Skip to main content

Advertisement

SpringerLink
Log in

Genetics of serum concentration of IL-6 and TNFα in systemic lupus erythematosus and rheumatoid arthritis: a candidate gene analysis

  • Original Article
  • Published:
Clinical Rheumatology Aims and scope Submit manuscript

Abstract

Elevated concentrations of inflammatory mediators are characteristic of autoimmune disease accompanied by chronic or recurrent inflammation. We examined the hypothesis that mediators of inflammation known to be elevated in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are associated with genetic polymorphism previously identified in studies of inflammatory disease. Serum interleukin 6 (IL-6) and tumor necrosis factor alpha (TNFα) concentrations in patients with SLE (n = 117) or RA (n = 164) and in inflammatory disease-free control subjects (n = 172) were measured by multiplex ELISA. Candidate genes were chosen from studies of autoimmune and inflammatory disease. Genotypes were determined for 345 SNP markers in 75 genes. Association between serum analytes and single alleles was tested by linear regression. Polymorphisms in several genes were associated with IL-6 levels (including IL10, TYK2, and CD40L in SLE and DRB1, NOD2, and CSF1 in RA) or with TNFα levels (including TNFSF4 and CSF2 in SLE and PTPN2, DRB1, and NOD2 in RA). Some associations were shared between disease and control groups or between IL-6 and TNFα within a group. In conclusion, variation in genes implicated in disease pathology is associated with serum IL-6 or TNFα concentration. Some genetic associations are more apparent in healthy controls than in SLE or RA, suggesting dysregulation of the principal mediators of chronic inflammation in disease. Susceptibility genes may affect inflammatory response with variable effect on disease etiology.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Tsokos GC (2011) Systemic lupus erythematosus. N Engl J Med 365(22):2110–2121

    Article  CAS  PubMed  Google Scholar 

  2. Scott DL, Wolfe F, Huizinga TW (2010) Rheumatoid arthritis. Lancet 376(9746):1094–1108

    Article  PubMed  Google Scholar 

  3. Cho JH, Gregersen PK (2011) Genomics and the multifactorial nature of human autoimmune disease. N Engl J Med 365(17):1612–1623

    Article  CAS  PubMed  Google Scholar 

  4. Yap DY, Lai KN (2010) Cytokines and their roles in the pathogenesis of systemic lupus erythematosus: from basics to recent advances. J Biomed Biotechnol 2010:365083

    Article  PubMed Central  PubMed  Google Scholar 

  5. McInnes IB, Schett G (2007) Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol 7(6):429–442

    Article  CAS  PubMed  Google Scholar 

  6. Sanchez E, Nadig A, Richardson BC et al (2011) Phenotypic associations of genetic susceptibility loci in systemic lupus erythematosus. Ann Rheum Dis 70(10):1752–1757

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Zhernakova A, van Diemen CC, Wijmenga C (2009) Detecting shared pathogenesis from the shared genetics of immune-related diseases. Nat Rev Genet 10(1):43–55

    Article  CAS  PubMed  Google Scholar 

  8. Maier LM, Hafler DA (2009) Autoimmunity risk alleles in costimulation pathways. Immunol Rev 229(1):322–336

    Article  CAS  PubMed  Google Scholar 

  9. Shah T, Zabaneh D, Gaunt T et al (2013) Gene-centric analysis identifies variants associated with interleukin-6 levels and shared pathways with other inflammation markers. Circ Cardiovasc Genet 6(2):163–170

    Article  CAS  PubMed  Google Scholar 

  10. Weinstock M, Grimm I, Dreier J, Knabbe C, Vollmer T (2014) Genetic variants in genes of the inflammatory response in association with infective endocarditis. PLoS One 9(10):e110151

    Article  PubMed Central  PubMed  Google Scholar 

  11. Vaughn CB, Ochs-Balcom HM, Nie J et al (2013) No association between circulating levels and genetic variants of IL-6 and TNF-alpha and colon adenoma. Gastroenterol Res 6(2)

  12. Tan EM, Cohen AS, Fries JF et al (1982) The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 25(11):1271–1277

    Article  CAS  PubMed  Google Scholar 

  13. Arnett FC, Edworthy SM, Bloch DA et al (1988) The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 31:315–324

    Article  CAS  PubMed  Google Scholar 

  14. Asanuma Y (2003) Premature coronary-artery atherosclerosis in systemic lupus erythematosus. N Engl J Med 349:2407–2415

    Article  CAS  PubMed  Google Scholar 

  15. Chung CP, Oeser A, Raggi P et al (2005) Increased coronary-artery atherosclerosis in rheumatoid arthritis: relationship to disease duration and cardiovascular risk factors. Arthritis Rheum 52:3045–3053

    Article  PubMed  Google Scholar 

  16. Rho YH (2011) Macrophage activation and coronary atherosclerosis in systemic lupus erythematosus and rheumatoid arthritis. Arthritis Care Res (Hoboken) 63:535–541

    Article  CAS  Google Scholar 

  17. Chung CP, Oeser A, Solus JF et al (2008) Inflammation-associated insulin resistance: differential effects in rheumatoid arthritis and systemic lupus erythematosus define potential mechanisms. Arthritis Rheum 58(7):2105–2112

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Rho YH, Solus J, Sokka T et al (2009) Adipocytokines are associated with radiographic joint damage in rheumatoid arthritis. Arthritis Rheum 60(7):1906–1914

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Rho YH, Chung CP, Oeser A et al (2008) Novel cardiovascular risk factors in premature coronary atherosclerosis associated with systemic lupus erythematosus. J Rheumatol 35(9):1789–1794

    CAS  PubMed Central  PubMed  Google Scholar 

  20. Prevoo ML, van ’t Hof MA, Kuper HH, van Leeuwen MA, Van de Putte LB, Van Riel PL (1995) Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum 38:44–48

    Article  CAS  PubMed  Google Scholar 

  21. Bombardier C, Gladman DD, Urowitz MB, Caron D, Chang CH (1992) Derivation of the SLEDAI. A disease activity index for lupus patients. The Committee on Prognosis Studies in SLE. Arthritis Rheum 35(6):630–640

    Article  CAS  PubMed  Google Scholar 

  22. Schnabel RB, Lunetta KL, Larson MG et al (2009) The relation of genetic and environmental factors to systemic inflammatory biomarker concentrations. Circ Cardiovasc Genet 2(3):229–237

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Raychaudhuri S, Sandor C, Stahl EA et al (2012) Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis. Nat Genet 44(3):291–296

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Cooles FA, Isaacs JD (2011) Pathophysiology of rheumatoid arthritis. Curr Opin Rheumatol 23(3):233–240

    Article  CAS  PubMed  Google Scholar 

  25. van der Helm-van Mil AH, Huizinga TW (2008) Advances in the genetics of rheumatoid arthritis point to subclassification into distinct disease subsets. Arthritis Res Ther 10(2):205

    Article  PubMed Central  PubMed  Google Scholar 

  26. du Montcel ST, Michou L, Petit-Teixeira E et al (2005) New classification of HLA-DRB1 alleles supports the shared epitope hypothesis of rheumatoid arthritis susceptibility. Arthritis Rheum 52(4):1063–1068

    Article  PubMed  Google Scholar 

  27. Samet JM, Tal TL (2010) Toxicological disruption of signaling homeostasis: tyrosine phosphatases as targets. Annu Rev Pharmacol Toxicol 50:215–235

    Article  CAS  PubMed  Google Scholar 

  28. Dube N, Tremblay ML (2005) Involvement of the small protein tyrosine phosphatases TC-PTP and PTP1B in signal transduction and diseases: from diabetes, obesity to cell cycle, and cancer. Biochim Biophys Acta 1754(1–2):108–117

    Article  CAS  PubMed  Google Scholar 

  29. Lees CW, Barrett JC, Parkes M, Satsangi J (2011) New IBD genetics: common pathways with other diseases. Gut 60(12):1739–1753

    Article  CAS  PubMed  Google Scholar 

  30. Scharl M, Paul G, Weber A et al (2009) Protection of epithelial barrier function by the Crohn’s disease associated gene protein tyrosine phosphatase n2. Gastroenterology 137(6):2030–2040

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Scharl M, Mwinyi J, Fischbeck A et al (2012) Crohn’s disease-associated polymorphism within the PTPN2 gene affects muramyl-dipeptide-induced cytokine secretion and autophagy. Inflamm Bowel Dis 18(5):900–912

    Article  PubMed  Google Scholar 

  32. Doody KM, Bourdeau A, Tremblay ML (2009) T-cell protein tyrosine phosphatase is a key regulator in immune cell signaling: lessons from the knockout mouse model and implications in human disease. Immunol Rev 228(1):325–341

    Article  CAS  PubMed  Google Scholar 

  33. Hassan SW, Doody KM, Hardy S, Uetani N, Cournoyer D, Tremblay ML (2010) Increased susceptibility to dextran sulfate sodium induced colitis in the T cell protein tyrosine phosphatase heterozygous mouse. PLoS One 5(1):e8868

    Article  PubMed Central  PubMed  Google Scholar 

  34. Yamamoto T, Sekine Y, Kashima K et al (2002) The nuclear isoform of protein-tyrosine phosphatase TC-PTP regulates interleukin-6-mediated signaling pathway through STAT3 dephosphorylation. Biochem Biophys Res Commun 297(4):811–817

    Article  CAS  PubMed  Google Scholar 

  35. Vanden Berghe W, Vermeulen L, De WG, De BK, Boone E, Haegeman G (2000) Signal transduction by tumor necrosis factor and gene regulation of the inflammatory cytokine interleukin-6. Biochem Pharmacol 60(8):1185–1195

    Article  CAS  PubMed  Google Scholar 

  36. Chen G, Shaw MH, Kim YG, Nunez G (2009) NOD-like receptors: role in innate immunity and inflammatory disease. Annu Rev Pathol 4:365–398

    Article  CAS  PubMed  Google Scholar 

  37. Zhu S, Qian Y (2012) IL-17/IL-17 receptor system in autoimmune disease: mechanisms and therapeutic potential. Clin Sci (Lond) 122(11):487–511

    Article  CAS  Google Scholar 

  38. Hume DA, MacDonald KP (2012) Therapeutic applications of macrophage colony-stimulating factor-1 (CSF-1) and antagonists of CSF-1 receptor (CSF-1R) signaling. Blood 119(8):1810–1820

    Article  CAS  PubMed  Google Scholar 

  39. Ramos PS, Criswell LA, Moser KL et al (2011) A comprehensive analysis of shared loci between systemic lupus erythematosus (SLE) and sixteen autoimmune diseases reveals limited genetic overlap. PLoS Genet 7(12):e1002406

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Orozco G, Eyre S, Hinks A et al (2011) Study of the common genetic background for rheumatoid arthritis and systemic lupus erythematosus. Ann Rheum Dis 70(3):463–468

    Article  PubMed Central  PubMed  Google Scholar 

  41. Gateva V, Sandling JK, Hom G et al (2009) A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus. Nat Genet 41(11):1228–1233

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. Cunninghame Graham DS, Morris DL, Bhangale TR et al (2011) Association of NCF2, IKZF1, IRF8, IFIH1, and TYK2 with systemic lupus erythematosus. PLoS Genet 7(10):e1002341

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. Budarf ML, Goyette P, Boucher G et al (2011) A targeted association study in systemic lupus erythematosus identifies multiple susceptibility alleles. Genes Immun 12(1):51–58

    Article  CAS  PubMed  Google Scholar 

  44. Oxer DS, Godoy LC, Borba E et al (2011) PPARgamma expression is increased in systemic lupus erythematosus patients and represses CD40/CD40L signaling pathway. Lupus 20(6):575–587

    Article  CAS  PubMed  Google Scholar 

  45. Savitsky D, Tamura T, Yanai H, Taniguchi T (2010) Regulation of immunity and oncogenesis by the IRF transcription factor family. Cancer Immunol Immunother 59(4):489–510

    Article  CAS  PubMed  Google Scholar 

  46. Tada Y, Kondo S, Aoki S et al (2011) Interferon regulatory factor 5 is critical for the development of lupus in MRL/lpr mice. Arthritis Rheum 63(3):738–748

    Article  CAS  PubMed  Google Scholar 

  47. Panchanathan R, Liu H, Liu H et al (2012) Distinct regulation of murine lupus susceptibility genes by the IRF5/Blimp-1 axis. J Immunol 188(1):270–278

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  48. Feng D, Stone RC, Eloranta ML et al (2010) Genetic variants and disease-associated factors contribute to enhanced interferon regulatory factor 5 expression in blood cells of patients with systemic lupus erythematosus. Arthritis Rheum 62(2):562–573

    CAS  PubMed Central  PubMed  Google Scholar 

  49. Yasuda K, Richez C, Maciaszek JW et al (2007) Murine dendritic cell type I IFN production induced by human IgG-RNA immune complexes is IFN regulatory factor (IRF)5 and IRF7 dependent and is required for IL-6 production. J Immunol 178(11):6876–6885

    Article  CAS  PubMed  Google Scholar 

  50. Yanai H, Chen HM, Inuzuka T et al (2007) Role of IFN regulatory factor 5 transcription factor in antiviral immunity and tumor suppression. Proc Natl Acad Sci U S A 104(9):3402–3407

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  51. Stanford SM, Mustelin TM, Bottini N (2010) Lymphoid tyrosine phosphatase and autoimmunity: human genetics rediscovers tyrosine phosphatases. Semin Immunopathol 32(2):127–136

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  52. Burn GL, Svensson L, Sanchez-Blanco C, Saini M, Cope AP (2011) Why is PTPN22 a good candidate susceptibility gene for autoimmune disease? FEBS Lett 585(23):3689–3698

    Article  CAS  PubMed  Google Scholar 

  53. Siasos G, Tousoulis D, Kioufis S et al (2012) Inflammatory mechanisms in atherosclerosis: the impact of matrix metalloproteinases. Curr Top Med Chem 12(10):1132–1148

    Article  CAS  PubMed  Google Scholar 

  54. Dai C, Deng Y, Quinlan A, Gaskin F, Tsao BP, Fu SM (2014) Genetics of systemic lupus erythematosus: immune responses and end organ resistance to damage. Curr Opin Immunol 31C:87–96

    Article  Google Scholar 

  55. Fu Q, Zhao J, Qian X et al (2011) Association of a functional IRF7 variant with systemic lupus erythematosus. Arthritis Rheum 63(3):749–754

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Sources of funding

This study was supported by NIH grants HL65082, HL67964, GM07569, 2UL1 TR00044506, P60 AR056116, K23AR064768, the Vanderbilt Physician Scientist Development award, and the Dan May Chair in Medicine.

Conflict of interest

None of the authors has a conflict of interest related to this work.

Author information

Authors and Affiliations

  1. Division of Rheumatology, Vanderbilt University, Nashville, TN, USA

    Joseph F. Solus, Cecilia P. Chung, Young Hee Rho & C. Michael Stein

  2. Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University, Nashville, TN, USA

    Joseph F. Solus

  3. Division of Clinical Pharmacology, Vanderbilt University, Nashville, TN, USA

    Annette Oeser, Young Hee Rho, Vivian K. Kawai & C. Michael Stein

  4. Department of Biostatistics, Vanderbilt University, Nashville, TN, USA

    Chun Li

  5. Division of Genetic Medicine, Vanderbilt University, Nashville, TN, USA

    Kevin M. Bradley & Jeffrey R. Smith

Authors
  1. Joseph F. Solus
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cecilia P. Chung
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Annette Oeser
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chun Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Young Hee Rho
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kevin M. Bradley
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Vivian K. Kawai
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jeffrey R. Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. C. Michael Stein
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Joseph F. Solus.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Table 1

(PDF 181 kb)

Supplementary Table 2

(PDF 162 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Solus, J.F., Chung, C.P., Oeser, A. et al. Genetics of serum concentration of IL-6 and TNFα in systemic lupus erythematosus and rheumatoid arthritis: a candidate gene analysis. Clin Rheumatol 34, 1375–1382 (2015). https://doi.org/10.1007/s10067-015-2881-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10067-015-2881-6

Keywords

Search

Navigation