Associations of TNF-Α -308 and -238 Polymorphisms with Inflammatory Bowel Disease: A Case-Control Study and Meta-Analysis of Published Data
-
Shirin Moosavi
,
Aaron Shanker
,
Maryam Sadr
,
Samaneh Soltani
,
Sepideh Shahkarami
,
Elham Farhadi
,
Nasser Ebrahimi Daryani
,
Behnoud Baradaran Noveiry
,
Farnaz Najmi Varzaneh
,
Mohammad Bashashati
,
Nima Rezaei
Abstract
Background: Inflammatory bowel disease (IBD) is a chronic relapsing-remitting inflammatory disease of the intestinal tract. Tumor necrosis factor-alpha (TNF-α) signaling plays a major role in the pathogenesis of IBD and is commonly targeted for therapeutic purposes. Results on the contribution of TNF-α -308 and -238 single nucleotide polymorphisms (SNP) to the susceptibility to IBD have been contradictory in different populations.
Methods: Allele frequency and genotype status of TNF-α -308 and -238 SNPs were investigated in 75 unrelated patients with IBD [40 Crohn’s disease (CD) and 35 ulcerative colitis (UC)] and 140 healthy controls by polymerase chain reaction with sequence-specific primers (PCR-SSP). We also conducted a systematic review and meta-analysis of the published reports.
Results: TNF-α -238 GG was detected at a higher frequency in CD and UC. TNF-α -308 GG was more frequently detected in UC compared to control. There was no significant association between TNF-α -238 or -308 gene polymorphisms and patients’ demography (i.e., gender and age) or disease phenotype (i.e., extraintestinal manifestations, treatment, activity index, age at onset, and duration of the disease). In the meta-analysis, TNF-α -238 (AA/AG) genotype tended to be less frequent in patients with UC compared to healthy controls. There was no association between TNF-α -238 gene polymorphisms (AA/AG or GG genotypes) and either form of IBD.
Conclusion: TNF-α -308 and -238 SNPs are associated with IBD in Iranian patients. The TNF-α -308 AA genotype is positively correlated with UC in this meta-analysis.
1. Bashashati M, Rezaei N, Bashashati H, Shafieyoun A, Daryani NE, Sharkey KA, et al. Cytokine gene polymorphisms are associated with irritable bowel syndrome: a systematic review and meta-analysis. Neurogastroenterol Motil. 2012;24(12):1102-e566.
2. 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(3):391-6.
3. Celik Y, Dagli U, Kilic MY, Toruner M, Ozen SC, Ozkan M, et al. Cytokine gene polymorphisms in Turkish patients with inflammatory bowel disease. Scand J Gastroenterol. 2006;41(5):559-65.
4. Ferguson LR, Huebner C, Petermann I, Gearry RB, Barclay ML, Demmers P, et al. Single nucleotide polymorphism in the tumor necrosis factor-alpha gene affects inflammatory bowel diseases risk. World J Gastroenterol. 2008;14(29):4652-61.
5. Lopez-Hernandez R, Valdes M, Campillo JA, Martinez-Garcia P, Salama H, Salgado G, et al. Genetic polymorphisms of tumour necrosis factor alpha (TNF-alpha) promoter gene and response to TNF-alpha inhibitors in Spanish patients with inflammatory bowel disease. Int J Immunogenet. 2014;41(1):63-8.
6. Negoro K, Kinouchi Y, Hiwatashi N, Takahashi S, Takagi S, Satoh J, et al. Crohn's disease is associated with novel polymorphisms in the 5'-flanking region of the tumor necrosis factor gene. Gastroenterology. 1999;117(5):1062-8.
7. 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(12):1020-7.
8. Naderi N, Farnood A, Dadaei T, Habibi M, Balaii H, Firouzi F, et al. Association of Tumor Necrosis Factor Alpha Gene Polymorphisms with Inflammatory Bowel Disease in Iran. Iran J Public Health. 2014;43(5):630-6.
9. Yang SK, Lee SG, Cho YK, Lim J, Lee ISong K. Association of TNF-alpha/LTA polymorphisms with Crohn's disease in Koreans. Cytokine. 2006;35(1-2):13-20.
10. Zipperlen K, Peddle L, Melay B, Hefferton DRahman P. Association of TNF-alpha polymorphisms in Crohn disease. Hum Immunol. 2005;66(1):56-9.
11. 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(4):247-52.
12. Stankovic B, Dragasevic S, Popovic D, Zukic B, Kotur N, Sokic-Milutinovic A, et al. Variations in inflammatory genes as molecular markers for prediction of inflammatory bowel disease occurrence. J Dig Dis. 2015;16(12):723-33.
13. Yamamoto-Furusho JK, Uscanga LF, Vargas-Alarcon G, Rodriguez-Perez JM, Zuniga JGranados J. Polymorphisms in the promoter region of tumor necrosis factor alpha (TNF-alpha) and the HLA-DRB1 locus in Mexican mestizo patients with ulcerative colitis. Immunol Lett. 2004;95(1):31-5.
14. Cantor MJ, Nickerson PBernstein CN. The role of cytokine gene polymorphisms in determining disease susceptibility and phenotype in inflammatory bowel disease. Am J Gastroenterol. 2005;100(5):1134-42.
15. Castro-Santos P, Suarez A, Lopez-Rivas L, Mozo LGutierrez C. TNFalpha and IL-10 gene polymorphisms in inflammatory bowel disease. Association of -1082 AA low producer IL-10 genotype with steroid dependency. Am J Gastroenterol. 2006;101(5):1039-47.
16. Mittal RD, Manchanda PK, Bid HKGhoshal UC. Analysis of polymorphisms of tumor necrosis factor-alpha and polymorphic xenobiotic metabolizing enzymes in inflammatory bowel disease: study from northern India. J Gastroenterol Hepatol. 2007;22(6):920-4.
17. Bonyadi M, Abdolmohammadi R, Jahanafrooz Z, Somy MHKhoshbaten M. TNF-alpha gene polymorphisms in Iranian Azari Turkish patients with inflammatory bowel diseases. Saudi J Gastroenterol. 2014;20(2):108-12.
18. Al-Meghaiseeb ES, Al-Robayan AA, Al-Otaibi MM, Arfin MAl-Asmari AK. Association of tumor necrosis factor-alpha and -beta gene polymorphisms in inflammatory bowel disease. J Inflamm Res. 2016;9:133-40.
19. Balding J, Livingstone WJ, Conroy J, Mynett-Johnson L, Weir DG, Mahmud N, et al. Inflammatory bowel disease: the role of inflammatory cytokine gene polymorphisms. Mediators Inflamm. 2004;13(3):181-7.
20. Ferreira AC, Almeida S, Tavares M, Canedo P, Pereira F, Regalo G, et al. NOD2/CARD15 and TNFA, but not IL1B and IL1RN, are associated with Crohn's disease. Inflamm Bowel Dis. 2005;11(4):331-9.
21. Fowler EV, Eri R, Hume G, Johnstone S, Pandeya N, Lincoln D, et al. TNFalpha and IL10 SNPs act together to predict disease behaviour in Crohn's disease. J Med Genet. 2005;42(6):523-8.
22. Hong J, Leung E, Fraser AG, Merriman TR, Vishnu PKrissansen GW. IL4, IL10, IL16, and TNF polymorphisms in New Zealand Caucasian Crohn's disease patients. Int J Colorectal Dis. 2008;23(3):335-7.
23. Hradsky O, Lenicek M, Dusatkova P, Bronsky J, Nevoral J, Valtrova V, et al. Variants of CARD15, TNFA and PTPN22 and susceptibility to Crohn's disease in the Czech population: high frequency of the CARD15 1007fs. Tissue Antigens. 2008;71(6):538-47.
24. Santana G, Bendicho MT, Santana TC, Reis LB, Lemaire DLyra AC. The TNF-alpha -308 polymorphism may affect the severity of Crohn's disease. Clinics (Sao Paulo). 2011;66(8):1373-8.
25. 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(4):170-4.
26. Cao Q, Zhu Q, Wu ML, Hu WL, Gao MSi JM. Genetic susceptibility to ulcerative colitis in the Chinese Han ethnic population: association with TNF polymorphisms. Chin Med J (Engl). 2006;119(14):1198-203.
27. Gok I, Ucar FOzgur O. Inflammatory cytokine gene polymorphism profiles in Turkish patients with ulcerative colitis. Med Glas (Zenica). 2015;12(1):33-9.
28. Tavares M, de Lima C, Fernandes W, Martinelli V, de Lucena M, Lima F, et al. Tumour necrosis factor-alpha (-308G/A) promoter polymorphism is associated with ulcerative colitis in Brazilian patients. Int J Immunogenet. 2016;43(6):376-82.
29. Sanchez R, Levy E, Costea FSinnett D. IL-10 and TNF-alpha promoter haplotypes are associated with childhood Crohn's disease location. World J Gastroenterol. 2009;15(30):3776-82.
30. Kim TH, Kim BG, Shin HD, Kim JW, Kim CG, Kim JS, et al. [Tumor necrosis factor-alpha and interleukin-10 gene polymorphisms in Korean patients with inflammatory bowel disease]. Korean J Gastroenterol. 2003;42(5):377-86.
31. 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(2):127-36.
32. Dalal I, Karban A, Wine E, Eliakim R, Shirin H, Fridlender M, et al. Polymorphisms in the TNF-alpha promoter and variability in the granulomatous response in patients with Crohn's disease. Pediatr Res. 2006;59(6):825-8.
33. 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(5):479-87.
34. Louis E, Peeters M, Franchimont D, Seidel L, Fontaine F, Demolin G, et al. Tumour necrosis factor (TNF) gene polymorphism in Crohn's disease (CD): influence on disease behaviour? Clin Exp Immunol. 2000;119(1):64-8.
35. Louis E, Vermeire S, Rutgeerts P, De Vos M, Van Gossum A, Pescatore P, et al. A positive response to infliximab in Crohn disease: association with a higher systemic inflammation before treatment but not with -308 TNF gene polymorphism. Scand J Gastroenterol. 2002;37(7):818-24.
36. Gonzalez S, Rodrigo L, Martinez-Borra J, Lopez-Vazquez A, Fuentes D, Nino P, et al. TNF-alpha -308A promoter polymorphism is associated with enhanced TNF-alpha production and inflammatory activity in Crohn's patients with fistulizing disease. Am J Gastroenterol. 2003;98(5):1101-6.
37. Castro-Santos P, Suarez A, Mozo LGutierrez C. Association of IL-10 and TNFalpha genotypes with ANCA appearance in ulcerative colitis. Clin Immunol. 2007;122(1):108-14.
38. Papo M, Quer JC, Gutierrez C, Broch M, Casellas F, Pastor RM, et al. Genetic heterogeneity within ulcerative colitis determined by an interleukin-1 receptor antagonist gene polymorphism and antineutrophil cytoplasmic antibodies. Eur J Gastroenterol Hepatol. 1999;11(4):413-20.
39. Lacruz-Guzman D, Torres-Moreno D, Pedrero F, Romero-Cara P, Garcia-Tercero I, Trujillo-Santos J, et al. Influence of polymorphisms and TNF and IL1beta serum concentration on the infliximab response in Crohn's disease and ulcerative colitis. Eur J Clin Pharmacol. 2013;69(3):431-8.
2. 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(3):391-6.
3. Celik Y, Dagli U, Kilic MY, Toruner M, Ozen SC, Ozkan M, et al. Cytokine gene polymorphisms in Turkish patients with inflammatory bowel disease. Scand J Gastroenterol. 2006;41(5):559-65.
4. Ferguson LR, Huebner C, Petermann I, Gearry RB, Barclay ML, Demmers P, et al. Single nucleotide polymorphism in the tumor necrosis factor-alpha gene affects inflammatory bowel diseases risk. World J Gastroenterol. 2008;14(29):4652-61.
5. Lopez-Hernandez R, Valdes M, Campillo JA, Martinez-Garcia P, Salama H, Salgado G, et al. Genetic polymorphisms of tumour necrosis factor alpha (TNF-alpha) promoter gene and response to TNF-alpha inhibitors in Spanish patients with inflammatory bowel disease. Int J Immunogenet. 2014;41(1):63-8.
6. Negoro K, Kinouchi Y, Hiwatashi N, Takahashi S, Takagi S, Satoh J, et al. Crohn's disease is associated with novel polymorphisms in the 5'-flanking region of the tumor necrosis factor gene. Gastroenterology. 1999;117(5):1062-8.
7. 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(12):1020-7.
8. Naderi N, Farnood A, Dadaei T, Habibi M, Balaii H, Firouzi F, et al. Association of Tumor Necrosis Factor Alpha Gene Polymorphisms with Inflammatory Bowel Disease in Iran. Iran J Public Health. 2014;43(5):630-6.
9. Yang SK, Lee SG, Cho YK, Lim J, Lee ISong K. Association of TNF-alpha/LTA polymorphisms with Crohn's disease in Koreans. Cytokine. 2006;35(1-2):13-20.
10. Zipperlen K, Peddle L, Melay B, Hefferton DRahman P. Association of TNF-alpha polymorphisms in Crohn disease. Hum Immunol. 2005;66(1):56-9.
11. 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(4):247-52.
12. Stankovic B, Dragasevic S, Popovic D, Zukic B, Kotur N, Sokic-Milutinovic A, et al. Variations in inflammatory genes as molecular markers for prediction of inflammatory bowel disease occurrence. J Dig Dis. 2015;16(12):723-33.
13. Yamamoto-Furusho JK, Uscanga LF, Vargas-Alarcon G, Rodriguez-Perez JM, Zuniga JGranados J. Polymorphisms in the promoter region of tumor necrosis factor alpha (TNF-alpha) and the HLA-DRB1 locus in Mexican mestizo patients with ulcerative colitis. Immunol Lett. 2004;95(1):31-5.
14. Cantor MJ, Nickerson PBernstein CN. The role of cytokine gene polymorphisms in determining disease susceptibility and phenotype in inflammatory bowel disease. Am J Gastroenterol. 2005;100(5):1134-42.
15. Castro-Santos P, Suarez A, Lopez-Rivas L, Mozo LGutierrez C. TNFalpha and IL-10 gene polymorphisms in inflammatory bowel disease. Association of -1082 AA low producer IL-10 genotype with steroid dependency. Am J Gastroenterol. 2006;101(5):1039-47.
16. Mittal RD, Manchanda PK, Bid HKGhoshal UC. Analysis of polymorphisms of tumor necrosis factor-alpha and polymorphic xenobiotic metabolizing enzymes in inflammatory bowel disease: study from northern India. J Gastroenterol Hepatol. 2007;22(6):920-4.
17. Bonyadi M, Abdolmohammadi R, Jahanafrooz Z, Somy MHKhoshbaten M. TNF-alpha gene polymorphisms in Iranian Azari Turkish patients with inflammatory bowel diseases. Saudi J Gastroenterol. 2014;20(2):108-12.
18. Al-Meghaiseeb ES, Al-Robayan AA, Al-Otaibi MM, Arfin MAl-Asmari AK. Association of tumor necrosis factor-alpha and -beta gene polymorphisms in inflammatory bowel disease. J Inflamm Res. 2016;9:133-40.
19. Balding J, Livingstone WJ, Conroy J, Mynett-Johnson L, Weir DG, Mahmud N, et al. Inflammatory bowel disease: the role of inflammatory cytokine gene polymorphisms. Mediators Inflamm. 2004;13(3):181-7.
20. Ferreira AC, Almeida S, Tavares M, Canedo P, Pereira F, Regalo G, et al. NOD2/CARD15 and TNFA, but not IL1B and IL1RN, are associated with Crohn's disease. Inflamm Bowel Dis. 2005;11(4):331-9.
21. Fowler EV, Eri R, Hume G, Johnstone S, Pandeya N, Lincoln D, et al. TNFalpha and IL10 SNPs act together to predict disease behaviour in Crohn's disease. J Med Genet. 2005;42(6):523-8.
22. Hong J, Leung E, Fraser AG, Merriman TR, Vishnu PKrissansen GW. IL4, IL10, IL16, and TNF polymorphisms in New Zealand Caucasian Crohn's disease patients. Int J Colorectal Dis. 2008;23(3):335-7.
23. Hradsky O, Lenicek M, Dusatkova P, Bronsky J, Nevoral J, Valtrova V, et al. Variants of CARD15, TNFA and PTPN22 and susceptibility to Crohn's disease in the Czech population: high frequency of the CARD15 1007fs. Tissue Antigens. 2008;71(6):538-47.
24. Santana G, Bendicho MT, Santana TC, Reis LB, Lemaire DLyra AC. The TNF-alpha -308 polymorphism may affect the severity of Crohn's disease. Clinics (Sao Paulo). 2011;66(8):1373-8.
25. 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(4):170-4.
26. Cao Q, Zhu Q, Wu ML, Hu WL, Gao MSi JM. Genetic susceptibility to ulcerative colitis in the Chinese Han ethnic population: association with TNF polymorphisms. Chin Med J (Engl). 2006;119(14):1198-203.
27. Gok I, Ucar FOzgur O. Inflammatory cytokine gene polymorphism profiles in Turkish patients with ulcerative colitis. Med Glas (Zenica). 2015;12(1):33-9.
28. Tavares M, de Lima C, Fernandes W, Martinelli V, de Lucena M, Lima F, et al. Tumour necrosis factor-alpha (-308G/A) promoter polymorphism is associated with ulcerative colitis in Brazilian patients. Int J Immunogenet. 2016;43(6):376-82.
29. Sanchez R, Levy E, Costea FSinnett D. IL-10 and TNF-alpha promoter haplotypes are associated with childhood Crohn's disease location. World J Gastroenterol. 2009;15(30):3776-82.
30. Kim TH, Kim BG, Shin HD, Kim JW, Kim CG, Kim JS, et al. [Tumor necrosis factor-alpha and interleukin-10 gene polymorphisms in Korean patients with inflammatory bowel disease]. Korean J Gastroenterol. 2003;42(5):377-86.
31. 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(2):127-36.
32. Dalal I, Karban A, Wine E, Eliakim R, Shirin H, Fridlender M, et al. Polymorphisms in the TNF-alpha promoter and variability in the granulomatous response in patients with Crohn's disease. Pediatr Res. 2006;59(6):825-8.
33. 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(5):479-87.
34. Louis E, Peeters M, Franchimont D, Seidel L, Fontaine F, Demolin G, et al. Tumour necrosis factor (TNF) gene polymorphism in Crohn's disease (CD): influence on disease behaviour? Clin Exp Immunol. 2000;119(1):64-8.
35. Louis E, Vermeire S, Rutgeerts P, De Vos M, Van Gossum A, Pescatore P, et al. A positive response to infliximab in Crohn disease: association with a higher systemic inflammation before treatment but not with -308 TNF gene polymorphism. Scand J Gastroenterol. 2002;37(7):818-24.
36. Gonzalez S, Rodrigo L, Martinez-Borra J, Lopez-Vazquez A, Fuentes D, Nino P, et al. TNF-alpha -308A promoter polymorphism is associated with enhanced TNF-alpha production and inflammatory activity in Crohn's patients with fistulizing disease. Am J Gastroenterol. 2003;98(5):1101-6.
37. Castro-Santos P, Suarez A, Mozo LGutierrez C. Association of IL-10 and TNFalpha genotypes with ANCA appearance in ulcerative colitis. Clin Immunol. 2007;122(1):108-14.
38. Papo M, Quer JC, Gutierrez C, Broch M, Casellas F, Pastor RM, et al. Genetic heterogeneity within ulcerative colitis determined by an interleukin-1 receptor antagonist gene polymorphism and antineutrophil cytoplasmic antibodies. Eur J Gastroenterol Hepatol. 1999;11(4):413-20.
39. Lacruz-Guzman D, Torres-Moreno D, Pedrero F, Romero-Cara P, Garcia-Tercero I, Trujillo-Santos J, et al. Influence of polymorphisms and TNF and IL1beta serum concentration on the infliximab response in Crohn's disease and ulcerative colitis. Eur J Clin Pharmacol. 2013;69(3):431-8.
| Files | ||
| Issue | Vol 8, No 2 (2025) | |
| Section | Original Article | |
| DOI | https://doi.org/10.18502/igj.v8i2.18003 | |
| Keywords | ||
| Allele Frequency Crohn's Disease Inflammatory Bowel Disease Meta-Analysis Polymorphisms Ulcerative Colitis | ||
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How to Cite
1.
Moosavi S, Shanker A, Sadr M, Soltani S, Shahkarami S, Farhadi E, Ebrahimi Daryani N, Baradaran Noveiry B, Najmi Varzaneh F, Bashashati M, Rezaei N. Associations of TNF-Α -308 and -238 Polymorphisms with Inflammatory Bowel Disease: A Case-Control Study and Meta-Analysis of Published Data. Immunol Genet J. 2025;8(2):236-247.
