Review Article

IL-6 174 G/C Polymorphism in Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis

Abstract

The results of previous studies on the association between IL-6-174G/C (rs1800795) polymorphism and inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC) are not consistent. The present meta-analysis has pooled all eligible studies to understand the relation between this gene polymorphism and IBD risk. A structured search of Medline, EMBASE, and Scopus databases were performed to identify all eligible studies published before June 2017. Odds ratio (OR) and 95% confidence intervals (CIs) were assessed applying fixed- or random-effect models to evaluate the strength of association in recessive model, dominant model, allelic model, heterozygote contrast, and homozygotes contrast. A sum of 9 articles with 1524 IBD cases and 1586 healthy subjects were included in this study. No significant association between the IL-6 -174 G/C polymorphism and overall IBD susceptibility in any tested genetic model was found. Moreover, in the subgroup analysis based on subtypes, the associations between the IL-6 174-G/C polymorphism and CD and UC missed statistical significance. The current meta-analysis suggests that the IL-6-174 G/C polymorphism is not associated with IBD susceptibility. Further and comprehensive studies are necessary to warrant this result.

Kaplan GG. The global burden of IBD: from 2015 to 2025. Nature reviews Gastroenterology & hepatology 2015; 12: 720-727.

Liu TC , Stappenbeck TS. Genetics and Pathogenesis of Inflammatory Bowel Disease. Annual review of pathology 2016; 11: 127-148.

Kevans D, Silverberg MS, Borowski K, Griffiths A, Xu W, Onay V, Paterson AD, Knight J,Croitoru K. IBD Genetic Risk Profile in Healthy First-Degree Relatives of Crohn's Disease Patients. Journal of Crohn's & colitis 2016; 10: 209-215.

Powrie F, Leach MW, Mauze S, Menon S, Caddle LB,Coffman RL. Inhibition of Th1 responses prevents inflammatory bowel disease in scid mice reconstituted with CD45RBhi CD4+ T cells. Immunity 1994; 1: 553-562.

Neurath MF, Finotto S,Glimcher LH. The role of Th1/Th2 polarization in mucosal immunity. Nature medicine 2002; 8: 567-573.

Nguyen DP, Li J,Tewari AK. Inflammation and prostate cancer: the role of interleukin 6 (IL-6). BJU international 2014; 113: 986-992.

Takac B, Mihaljevic S, Stefanic M, Glavas-Obrovac L, Kibel A,Samardzija M. Importance of interleukin 6 in pathogenesis of inflammatory bowel disease. Collegium antropologicum 2014; 38: 659-664.

Lochhead P, Khalili H, Ananthakrishnan AN, Richter JM,Chan AT. Association Between Circulating Levels of C-Reactive Protein and Interleukin-6 and Risk of Inflammatory Bowel Disease. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association 2016; 14: 818-824.e816.

Cekic C, Arabul M, Alper E, Pakoz ZB, Saritas E, Yuksel,Unsal B. Evaluation of the relationship between serum ghrelin, C-reactive protein and interleukin-6 levels, and disease activity in inflammatory bowel diseases. Hepato-gastroenterology 2014; 61: 1196-1200.

Ataie-Kachoie P, Pourgholami MH, Richardson DR,Morris DL. Gene of the month: Interleukin 6 (IL-6). Journal of clinical pathology 2014; 67: 932-937.

Pereira DS, Garcia DM, Narciso FM, Santos ML, Dias JM, Queiroz BZ, Souza ER, Nobrega OT,Pereira LS. Effects of 174 G/C polymorphism in the promoter region of the interleukin-6 gene on plasma IL-6 levels and muscle strength in elderly women. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas / Sociedade Brasileira de Biofisica [et al] 2011; 44: 123-129.

Nie G, Xie CL, Cao YJ, Xu MM, Shi X, Zou AL,Qi JH. Meta-analysis of IL-6 -174G/C polymorphism and psoriasis risk. Genetics and molecular research : GMR 2016; 15.

Fishman D, Faulds G, Jeffery R, Mohamed-Ali V, Yudkin JS, Humphries S,Woo P. The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. The Journal of clinical investigation 1998; 102: 1369-1376.

Amirzargar AA, Rezaei N, Jabbari H, Danesh A-A, Khosravi F, Hajabdolbaghi M, Yalda A,Nikbin B. Cytokine single nucleotide polymorphisms in Iranian patients with pulmonary tuberculosis. European cytokine network 2006; 17: 84-89.

Amirzargar A, Shahram F, Nikoopour E, Rezaei N, Saeedfar K, Ziaei N,Davatchi F. Proinflammatory cytokine gene polymorphisms in Behcet's disease. European cytokine network 2010; 21: 292-296.

Ziaee V, Tahghighi F, Moradinejad MH, Harsini S, Mahmoudi M, Rezaei A, Soltani S, Sadr M, Aghighi Y,Rezaei N. Interleukin-6, interleukin-1 gene cluster and interleukin-1 receptor polymorphisms in Iranian patients with juvenile systemic lupus erythematosus. European cytokine network 2014; 25: 35-40.

Nasiri R, Movahedi M, Amirzargar AA, Hirbod-Mobarakeh A, Farhadi E, Ansaripour B, Moradi B,Rezaei N. Association of interleukin 6 single nucleotide polymorphisms with allergic rhinitis. International journal of pediatric otorhinolaryngology 2014; 78: 1426-1429.

Nieters A, Linseisen J,Becker N. Association of polymorphisms in Th1, Th2 cytokine genes with hayfever and atopy in a subsample of EPIC‐Heidelberg. Clinical & Experimental Allergy 2004; 34: 346-353.

Gharagozlou M, Farhadi E, Khaledi M, Behniafard N, Sotoudeh S, Salari R, Darabi B, Fathi S, Mahmoudi M,Aghamohammadi A. Association between the interleukin 6 genotype at position-174 and atopic dermatitis. J Investig Allergol Clin Immunol 2013; 23: 89-93.

Totaro F, Cimmino F, Pignataro P, Acierno G, De Mariano M, Longo L, Tonini GP, Iolascon A,Capasso M. Impact of interleukin-6 -174 G>C gene promoter polymorphism on neuroblastoma. PloS one 2013; 8: e76810.

Santos MJ, Fernandes D, Capela S, da Silva JC,Fonseca JE. Interleukin-6 promoter polymorphism -174 G/C is associated with nephritis in Portuguese Caucasian systemic lupus erythematosus patients. Clinical rheumatology 2011; 30: 409-413.

Spasojevic-Dimitrijeva B, Zivkovic M, Stankovic A, Stojkovic L,Kostic M. The IL-6 -174G/C polymorphism and renal scarring in children with first acute pyelonephritis. Pediatric nephrology (Berlin, Germany) 2010; 25: 2099-2106.

Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, Moher D, Becker BJ, Sipe TA,Thacker SB. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Jama 2000; 283: 2008-2012.

Wells G, Shea B, O’connell D, Peterson J, Welch V, Losos M,Tugwell P, The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. 2000.

Wigginton JE, Cutler DJ,Abecasis GR. A note on exact tests of Hardy-Weinberg equilibrium. The American Journal of Human Genetics 2005; 76: 887-893.

Woolf B. On estimating the relation between blood group and disease. Ann Hum Genet 1955; 19: 251-253.

Lau J, Ioannidis JP, Terrin N, Schmid CH,Olkin I. The case of the misleading funnel plot. Bmj 2006; 333: 597-600.

Balding J, Livingstone WJ, Conroy J, Mynett-Johnson L, Weir DG, Mahmud N,Smith OP. Inflammatory bowel disease: the role of inflammatory cytokine gene polymorphisms. Mediators of inflammation 2004; 13: 181-187.

Cantor MJ, Nickerson P,Bernstein CN. The role of cytokine gene polymorphisms in determining disease susceptibility and phenotype in inflammatory bowel disease. The American journal of gastroenterology 2005; 100: 1134-1142.

Gok I, Uçar F, Ozgur O,Efe H. Analysis of Cytokine Gene Polymorphism Allelic Variation in the Turkish Population with Inflammatory Bowel Disease. Biomedical Research 2014; 25: 551-559.

Guerreiro CS, Ferreira P, Tavares L, Santos PM, Neves M, Brito M,Cravo M. Fatty acids, IL6, and TNFα polymorphisms: an example of nutrigenetics in Crohn's disease. The American journal of gastroenterology 2009; 104: 2241-2249.

Klein W, Tromm A, Griga T, Fricke H, Folwaczny C, Hocke M, Eitner K, Marx M,Epplen JT. The polymorphism at position− 174 of the IL-6 gene is not associated with inflammatory bowel disease. European journal of gastroenterology & hepatology 2001; 13: 45-47.

López‐Hernández R, Valdés M, Campillo J, Martínez‐García P, Salama H, Bolarin J, Martínez H, Moya‐Quiles M, Minguela A,Sánchez‐Torres A. Pro‐and anti‐inflammatory cytokine gene single‐nucleotide polymorphisms in inflammatory bowel disease. International journal of immunogenetics 2015; 42: 38-45.

Sagiv-Friedgut K, Karban A, Weiss B, Shaoul R, Shamir R, Bujanover Y, Reif S, Boaz M, Shani I,Levine A. Early-onset Crohn disease is associated with male sex and a polymorphism in the IL-6 promoter. Journal of pediatric gastroenterology and nutrition 2010; 50: 22-26.

Schulte CM, Goebell H, Rõher H-D,Schulte K-M. Genetic determinants of IL-6 expression levels do not influence bone loss in inflammatory bowel disease. Digestive diseases and sciences 2001; 46: 2521-2528.

Stankovic B, Dragasevic S, Popovic D, Zukic B, Kotur N, Sokic‐Milutinovic A, Alempijevic T, Lukic S, Milosavljevic T,Nikcevic G. Variations in inflammatory genes as molecular markers for prediction of inflammatory bowel disease occurrence. Journal of digestive diseases 2015; 16: 723-733.

Atreya R , Neurath MF. Involvement of IL-6 in the pathogenesis of inflammatory bowel disease and colon cancer. Clinical reviews in allergy & immunology 2005; 28: 187-195.

Kishimoto T. IL-6: from its discovery to clinical applications. International immunology 2010: dxq030.

Hunter CA , Jones SA. IL-6 as a keystone cytokine in health and disease. Nature immunology 2015; 16: 448-457.

Grivennikov S, Karin E, Terzic J, Mucida D, Yu G-Y, Vallabhapurapu S, Scheller J, Rose-John S, Cheroutre H,Eckmann L. IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer cell 2009; 15: 103-113.

Dann SM, Spehlmann ME, Hammond DC, Iimura M, Hase K, Choi LJ, Hanson E,Eckmann L. IL-6-dependent mucosal protection prevents establishment of a microbial niche for attaching/effacing lesion-forming enteric bacterial pathogens. The Journal of Immunology 2008; 180: 6816-6826.

Kimura A , Kishimoto T. IL‐6: Regulator of Treg/Th17 balance. European journal of immunology 2010; 40: 1830-1835.

Todhunter CE, Sutherland-Craggs A, Bartram SA, Donaldson P, Daly A, Francis R, Mansfield JC,Thompson NP. Influence of IL-6, COL1A1, and VDR gene polymorphisms on bone mineral density in Crohn’s disease. Gut 2005; 54: 1579-1584.

Senhaji N, Serrano A, Badre W, Serbati N, Karkouri M, Zaid Y, Nadifi S,Martin J. Association of inflammatory cytokine gene polymorphisms with inflammatory bowel disease in a Moroccan cohort. Genes and immunity 2016; 17: 60-65.

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IssueVol 56, No 12 (2018) QRcode
SectionReview Article(s)
Keywords
Interleukin-6 Polymorphism Inflammatory bowel disease Meta-analysis

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1.
Imani D, Rezaei R, Jafari D, Razi B, Alizadeh S, Bashashati M, Rezaei N. IL-6 174 G/C Polymorphism in Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis. Acta Med Iran. 2019;56(12):740-749.