Association Study of Interleukin 23 Receptor (IL-23R) Polymorphisms with Inflammatory Bowel Disease (IBD) in Khuzestan Province of Iran
,
Abstract
Background: Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), is a complex multifactorial disease for which the exact cause is not clear. In this study, the researcher aimed to evaluate interleukin 23 receptor (IL23R) gene polymorphisms in patients with inflammatory bowel disease.
Methods: In this case-control study, we evaluated 125 patients of the Iranian population (Khuzestan) with IBD, including 35 patients with CD, 90 patients with UC, and 125 healthy controls. The polymorphisms of C/A-97952 (rs10889677), and G/A-43045 (rs1004819) were genotyped, using ARMS-PCR and G/A-78790 (rs11209026) using RFLP-PCR methods in the studied population. The collected data were analyzed using SPSS software.
Results: In this study, no significant association was observed between IL23R polymorphisms and IBD in this population, however the association between C/A-97952 AA genotype and penetrate to the tissue (P=0.048 OR=2.812 (1.23-6.44)), G/A-43045, AA genotype, and Ileocolic (P=0.031 OR=5 (1.071-31)). and G/A-43045 AA genotype and Pan Colitis (P=0.028 OR=4 (1.082-17.00)) in IBD were strengthened and emphasized.
Conclusion: The present study showed that there were no associations between IL23R polymorphisms, CD, and UC in the Khuzestan population. In addition, we found that C/A-97952 and G/A-43045 gene polymorphisms in IL-23R are related to special phenotypes. Further functional analysis with a larger sample size and other known IL-23 receptor genotypes is necessary to confirm our population's association with UC and CD.
1. Hendrickson BA, Gokhale RCho JH. Clinical aspects and pathophysiology of inflammatory bowel disease. Clin Microbiol Rev. 2002;15(1):79-94.
2. Mathew CG. New links to the pathogenesis of Crohn's disease provided by genome-wide association scans. Nat Rev Genet. 2008;9(1):9-14.
3. Fiocchi C. Inflammatory bowel disease: etiology and pathogenesis. Gastroenterology. 1998;115(1):182-205.
4. Kaser A, Zeissig SBlumberg RS. Inflammatory bowel disease. Annu Rev Immunol. 2010;28:573-621.
5. Macpherson AJHarris NL. Interactions between commensal intestinal bacteria and the immune system. Nat Rev Immunol. 2004;4(6):478-85.
6. Ghoreschi K, Laurence A, Yang XP, Tato CM, McGeachy MJ, Konkel JE, et al. Generation of pathogenic T(H)17 cells in the absence of TGF-beta signaling. Nature. 2010;467(7318):967-71.
7. Hazlett J, Stamp LK, Merriman T, Highton JHessian PA. IL-23R rs11209026 polymorphism modulates IL-17A expression in patients with rheumatoid arthritis. Genes Immun. 2012;13(3):282-7.
8. Holtta V, Klemetti P, Sipponen T, Westerholm-Ormio M, Kociubinski G, Salo H, et al. IL-23/IL-17 immunity is a hallmark of Crohn's disease. Inflamm Bowel Dis. 2008;14(9):1175-84.
9. Korn T, Bettelli E, Oukka MKuchroo VK. IL-17 and Th17 Cells. Annu Rev Immunol. 2009;27:485-517.
10. Dubinsky MC, Wang D, Picornell Y, Wrobel I, Katzir L, Quiros A, et al. The IL-23 receptor (IL-23R) gene protects against pediatric Crohn's disease. Inflamm Bowel Dis. 2007;13(5):511-5.
11. Cho JH. The genetics and immunopathogenesis of inflammatory bowel disease. Nat Rev Immunol. 2008;8(6):458-66.
12. Loddo IRomano C. Inflammatory Bowel Disease: Genetics, Epigenetics, and Pathogenesis. Front Immunol. 2015;6:551.
13. Lord JD. Promises and paradoxes of regulatory T cells in inflammatory bowel disease. World J Gastroenterol. 2015;21(40):11236-45.
14. Brown SRCoviello LC. Extraintestinal Manifestations Associated with Inflammatory Bowel Disease. Surg Clin North Am. 2015;95(6):1245-59.
15. Steiner S, Daniel C, Fischer A, Atreya I, Hirschmann S, Waldner M, et al. Cyclosporine A regulates pro-inflammatory cytokine production in ulcerative colitis. Arch Immunol Ther Exp (Warsz). 2015;63(1):53-63.
16. Ballester V, Guo X, Vendrell R, Haritunians T, Klomhaus AM, Li D, et al. Association of NOD2 and IL23R with inflammatory bowel disease in Puerto Rico. PLoS One. 2014;9(9):e108204.
17. 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(6):e98815.
18. Brant SR, Okou DT, Simpson CL, Cutler DJ, Haritunians T, Bradfield JP, et al. Genome-Wide Association Study Identifies African-Specific Susceptibility Loci in African Americans With Inflammatory Bowel Disease. Gastroenterology. 2016.
19. Serbati N, Senhaji N, Diakite B, Badre WNadifi S. IL23R and ATG16L1 variants in Moroccan patients with inflammatory bowel disease. BMC Res Notes. 2014;7:570.
20. Xiao Y, Wang XQ, Yu Y, Guo Y, Xu X, Gong L, et al. Comprehensive mutation screening for 10 genes in Chinese patients suffering very early onset inflammatory bowel disease. World J Gastroenterol. 2016;22(24):5578-88.
21. Pidasheva S, Trifari S, Phillips A, Hackney JA, Ma Y, Smith A, et al. Functional studies on the IBD susceptibility gene IL23R implicate reduced receptor function in the protective genetic variant R381Q. PLoS One. 2011;6(10):e25038.
22. Karaderi T, Harvey D, Farrar C, Appleton LH, Stone MA, Sturrock RD, et al. Association between the interleukin 23 receptor and ankylosing spondylitis is confirmed by a new UK case-control study and meta-analysis of published series. Rheumatology (Oxford). 2009;48(4):386-9.
23. Baldassano RN, Bradfield JP, Monos DS, Kim CE, Glessner JT, Casalunovo T, et al. Association of variants of the interleukin-23 receptor gene with susceptibility to pediatric Crohn's disease. Clin Gastroenterol Hepatol. 2007;5(8):972-6.
24. Brant SR, Okou DT, Simpson CL, Cutler DJ, Haritunians T, Bradfield JP, et al. Genome-Wide Association Study Identifies African-Specific Susceptibility Loci in African Americans With Inflammatory Bowel Disease. Gastroenterology. 2017;152(1):206-17 e2.
25. Cotterill L, Payne D, Levinson S, McLaughlin J, Wesley E, Feeney M, et al. Replication and meta-analysis of 13,000 cases define the risk for interleukin-23 receptor and autophagy-related 16-like 1 variants in Crohn's disease. Can J Gastroenterol. 2010;24(5):297-302.
26. Duerr RH, Taylor KD, Brant SR, Rioux JD, Silverberg MS, Daly MJ, et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science. 2006;314(5804):1461-3.
27. Fischer S, Kovesdi E, Magyari L, Csongei V, Hadzsiev K, Melegh B, et al. IL23R single nucleotide polymorphisms could be either beneficial or harmful in ulcerative colitis. World J Gastroenterol. 2017;23(3):447-54.
28. Glas J, Seiderer J, Wetzke M, Konrad A, Torok HP, Schmechel S, et al. rs1004819 is the main disease-associated IL23R variant in German Crohn's disease patients: combined analysis of IL23R, CARD15, and OCTN1/2 variants. PLoS One. 2007;2(9):e819.
29. Jung C, Colombel JF, Lemann M, Beaugerie L, Allez M, Cosnes J, et al. Genotype/phenotype analyses for 53 Crohn's disease-associated genetic polymorphisms. PLoS One. 2012;7(12):e52223.
30. Kramp P, Hemmingsen RRafaelsen OJ. Delirium tremens. Some clinical features. Part II. Acta Psychiatr Scand. 1979;60(5):405-22.
31. Latiano A, Palmieri O, Valvano MR, D'Inca R, Cucchiara S, Riegler G, et al. Replication of interleukin 23 receptor and autophagy-related 16-like 1 association in adult- and pediatric-onset inflammatory bowel disease in Italy. World J Gastroenterol. 2008;14(29):4643-51.
32. Liu M, Zhu W, Wang J, Zhang J, Guo X, Wang J, et al. Interleukin-23 receptor genetic polymorphisms and ulcerative colitis susceptibility: A meta-analysis. Clin Res Hepatol Gastroenterol. 2015;39(4):516-25.
33. Okazaki T, Wang MH, Rawsthorne P, Sargent M, Datta LW, Shugart YY, et al. Contributions of IBD5, IL23R, ATG16L1, and NOD2 to Crohn's disease risk in a population-based case-control study: evidence of gene-gene interactions. Inflamm Bowel Dis. 2008;14(11):1528-41.
34. Peng LL, Wang Y, Zhu FL, Xu WD, Ji XLNi J. IL-23R mutation is associated with ulcerative colitis: A systemic review and meta-analysis. Oncotarget. 2017;8(3):4849-63.
35. Sventoraityte J, Zvirbliene A, Franke A, Kwiatkowski R, Kiudelis G, Kupcinskas L, et al. NOD2, IL23R, and ATG16L1 polymorphisms in Lithuanian patients with inflammatory bowel disease. World J Gastroenterol. 2010;16(3):359-64.
36. Tremelling M, Cummings F, Fisher SA, Mansfield J, Gwilliam R, Keniry A, et al. IL23R variation determines susceptibility but not disease phenotype in inflammatory bowel disease. Gastroenterology. 2007;132(5):1657-64.
37. Van Limbergen J, Russell RK, Nimmo ER, Drummond HE, Smith L, Davies G, et al. IL23R Arg381Gln is associated with childhood-onset inflammatory bowel disease in Scotland. Gut. 2007;56(8):1173-4.
38. Xu WD, Xie QB, Zhao YLiu Y. Association of Interleukin-23 receptor gene polymorphisms with susceptibility to Crohn's disease: A meta-analysis. Sci Rep. 2015;5:18584.
39. Chua KH, Hilmi I, Lian LH, Patmanathan SN, Hoe SZ, Lee WS, et al. Association between inflammatory bowel disease gene 5 (IBD5) and interleukin-23 receptor (IL23R) genetic polymorphisms in Malaysian patients with Crohn's disease. J Dig Dis. 2012;13(9):459-65.
40. Hayatbakhsh MM, Zahedi MJ, Shafiepour M, Nikpoor ARMohammadi M. IL-23 receptor gene rs7517847 and rs1004819 SNPs in ulcerative colitis. Iran J Immunol. 2012;9(2):128-35.
41. Lacher M, Schroepf S, Helmbrecht J, von Schweinitz D, Ballauff A, Koch I, et al. Association of the interleukin-23 receptor gene variant rs11209026 with Crohn's disease in German children. Acta Paediatr. 2010;99(5):727-33.
42. Frederick M. Ausubel RB, Robert E. Kingston, David D. Moore, J.G. Seidman, John A. Smith,Kevin Struhl. Current Protocols in Molecular Biology: John Wiley & Sons, Inc; 2003.
43. Sarin R, Wu XAbraham C. Inflammatory disease protective R381Q IL23 receptor polymorphism results in decreased primary CD4+ and CD8+ human T-cell functional responses. Proc Natl Acad Sci U S A. 2011;108(23):9560-5.
44. Buning C, Schmidt HH, Molnar T, De Jong DJ, Fiedler T, Buhner S, et al. Heterozygosity for IL23R p.Arg381Gln confers a protective effect not only against Crohn's disease but also ulcerative colitis. Aliment Pharmacol Ther. 2007;26(7):1025-33.
45. Safrany E, Szabo M, Szell M, Kemeny L, Sumegi K, Melegh BI, et al. Difference of interleukin-23 receptor gene haplotype variants in ulcerative colitis compared to Crohn's disease and psoriasis. Inflamm Res. 2013;62(2):195-200.
46. Ferguson LR, Han DY, Fraser AG, Huebner C, Lam WJMorgan AR. IL23R and IL12B SNPs and Haplotypes Strongly Associate with Crohn's Disease Risk in a New Zealand Population. Gastroenterol Res Pract. 2010;2010:539461.
2. Mathew CG. New links to the pathogenesis of Crohn's disease provided by genome-wide association scans. Nat Rev Genet. 2008;9(1):9-14.
3. Fiocchi C. Inflammatory bowel disease: etiology and pathogenesis. Gastroenterology. 1998;115(1):182-205.
4. Kaser A, Zeissig SBlumberg RS. Inflammatory bowel disease. Annu Rev Immunol. 2010;28:573-621.
5. Macpherson AJHarris NL. Interactions between commensal intestinal bacteria and the immune system. Nat Rev Immunol. 2004;4(6):478-85.
6. Ghoreschi K, Laurence A, Yang XP, Tato CM, McGeachy MJ, Konkel JE, et al. Generation of pathogenic T(H)17 cells in the absence of TGF-beta signaling. Nature. 2010;467(7318):967-71.
7. Hazlett J, Stamp LK, Merriman T, Highton JHessian PA. IL-23R rs11209026 polymorphism modulates IL-17A expression in patients with rheumatoid arthritis. Genes Immun. 2012;13(3):282-7.
8. Holtta V, Klemetti P, Sipponen T, Westerholm-Ormio M, Kociubinski G, Salo H, et al. IL-23/IL-17 immunity is a hallmark of Crohn's disease. Inflamm Bowel Dis. 2008;14(9):1175-84.
9. Korn T, Bettelli E, Oukka MKuchroo VK. IL-17 and Th17 Cells. Annu Rev Immunol. 2009;27:485-517.
10. Dubinsky MC, Wang D, Picornell Y, Wrobel I, Katzir L, Quiros A, et al. The IL-23 receptor (IL-23R) gene protects against pediatric Crohn's disease. Inflamm Bowel Dis. 2007;13(5):511-5.
11. Cho JH. The genetics and immunopathogenesis of inflammatory bowel disease. Nat Rev Immunol. 2008;8(6):458-66.
12. Loddo IRomano C. Inflammatory Bowel Disease: Genetics, Epigenetics, and Pathogenesis. Front Immunol. 2015;6:551.
13. Lord JD. Promises and paradoxes of regulatory T cells in inflammatory bowel disease. World J Gastroenterol. 2015;21(40):11236-45.
14. Brown SRCoviello LC. Extraintestinal Manifestations Associated with Inflammatory Bowel Disease. Surg Clin North Am. 2015;95(6):1245-59.
15. Steiner S, Daniel C, Fischer A, Atreya I, Hirschmann S, Waldner M, et al. Cyclosporine A regulates pro-inflammatory cytokine production in ulcerative colitis. Arch Immunol Ther Exp (Warsz). 2015;63(1):53-63.
16. Ballester V, Guo X, Vendrell R, Haritunians T, Klomhaus AM, Li D, et al. Association of NOD2 and IL23R with inflammatory bowel disease in Puerto Rico. PLoS One. 2014;9(9):e108204.
17. 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(6):e98815.
18. Brant SR, Okou DT, Simpson CL, Cutler DJ, Haritunians T, Bradfield JP, et al. Genome-Wide Association Study Identifies African-Specific Susceptibility Loci in African Americans With Inflammatory Bowel Disease. Gastroenterology. 2016.
19. Serbati N, Senhaji N, Diakite B, Badre WNadifi S. IL23R and ATG16L1 variants in Moroccan patients with inflammatory bowel disease. BMC Res Notes. 2014;7:570.
20. Xiao Y, Wang XQ, Yu Y, Guo Y, Xu X, Gong L, et al. Comprehensive mutation screening for 10 genes in Chinese patients suffering very early onset inflammatory bowel disease. World J Gastroenterol. 2016;22(24):5578-88.
21. Pidasheva S, Trifari S, Phillips A, Hackney JA, Ma Y, Smith A, et al. Functional studies on the IBD susceptibility gene IL23R implicate reduced receptor function in the protective genetic variant R381Q. PLoS One. 2011;6(10):e25038.
22. Karaderi T, Harvey D, Farrar C, Appleton LH, Stone MA, Sturrock RD, et al. Association between the interleukin 23 receptor and ankylosing spondylitis is confirmed by a new UK case-control study and meta-analysis of published series. Rheumatology (Oxford). 2009;48(4):386-9.
23. Baldassano RN, Bradfield JP, Monos DS, Kim CE, Glessner JT, Casalunovo T, et al. Association of variants of the interleukin-23 receptor gene with susceptibility to pediatric Crohn's disease. Clin Gastroenterol Hepatol. 2007;5(8):972-6.
24. Brant SR, Okou DT, Simpson CL, Cutler DJ, Haritunians T, Bradfield JP, et al. Genome-Wide Association Study Identifies African-Specific Susceptibility Loci in African Americans With Inflammatory Bowel Disease. Gastroenterology. 2017;152(1):206-17 e2.
25. Cotterill L, Payne D, Levinson S, McLaughlin J, Wesley E, Feeney M, et al. Replication and meta-analysis of 13,000 cases define the risk for interleukin-23 receptor and autophagy-related 16-like 1 variants in Crohn's disease. Can J Gastroenterol. 2010;24(5):297-302.
26. Duerr RH, Taylor KD, Brant SR, Rioux JD, Silverberg MS, Daly MJ, et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science. 2006;314(5804):1461-3.
27. Fischer S, Kovesdi E, Magyari L, Csongei V, Hadzsiev K, Melegh B, et al. IL23R single nucleotide polymorphisms could be either beneficial or harmful in ulcerative colitis. World J Gastroenterol. 2017;23(3):447-54.
28. Glas J, Seiderer J, Wetzke M, Konrad A, Torok HP, Schmechel S, et al. rs1004819 is the main disease-associated IL23R variant in German Crohn's disease patients: combined analysis of IL23R, CARD15, and OCTN1/2 variants. PLoS One. 2007;2(9):e819.
29. Jung C, Colombel JF, Lemann M, Beaugerie L, Allez M, Cosnes J, et al. Genotype/phenotype analyses for 53 Crohn's disease-associated genetic polymorphisms. PLoS One. 2012;7(12):e52223.
30. Kramp P, Hemmingsen RRafaelsen OJ. Delirium tremens. Some clinical features. Part II. Acta Psychiatr Scand. 1979;60(5):405-22.
31. Latiano A, Palmieri O, Valvano MR, D'Inca R, Cucchiara S, Riegler G, et al. Replication of interleukin 23 receptor and autophagy-related 16-like 1 association in adult- and pediatric-onset inflammatory bowel disease in Italy. World J Gastroenterol. 2008;14(29):4643-51.
32. Liu M, Zhu W, Wang J, Zhang J, Guo X, Wang J, et al. Interleukin-23 receptor genetic polymorphisms and ulcerative colitis susceptibility: A meta-analysis. Clin Res Hepatol Gastroenterol. 2015;39(4):516-25.
33. Okazaki T, Wang MH, Rawsthorne P, Sargent M, Datta LW, Shugart YY, et al. Contributions of IBD5, IL23R, ATG16L1, and NOD2 to Crohn's disease risk in a population-based case-control study: evidence of gene-gene interactions. Inflamm Bowel Dis. 2008;14(11):1528-41.
34. Peng LL, Wang Y, Zhu FL, Xu WD, Ji XLNi J. IL-23R mutation is associated with ulcerative colitis: A systemic review and meta-analysis. Oncotarget. 2017;8(3):4849-63.
35. Sventoraityte J, Zvirbliene A, Franke A, Kwiatkowski R, Kiudelis G, Kupcinskas L, et al. NOD2, IL23R, and ATG16L1 polymorphisms in Lithuanian patients with inflammatory bowel disease. World J Gastroenterol. 2010;16(3):359-64.
36. Tremelling M, Cummings F, Fisher SA, Mansfield J, Gwilliam R, Keniry A, et al. IL23R variation determines susceptibility but not disease phenotype in inflammatory bowel disease. Gastroenterology. 2007;132(5):1657-64.
37. Van Limbergen J, Russell RK, Nimmo ER, Drummond HE, Smith L, Davies G, et al. IL23R Arg381Gln is associated with childhood-onset inflammatory bowel disease in Scotland. Gut. 2007;56(8):1173-4.
38. Xu WD, Xie QB, Zhao YLiu Y. Association of Interleukin-23 receptor gene polymorphisms with susceptibility to Crohn's disease: A meta-analysis. Sci Rep. 2015;5:18584.
39. Chua KH, Hilmi I, Lian LH, Patmanathan SN, Hoe SZ, Lee WS, et al. Association between inflammatory bowel disease gene 5 (IBD5) and interleukin-23 receptor (IL23R) genetic polymorphisms in Malaysian patients with Crohn's disease. J Dig Dis. 2012;13(9):459-65.
40. Hayatbakhsh MM, Zahedi MJ, Shafiepour M, Nikpoor ARMohammadi M. IL-23 receptor gene rs7517847 and rs1004819 SNPs in ulcerative colitis. Iran J Immunol. 2012;9(2):128-35.
41. Lacher M, Schroepf S, Helmbrecht J, von Schweinitz D, Ballauff A, Koch I, et al. Association of the interleukin-23 receptor gene variant rs11209026 with Crohn's disease in German children. Acta Paediatr. 2010;99(5):727-33.
42. Frederick M. Ausubel RB, Robert E. Kingston, David D. Moore, J.G. Seidman, John A. Smith,Kevin Struhl. Current Protocols in Molecular Biology: John Wiley & Sons, Inc; 2003.
43. Sarin R, Wu XAbraham C. Inflammatory disease protective R381Q IL23 receptor polymorphism results in decreased primary CD4+ and CD8+ human T-cell functional responses. Proc Natl Acad Sci U S A. 2011;108(23):9560-5.
44. Buning C, Schmidt HH, Molnar T, De Jong DJ, Fiedler T, Buhner S, et al. Heterozygosity for IL23R p.Arg381Gln confers a protective effect not only against Crohn's disease but also ulcerative colitis. Aliment Pharmacol Ther. 2007;26(7):1025-33.
45. Safrany E, Szabo M, Szell M, Kemeny L, Sumegi K, Melegh BI, et al. Difference of interleukin-23 receptor gene haplotype variants in ulcerative colitis compared to Crohn's disease and psoriasis. Inflamm Res. 2013;62(2):195-200.
46. Ferguson LR, Han DY, Fraser AG, Huebner C, Lam WJMorgan AR. IL23R and IL12B SNPs and Haplotypes Strongly Associate with Crohn's Disease Risk in a New Zealand Population. Gastroenterol Res Pract. 2010;2010:539461.
| Files | ||
| Issue | Vol 4, No 4 (2021) | |
| Section | Original Article | |
| DOI | https://doi.org/10.18502/igj.v4i4.12756 | |
| Keywords | ||
| IL-23R Inflammatory Bowel Disease Crohn's Disease Ulcerative Colitis Polymorphism | ||
| Rights and permissions | |
|
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Esmaeili H, Ghandil P, Ghadiri A, Ghafourian M, Hashem S. Association Study of Interleukin 23 Receptor (IL-23R) Polymorphisms with Inflammatory Bowel Disease (IBD) in Khuzestan Province of Iran. Immunol Genet J. 2021;4(4):186-195.
