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.

  • Original Article
  • Published:

Genetically determined high activity of IL-12 and IL-18 in ulcerative colitis and TLR5 in Crohns disease were associated with non-response to anti-TNF therapy

The Pharmacogenomics Journal volume 18, pages 87–97 (2018)Cite this article

Subjects

Abstract

Anti-tumour necrosis factor-α (TNF-α) is used for treatment of severe cases of inflammatory bowel diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC). However, one-third of the patients do not respond to the treatment. A recent study indicated that genetically determined high activity of pro-inflammatory cytokines, including interleukin-1β (IL-1β), IL-6 and interferon gamma (IFN-γ), are associated with non-response to anti-TNF therapy. Using a candidate gene approach, 21 functional single-nucleotide polymorphisms (SNPs) in 14 genes in the Toll-like receptors, the inflammasome and the IFNG pathways were assessed in 482 and 256 prior anti-TNF naïve Danish patients with CD and UC, respectively. The results were analysed using logistic regression (adjusted for age and gender). Eight functional SNPs were associated with anti-TNF response either among patients with CD (TLR5 (rs5744174) and IFNGR2 (rs8126756)), UC (IL12B (rs3212217), IL18 (rs1946518), IFNGR1 (rs2234711), TBX21 (rs17250932) and JAK2 (rs12343867)) or in the combined cohort of patient with CD and UC (IBD) (NLRP3 (rs10754558), IL12B (rs3212217) and IFNGR1 (rs2234711)) (P<0.05). Only the association with heterozygous genotype of IL12B (rs3212217) (OR: 0.24, 95% CI: 0.11–0.53, P=0.008) among patients with UC withstood Bonferroni correction for multiple testing. In conclusion, Our results suggest that SNPs associated with genetically determined high activity of TLR5 among patients with CD and genetically determined high IL-12 and IL-18 levels among patients with UC were associated with non-response. Further studies will evaluate whether these genes may help stratifying patients according to the expected response to anti-TNF treatment.

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

Figure 1

Similar content being viewed by others

References

  1. Podolsky DK . Inflammatory bowel disease. N Engl J Med 2002; 347: 417–429.

    Article  CAS  Google Scholar 

  2. Knight DM, Trinh H, Le J, Siegel S, Shealy D, McDonough M et al. Construction and initial characterization of a mouse-human chimeric anti-TNF antibody. Mol Immunol 1993; 30: 1443–1453.

    Article  CAS  Google Scholar 

  3. Siegel SA, Shealy DJ, Nakada MT, Le J, Woulfe DS, Probert L et al. The mouse/human chimeric monoclonal antibody cA2 neutralizes TNF in vitro and protects transgenic mice from cachexia and TNF lethality in vivo. Cytokine 1995; 7: 15–25.

    Article  CAS  Google Scholar 

  4. Scallon BJ, Moore MA, Trinh H, Knight DM, Ghrayeb J . Chimeric anti-TNF-alpha monoclonal antibody cA2 binds recombinant transmembrane TNF-alpha and activates immune effector functions. Cytokine 1995; 7: 251–259.

    Article  CAS  Google Scholar 

  5. ten HT, van MC, Peppelenbosch MP, van Deventer SJ . Infliximab treatment induces apoptosis of lamina propria T lymphocytes in Crohn's disease. Gut 2002; 50: 206–211.

    Article  Google Scholar 

  6. Rutgeerts P, Sandborn WJ, Feagan BG, Reinisch W, Olson A, Johanns J et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med 2005; 353: 2462–2476.

    Article  CAS  Google Scholar 

  7. Mascheretti S, Hampe J, Kuhbacher T, Herfarth H, Krawczak M, Folsch UR et al. Pharmacogenetic investigation of the TNF/TNF-receptor system in patients with chronic active Crohn's disease treated with infliximab. Pharmacogenomics J 2002; 2: 127–136.

    Article  CAS  Google Scholar 

  8. Paramel GV, Folkersen L, Strawbridge RJ, Elmabsout AA, Sarndahl E, Lundman P et al. CARD8 gene encoding a protein of innate immunity is expressed in human atherosclerosis and associated with markers of inflammation. Clin Sci (Lond) 2013; 125: 401–407.

    Article  CAS  Google Scholar 

  9. Strowig T, Henao-Mejia J, Elinav E, Flavell R . Inflammasomes in health and disease. Nature 2012; 481: 278–286.

    Article  CAS  Google Scholar 

  10. Chang HD, Radbruch A . The pro- and anti-inflammatory potential of interleukin-12. Ann NY Acad Sci 2007; 1109: 40–46.

    Article  CAS  Google Scholar 

  11. Schroder K, Hertzog PJ, Ravasi T, Hume DA . Interferon-gamma: an overview of signals, mechanisms and functions. J Leukoc Biol 2004; 75: 163–189.

    Article  CAS  Google Scholar 

  12. D'Osualdo A, Reed JC . NLRP1, a regulator of innate immunity associated with vitiligo. Pigment Cell Melanoma Res 2012; 25: 5–8.

    Article  CAS  Google Scholar 

  13. Sagulenko V, Thygesen SJ, Sester DP, Idris A, Cridland JA, Vajjhala PR et al. AIM2 and NLRP3 inflammasomes activate both apoptotic and pyroptotic death pathways via ASC. Cell Death Differ 2013; 20: 1149–1160.

    Article  CAS  Google Scholar 

  14. Hong GS, Jung YK . Caspase recruitment domain (CARD) as a bi-functional switch of caspase regulation and NF-kappaB signals. J Biochem Mol Biol 2002; 35: 19–23.

    CAS  PubMed  Google Scholar 

  15. Bank S, Andersen PS, Burisch J, Pedersen N, Roug S, Galsgaard J et al. Associations between functional polymorphisms in the NFkappaB signaling pathway and response to anti-TNF treatment in Danish patients with inflammatory bowel disease. Pharmacogenomics J 2014; 14: 526–34.

    Article  CAS  Google Scholar 

  16. Bank S, Skytt AP, Burisch J, Pedersen N, Roug S, Galsgaard J et al. Polymorphisms in the inflammatory pathway genes TLR2, TLR4, TLR9, LY96, NFKBIA, NFKB1, TNFA, TNFRSF1A, IL6R, IL10, IL23R, PTPN22, and PPARG are associated with susceptibility of inflammatory bowel disease in a Danish cohort. PLoS One 2014; 9: e98815.

    Article  Google Scholar 

  17. Sode J, Vogel U, Bank S, Andersen PS, Thomsen MK, Hetland ML et al. Anti-TNF treatment response in rheumatoid arthritis patients is associated with genetic variation in the NLRP3-inflammasome. PLoS One 2014; 9: e100361.

    Article  Google Scholar 

  18. Bank S, Andersen PS, Burisch J, Pedersen N, Roug S, Galsgaard J et al. Effectiveness of anti-tumour necrosis factor-alpha therapy in Danish patients with inflammatory bowel diseases. Dan Med J 2015; 62: A4994.

    PubMed  Google Scholar 

  19. Bank S . A cohort of anti-TNF treated Danish patients with inflammatory bowel disease, used for identifying genetic markers associated with treatment response. Dan Med J 2015; 62: B5087.

    PubMed  Google Scholar 

  20. Ljung T, Karlen P, Schmidt D, Hellstrom PM, Lapidus A, Janczewska I et al. Infliximab in inflammatory bowel disease: clinical outcome in a population based cohort from Stockholm County. Gut 2004; 53: 849–853.

    Article  CAS  Google Scholar 

  21. Caspersen S, Elkjaer M, Riis L, Pedersen N, Mortensen C, Jess T et al. Infliximab for inflammatory bowel disease in Denmark 1999-2005: clinical outcome and follow-up evaluation of malignancy and mortality. Clin Gastroenterol Hepatol 2008; 6: 1212–1217.

    Article  Google Scholar 

  22. Cohen RD, Tsang JF, Hanauer SB . Infliximab in Crohn's disease: first anniversary clinical experience. Am J Gastroenterol 2000; 95: 3469–3477.

    Article  CAS  Google Scholar 

  23. Bank S, Nexo BA, Andersen V, Vogel U, Andersen PS . High-quality and -quantity DNA extraction from frozen archival blood clots for genotyping of single-nucleotide polymorphisms. Genet Test Mol Biomarkers 2013; 17: 501–503.

    Article  CAS  Google Scholar 

  24. Dhiman N, Ovsyannikova IG, Vierkant RA, Ryan JE, Pankratz VS, Jacobson RM et al. Associations between SNPs in toll-like receptors and related intracellular signaling molecules and immune responses to measles vaccine: preliminary results. Vaccine 2008; 26: 1731–1736.

    Article  CAS  Google Scholar 

  25. Sheridan J, Mack DR, Amre DK, Israel DM, Cherkasov A, Li H et al. A non-synonymous coding variant (L616F) in the TLR5 gene is potentially associated with Crohn's disease and influences responses to bacterial flagellin. PLoS One 2013; 8: e61326.

    Article  CAS  Google Scholar 

  26. Klimosch SN, Forsti A, Eckert J, Knezevic J, Bevier M, Schonfels V et al. Functional TLR5 genetic variants affect human colorectal cancer survival. Cancer Res 2013; 73: 7232–7242.

    Article  CAS  Google Scholar 

  27. Hijikata M, Shojima J, Matsushita I, Tokunaga K, Ohashi J, Hang NT et al. Association of IFNGR2 gene polymorphisms with pulmonary tuberculosis among the Vietnamese. Hum Genet 2012; 131: 675–682.

    Article  CAS  Google Scholar 

  28. Wu JF, Wu TC, Chen CH, Ni YH, Chen HL, Hsu HY et al. Serum levels of interleukin-10 and interleukin-12 predict early, spontaneous hepatitis B virus e antigen seroconversion. Gastroenterology 2010; 138: 165–172.

    Article  CAS  Google Scholar 

  29. Jaiswal PK, Singh V, Srivastava P, Mittal RD . Association of IL-12, IL-18 variants and serum IL-18 with bladder cancer susceptibility in North Indian population. Gene 2013; 519: 128–134.

    Article  CAS  Google Scholar 

  30. Dziedziejko V, Kurzawski M, Paczkowska E, Machalinski B, Pawlik A . The impact of IL18 gene polymorphisms on mRNA levels and interleukin-18 release by peripheral blood mononuclear cells. Postepy Hig Med Dosw (Online) 2012; 66: 409–414.

    Article  Google Scholar 

  31. Hitomi Y, Ebisawa M, Tomikawa M, Imai T, Komata T, Hirota T et al. Associations of functional NLRP3 polymorphisms with susceptibility to food-induced anaphylaxis and aspirin-induced asthma. J Allergy Clin Immunol 2009; 124: 779–785.

    Article  CAS  Google Scholar 

  32. Lugering A, Schmidt M, Lugering N, Pauels HG, Domschke W, Kucharzik T . Infliximab induces apoptosis in monocytes from patients with chronic active Crohn's disease by using a caspase-dependent pathway. Gastroenterology 2001; 121: 1145–1157.

    Article  CAS  Google Scholar 

  33. Di SA, Ciccocioppo R, Cinque B, Millimaggi D, Morera R, Ricevuti L et al. Defective mucosal T cell death is sustainably reverted by infliximab in a caspase dependent pathway in Crohn's disease. Gut 2004; 53: 70–77.

    Article  Google Scholar 

  34. Siegel CA, Melmed GY . Predicting response to anti-TNF agents for the treatment of Crohn's disease. Therap Adv Gastroenterol 2009; 2: 245–251.

    Article  Google Scholar 

  35. Hlavaty T, Pierik M, Henckaerts L, Ferrante M, Joossens S, van SN et al. Polymorphisms in apoptosis genes predict response to infliximab therapy in luminal and fistulizing Crohn's disease. Aliment Pharmacol Ther 2005; 22: 613–626.

    Article  CAS  Google Scholar 

  36. Pierik M, Vermeire S, Steen KV, Joossens S, Claessens G, Vlietinck R et al. Tumour necrosis factor-alpha receptor 1 and 2 polymorphisms in inflammatory bowel disease and their association with response to infliximab. Aliment Pharmacol Ther 2004; 20: 303–310.

    Article  CAS  Google Scholar 

  37. Bek S, Nielsen JV, Bojesen AB, Franke A, Bank S, Vogel U et al. Systematic review: genetic biomarkers associated with anti-TNF treatment response in inflammatory bowel diseases. Aliment Pharmacol Ther 2016; 44: 554–67.

    Article  CAS  Google Scholar 

  38. Bank S . A cohort of anti-TNF treated Danish patients with inflammatory bowel disease, used for identifying genetic markers associated with treatment response. Dan Med J 2015; 62: B5087.

    PubMed  Google Scholar 

  39. Murdaca G, Spanò F, Contatore M, Guastalla A, Magnani O, Puppo F . Pharmacogenetics of etanercept: role of TNF-α gene polymorphisms in improving its efficacy. Expert Opin Drug Metab Toxicol 2014; 10: 1703–1710.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The work was funded by Health Research Fund of Central Denmark Region, Colitis-Crohn Foreningen and University of Aarhus (PhD grant).

Author information

Authors and Affiliations

  1. Medical Department, Viborg Regional Hospital, Viborg, Denmark

    S Bank & V Andersen

  2. Biomedicine, University of Aarhus, Aarhus, Denmark

    S Bank & B A Nexø

  3. Microbiology and Infection Control, Statens Serum Institut, Copenhagen, Denmark

    P S Andersen

  4. Veterinary Disease Biology, University of Copenhagen, Copenhagen, Denmark

    P S Andersen

  5. Department of Gastroenterology, Herlev Hospital, Herlev, Denmark

    J Burisch & N Pedersen

  6. Department of Gastroenterology, Hvidovre Hospital, Hvidovre, Denmark

    S Roug

  7. Medical Department, Køge Hospital, Køge, Denmark

    J Galsgaard

  8. Department of Surgery, Hillerød Hospital, Hillerød, Denmark

    S Y Turino

  9. Medical Department, Sydvestjysk Hospital, Esbjerg, Denmark

    J B Brodersen

  10. Department of Medical Gastroenterology, Odense University Hospital, Odense, Denmark

    J B Brodersen

  11. Medical Department, Bispebjerg Hospital, Bispebjerg, Denmark

    S Rashid

  12. Medical Department, Nykøbing Falster Hospital, Nykøbing Falster, Denmark

    B K Rasmussen

  13. Department of Hepato-Gastroenterology, Aarhus University Hospital, Aarhus, Denmark

    S Avlund

  14. Medical Department, Slagelse Hospital, Slagelse, Denmark

    T B Olesen

  15. Department of Respiratory Diseases B, Institute for Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark

    H J Hoffmann

  16. Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark

    J Sode & V Andersen

  17. Department of Autoimmunology and Biomarkers, Statens Serum Institut, Copenhagen, Denmark

    J Sode

  18. Department of Rheumatology, Frederiksberg Hospital, Frederiksberg, Denmark

    J Sode

  19. National Research Centre for the Working Environment, Copenhagen, Denmark

    U Vogel

  20. Research Unit for Molecular Diagnostic, Hospital of Southern Jutland Aabenraa, Aabenraa, Denmark

    V Andersen

  21. OPEN Odense Patient Data Explorative Network, Odense University Hospital, Odense, Denmark

    V Andersen

Authors
  1. S Bank
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. P S Andersen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J Burisch
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. N Pedersen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S Roug
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J Galsgaard
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. S Y Turino
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. J B Brodersen
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. S Rashid
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. B K Rasmussen
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. S Avlund
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. T B Olesen
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. H J Hoffmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. B A Nexø
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. J Sode
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. U Vogel
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. V Andersen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S Bank.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the The Pharmacogenomics Journal website

Supplementary information

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bank, S., Andersen, P., Burisch, J. et al. Genetically determined high activity of IL-12 and IL-18 in ulcerative colitis and TLR5 in Crohns disease were associated with non-response to anti-TNF therapy. Pharmacogenomics J 18, 87–97 (2018). https://doi.org/10.1038/tpj.2016.84

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/tpj.2016.84

This article is cited by

Search

Advanced search

Quick links