptor and interleukin 6 levels. Am J Hum Genet. 2007;80:716–26.

    Article  CAS  Google Scholar 

  48. Ferreira RC, Freitag DF, Cutler AJ, Howson JMM, Rainbow DB, Smyth DJ, et al. Functional IL6R 358Ala allele impairs classical IL-6 receptor signaling and influences risk of diverse inflammatory diseases. PLoS Genet. 2013;9:e1003444.

    Article  CAS  Google Scholar 

  49. Wonnerth A, Katsaros KM, Krychtiuk KA, Speidl WS, Kaun C, Thaler K, et al. Glycoprotein 130 polymorphism predicts soluble glycoprotein 130 levels. Metabolism. 2014;63:647–53.

    Article  CAS  Google Scholar 

Download references

Acknowledgments

Peter R. Hansen is supported by an unrestricted grant from the LEO Foundation and a Borregaard Clinical Scientist Fellowship from the Novo Nordisk Foundation. Claus H. Nielsen and Christian Enevold are supported by a grant from the Danish Biotechnology Program, the Capital Region of Denmark.

Author information

Authors and Affiliations

  1. Department of Cardiology, Herlev-Gentofte Hospital, DK-2900, Hellerup, Denmark

    Peter R. Hansen

  2. Section for Periodontology, Department of Odontology, Faculty of Health and Medical Sciences, Copenhagen University, DK-2100, Copenhagen, Denmark

    Peter R. Hansen & Claus Henrik Nielsen

  3. Department of Nephrology, Rigshospitalet, DK-2100, Copenhagen, Denmark

    Karl Emil Nelveg-Kristensen

  4. Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Copenhagen University Hospital, DK-4000, Roskilde, Denmark

    Henrik B. Rasmussen

  5. Department of Science and Environment, Roskilde University, Universitetsvej 1, DK-4000, Roskilde, Denmark

    Henrik B. Rasmussen

  6. Department of Health and Science Technology, Aalborg University, DK-9100, Aalborg, Denmark

    Christian Torp-Pedersen

  7. Department of Cardiology, Rigshospitalet, DK-2100, Copenhagen, Denmark

    Lars Køber

  8. Institute for Inflammation Research, Center for Rheumatology and Spine Diseases, Rigshospitalet, Copenhagen University Hospital, DK-2100, Copenhagen, Denmark

    Claus Henrik Nielsen & Christian Enevold

Authors
  1. Peter R. Hansen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Karl Emil Nelveg-Kristensen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Henrik B. Rasmussen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Christian Torp-Pedersen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lars Køber
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Claus Henrik Nielsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Christian Enevold
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Peter R. Hansen.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hansen, P.R., Nelveg-Kristensen, K.E., Rasmussen, H.B. et al. Prognostic role of genetic polymorphisms of the interleukin-6 signaling pathway in patients with severe heart failure. Pharmacogenomics J 19, 428–437 (2019). https://doi.org/10.1038/s41397-019-0068-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41397-019-0068-2

This article is cited by

Search

Advanced search

Quick links