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:

Association of inflammatory cytokine gene polymorphisms with inflammatory bowel disease in a Moroccan cohort

Abstract

The purpose of this study was to investigate whether common variants in inflammatory and immune response genes influence inflammatory bowel disease (IBD) risk among Moroccan patients. Using a candidate gene approach, 10 single-nucleotide polymorphisms mapping on six genes (MIF_rs755622, TNFA_rs1800629, IL6_rs2069840, IL6R_rs2228145, IL6ST_rs2228044, IL17A (rs2275913, rs4711998, rs7747909, rs8193036, rs3819024)) were assessed in 510 subjects grouped in 199 IBD and 311 healthy controls. Genotyping was performed with the TaqMan allelic discrimination technology. The results were analyzed using PLINK software. The frequency of allele A for TNFA rs1800629 was significantly higher in ulcerative colitis (UC) patients compared with controls (30.16 vs 16.72%; P=0.0005; odds ratio (OR)=2.15; 95% confidence interval (CI)=1.39–3.32). Statistically significant association to UC was also found under dominant AA+AG vs GG (OR=1.85, 95% CI=1.07–3.21; P=0.02) and recessive models (OR=8.38; 95% CI=2.86–24.53; P=0.0001). In the same way, an association of TNFA rs1800629 variant was observed with IBD under recessive model AA vs AG+GG (OR=4.10; 95% CI=1.56–10.76; P=0.004). No evidence of significant associations was found for the remaining investigated polymorphisms. Our data suggest that TNFA gene promoter polymorphism participates in determining IBD susceptibility in Moroccan patients.

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

Access options

Buy this article

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

Similar content being viewed by others

References

  1. Xavier RJ, Podolsky DK . Unravelling the pathogenesis of inflammatory bowel disease. Nature 2007; 448: 427–434.

    Article  CAS  Google Scholar 

  2. Zhang YZ, Li YY . Inflammatory bowel disease: pathogenesis. World J Gastroenterol 2014; 20: 91–99.

    Article  Google Scholar 

  3. Jostins L, Ripke S, Weersma RK, Duerr RH, McGovern DP, Hui KY et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 2012; 491: 119–124.

    Article  CAS  Google Scholar 

  4. Senhaji N, Diakite B, Serbati N, Zaid Y, Badre W, Nadifi S . Toll-like receptor 4 Asp299Gly and Thr399Ile polymorphisms: new data and a meta-analysis. BMC Gastroenterol 2014; 14: 206.

    Article  Google Scholar 

  5. Hassig A, Kremer H, Liang WX, Stampfli K . The role of the Th-1 to Th-2 shift of the cytokine profiles of CD4 helper cells in the pathogenesis of autoimmune and hypercatabolic diseases. Med Hypotheses 1998; 51: 59–63.

    Article  CAS  Google Scholar 

  6. Quaglietta L, te Velde A, Staiano A, Troncone R, Hommes DW . Functional consequences of NOD2/CARD15 mutations in Crohn disease. J Pediatr Gastroenterol Nutr 2007; 44: 529–539.

    Article  Google Scholar 

  7. Reinecker HC, Steffen M, Witthoeft T, Pflueger I, Schreiber S, MacDermott RP et al. Enhanced secretion of tumour necrosis factor-alpha, IL-6, and IL-1 beta by isolated lamina propria mononuclear cells from patients with ulcerative colitis and Crohn's disease. Clin Exp Immunol 1993; 94: 174–181.

    Article  CAS  Google Scholar 

  8. Kobayashi T, Okamoto S, Hisamatsu T, Kamada N, Chinen H, Saito R et al. IL23 differentially regulates the Th1/Th17 balance in ulcerative colitis and Crohn's disease. Gut 2008; 57: 1682–1689.

    Article  CAS  Google Scholar 

  9. Ohkawara T, Nishihira J, Takeda H, Hige S, Kato M, Sugiyama T et al. Amelioration of dextran sulfate sodium-induced colitis by anti-macrophage migration inhibitory factor antibody in mice. Gastroenterology 2002; 123: 256–270.

    Article  CAS  Google Scholar 

  10. Atreya R, Mudter J, Finotto S, Mullberg J, Jostock T, Wirtz S et al. Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation: evidence in crohn disease and experimental colitis in vivo. Nat Med 2000; 6: 583–588.

    Article  CAS  Google Scholar 

  11. Song Y, Wu KC, Zhang L, Hao ZM, Li HT, Zhang LX et al. Correlation between a gene polymorphism of tumor necrosis factor and inflammatory bowel disease. Chin J Dig Dis 2005; 6: 170–174.

    Article  Google Scholar 

  12. Sykora J, Subrt I, Didek P, Siala K, Schwarz J, Machalova V et al. Cytokine tumor necrosis factor-alpha A promoter gene polymorphism at position -308 G—>A and pediatric inflammatory bowel disease: implications in ulcerative colitis and Crohn's disease. J Pediatr Gastroenterol Nutr 2006; 42: 479–487.

    Article  CAS  Google Scholar 

  13. Sashio H, Tamura K, Ito R, Yamamoto Y, Bamba H, Kosaka T et al. Polymorphisms of the TNF gene and the TNF receptor superfamily member 1B gene are associated with susceptibility to ulcerative colitis and Crohn's disease, respectively. Immunogenetics 2002; 53: 1020–1027.

    Article  CAS  Google Scholar 

  14. López-Hernández R, Valdés M, Campillo JA, Martínez-García P, Salama H, Bolarin JM et al. Pro- and anti-inflammatory cytokine gene single-nucleotide polymorphisms in inflammatory bowel disease. Int J Immunogenet 2015; 42: 38–45.

    Article  Google Scholar 

  15. Bank S, Skytt Andersen P, 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 

  16. Bouma G, Xia B, Crusius JB, Bioque G, Koutroubakis I, Von Blomberg BM et al. Distribution of four polymorphisms in the tumour necrosis factor (TNF) genes in patients with inflammatory bowel disease (IBD). Clin Exp Immunol 1996; 103: 391–396.

    Article  CAS  Google Scholar 

  17. Vatay A, Bene L, Kovacs A, Prohaszka Z, Szalai C, Romics L et al. Relationship between the tumor necrosis factor alpha polymorphism and the serum C-reactive protein levels in inflammatory bowel disease. Immunogenetics 2003; 55: 247–252.

    Article  CAS  Google Scholar 

  18. Fan W, Maoqing W, Wangyang C, Fulan H, Dandan L, Jiaojiao R et al. Relationship between the polymorphism of tumor necrosis factor-alpha-308 G>A and susceptibility to inflammatory bowel diseases and colorectal cancer: a meta-analysis. Eur J Hum Genet 2011; 19: 432–437.

    Article  CAS  Google Scholar 

  19. Qidwai T, Khan F . Tumour necrosis factor gene polymorphism and disease prevalence. Scand J Immunol 2011; 74: 522–547.

    Article  CAS  Google Scholar 

  20. Burke LE, Nerbonne MA . The influence of the guess factor on the speech reception threshold. J Am Aud Soc 1978; 4: 87–90.

    CAS  PubMed  Google Scholar 

  21. Hampe J, Schreiber S, Shaw SH, Lau KF, Bridger S, Macpherson AJ et al. A genomewide analysis provides evidence for novel linkages in inflammatory bowel disease in a large European cohort. Am J Hum Genet 1999; 64: 808–816.

    Article  CAS  Google Scholar 

  22. Wilson AG, Symons JA, McDowell TL, McDevitt HO, Duff GW . Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation. Proc Natl Acad Sci USA 1997; 94: 3195–3199.

    Article  CAS  Google Scholar 

  23. Elahi MM, Asotra K, Matata BM, Mastana SS . Tumor necrosis factor alpha -308 gene locus promoter polymorphism: an analysis of association with health and disease. Biochim Biophys Acta 2009; 1792: 163–172.

    Article  CAS  Google Scholar 

  24. Komatsu M, Kobayashi D, Saito K, Furuya D, Yagihashi A, Araake H et al. Tumor necrosis factor-alpha in serum of patients with inflammatory bowel disease as measured by a highly sensitive immuno-PCR. Clin Chem 2001; 47: 1297–1301.

    CAS  PubMed  Google Scholar 

  25. Braegger CP, Nicholls S, Murch SH, Stephens S, MacDonald TT . Tumour necrosis factor alpha in stool as a marker of intestinal inflammation. Lancet 1992; 339: 89–91.

    Article  CAS  Google Scholar 

  26. Breese EJ, Michie CA, Nicholls SW, Murch SH, Williams CB, Domizio P et al. Tumor necrosis factor alpha-producing cells in the intestinal mucosa of children with inflammatory bowel disease. Gastroenterology 1994; 106: 1455–1466.

    Article  CAS  Google Scholar 

  27. D'Haens G, Van Deventer S, Van Hogezand R, Chalmers D, Kothe C, Baert F et al. Endoscopic and histological healing with infliximab anti-tumor necrosis factor antibodies in Crohn's disease: a European multicenter trial. Gastroenterology 1999; 116: 1029–1034.

    Article  CAS  Google Scholar 

  28. Abraham C, Cho J . Interleukin-23/Th17 pathways and inflammatory bowel disease. Inflamm Bowel Dis 2009; 15: 1090–1100.

    Article  Google Scholar 

  29. Jiang W, Su J, Zhang X, Cheng X, Zhou J, Shi R, Zhang H . Elevated levels of Th17 cells and Th17-related cytokines are associated with disease activity in patients with inflammatory bowel disease. Inflammation Research. 2014; 63: 943–950.

    Article  CAS  Google Scholar 

  30. Nielsen OH, Kirman I, Rudiger N, Hendel J, Vainer B . Upregulation of interleukin-12 and -17 in active inflammatory bowel disease. Scand J Gastroenterol 2003; 38: 180–185.

    Article  CAS  Google Scholar 

  31. Jovanovic DV, Di Battista JA, Martel-Pelletier J, Jolicoeur FC, He Y, Zhang M et al. IL-17 stimulates the production and expression of proinflammatory cytokines, IL-beta and TNF-alpha, by human macrophages. J Immunol 1998; 160: 3513–3521.

    CAS  PubMed  Google Scholar 

  32. Arisawa T, Tahara T, Shibata T, Nagasaka M, Nakamura M, Kamiya Y et al. The influence of polymorphisms of interleukin-17A and interleukin-17F genes on the susceptibility to ulcerative colitis. J Clin Immunol 2008; 28: 44–49.

    Article  CAS  Google Scholar 

  33. Kim SW, Kim ES, Moon CM, Park JJ, Kim TI, Kim WH et al. Genetic polymorphisms of IL-23R and IL-17A and novel insights into their associations with inflammatory bowel disease. Gut 2011; 60: 1527–1536.

    Article  CAS  Google Scholar 

  34. Hayashi R, Tahara T, Shiroeda H, Saito T, Nakamura M, Tsutsumi M et al. Influence of IL17A polymorphisms (rs2275913 and rs3748067) on the susceptibility to ulcerative colitis. Clin Exp Med 2013; 13: 239–244.

    Article  CAS  Google Scholar 

  35. Serbati N, Senhaji N, Diakite B, Badre W, Nadifi S . IL23R and ATG16L1 variants in Moroccan patients with inflammatory bowel disease. BMC Res Notes 2014; 7: 570.

    Article  Google Scholar 

  36. Silverberg MS, Satsangi J, Ahmad T, Arnott ID, Bernstein CN, Brant SR et al. Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: report of a Working Party of the 2005 Montreal World Congress of Gastroenterology. Can J Gastroenterol 2005; 19 (Suppl A): 5A–36A.

    Article  Google Scholar 

  37. Levine A, Griffiths A, Markowitz J, Wilson DC, Turner D, Russell RK et al. Pediatric modification of the Montreal classification for inflammatory bowel disease: the Paris classification. Inflamm Bowel Dis 2011; 17: 1314–1321.

    Article  Google Scholar 

Download references

Acknowledgements

We gratefully acknowledge all the members of LGMP and the Gastroenterology department.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to N Senhaji.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Senhaji, N., Serrano, A., Badre, W. et al. Association of inflammatory cytokine gene polymorphisms with inflammatory bowel disease in a Moroccan cohort. Genes Immun 17, 60–65 (2016). https://doi.org/10.1038/gene.2015.52

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/gene.2015.52

This article is cited by

Search

Quick links