Epigenetics of Early Inflammatory Bowel Disease among Children: A Systematic Review

Document Type : systematic review

Authors

1 Gastroenterohepatology Research Center, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.

2 Student research committee, Faculty of Pharmacy, Zabol University of Medical Sciences, Zabol, Iran.

3 Pediatric Gastroenterology and Hepatology Research Center, Zabol University of Medical Sciences, Zabol, Iran.

Abstract

Background: Inflammatory bowel diseases (IBDs) are complex and multifaceted disorders characterized by recurrent and persistent intestinal inflammation. The incidence of inflammatory bowel disease (IBD) is on the rise among both children and adults worldwide. In this review, we provide an update on genomic studies of IBD, with a particular focus on Very Early-Onset IBD (VEO-IBD), which often presents with a more severe phenotype than IBD at an older age.
Methods: The methods used in this systematic review were performed according to the guidelines of the PRISMA checklist. A search was conducted by two independent researchers in international databases (PubMed, Web of Science, Scopus, and Google Scholar) to find relevant studies published in English.
Results: Patients with VEO-IBD have rare or novel genes associated with immunodeficiency that may play a role in the pathogenesis of the disease. To date, ten regions for 240 genes, which are usually monogenic, have been identified for this disease, mostly due to mutations. But the most important cause of VEO-IBD is mutation in interleukin 10. It has also been reported that VEO-IBD is associated with increased expression of S100A8 and S100A9 genes in rectal mucosa and serum.
Conclusion: Considering the multifactorial nature of IBD, all the changes that cause protein expression and function should be taken into account; so for early diagnosis and timely treatment of this disease, more extensive phenotypic sequencing is needed to discover new gene loci. And these children can be treated with hematopoietic stem cell transplantation, as the most efficient method.

Keywords

References

  1. Khor B, Gardet A, Xavier RJ. Genetics and pathogenesis of inflammatory bowel disease. Nature. 2011 Jun; 474(7351):307-17.
  2. Loddo I, Romano C. Inflammatory bowel disease: genetics, epigenetics, and pathogenesis. Frontiers in immunology. 2015 Nov 2; 6:551.
  3. Beser OF, Conde CD, Serwas NK, Cokugras FC, Kutlu T, Boztug K, Erkan T. Clinical features of interleukin 10 receptor gene mutations in children with very early–onset inflammatory bowel disease. Journal of Pediatric Gastroenterology and Nutrition. 2015 Mar 1; 60(3):332-8.
  4. Levine A, Griffiths A, Markowitz J, Wilson DC, Turner D, Russell RK, Fell J, Ruemmele FM, Walters T, Sherlock M, Dubinsky M. Pediatric modification of the Montreal classification for inflammatory bowel disease: the Paris classification. Inflammatory bowel diseases. 2011 Jun 1; 17(6):1314-21.
  5. Van Limbergen, Johan M.D., M.R.C.P.C.H.1,2; Russell, Richard K. M.R.C.P.C.H.2; Nimmo, Elaine R. B.Sc., M.Sc., Ph.D.1; Satsangi, Jack D.Phil., F.R.C.P.1. The Genetics of Inflammatory Bowel Disease. American Journal of Gastroenterology: December 2007 - Volume 102 - Issue 12 - p 2820-2831
  6. Chandrakasan S, Venkateswaran S, Kugathasan S. Nonclassic inflammatory bowel disease in young infants: immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome, and other disorders. Pediatric Clinics. 2017 Feb 1; 64(1):139-60.
  7. Silverberg MS, Satsangi J, Ahmad T, Arnott ID, Bernstein CN, Brant SR, Caprilli molecular and serological classification of inflammatory bowel disease: report of a Working Party of the 2005 Montreal World Congress of Gastroenterology. Canadian journal of gastroenterology. 2005 Sep 1; 19(Suppl A):5A-36A.
  8. Eaden JA, Abrams KR, Mayberry JF. The risk of colorectal cancer in ulcerative colitis: a meta-analysis. Gut 2001; 48:526–35.
  9. Barton JR, Gillon S, Ferguson A. Incidence of inflammatory bowel disease in Scottish children between 1968 and 1983; marginal fall in ulcerative colitis, three-fold rise in Crohn’s disease. Gut 1989; 30:618–22.
  10. Lashner BA, Shaheen NJ, Hanauer SB, Kirschner BS. Passive smoking is associated with an increased risk of developing inflammatory bowel disease in children Am J Gastroenterol 1993;88:356–9.
  11. Children With Very Early–Onset Inflammatory Bowel Disease. Journal of Pediatric Gastroenterology and Nutrition: March 2015 - Volume 60 - Issue 3 - p 332-338 doi: 10.1097/MPG.0000000000000621.
  12. Moher D, Liberati A, Tetzlaff J, Altman DG PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol. 2009; 62:1006–12. doi: 10.1016/j.jclinepi.2009.06.005.
  13. Hugot, J.P.; Laurent-Puig, P.; Gower-Rousseau, C.; Olson, J.M.; Lee, J.C.; Beaugerie, L.; Naom, I.; Dupas, J.L.; Van Gossum, A.; Orholm, M.; Lee JC, Beaugerie L, Naom I, Dupas JL, Gossum AV, Orholm M, Bonaiti-Pellie C, Weissenbach J, Mathew CG, Lennard-Jones JE, Cortot A, Colombel JF, Thomas G. Mapping of a susceptibility locus for Crohn’s disease on chromosome 16. Nature 1996, 379, 821–823.
  14. Tysk, C.; Lindberg, E.; Järnerot, G.; Flodérus-Myrhed, B. Ulcerative colitis and crohn’s disease in an unselected population of monozygotic and dizygotic twins. A Study of heritability and the influence of smoking. Gut 1988, 29, 990–996.
  15. Orholm, M.; Binder, V.; Sørensen, T.I.; Rasmussen, L.P.; Kyvik, K.O. Concordance of inflammatory bowel disease among danish twins. Results of a nationwide study. Scand. J. Gastroenterol. 2000, 35, 1075–1081.
  16. Cavanaugh J. International collaboration provides convincing linkage replication in complex disease through analysis of a large pooled data set: Crohn disease and chromosome 16. Am J Hum Genet 2001; 68: 1165– 71.
  17. Unravelling the complex genetics of inflammatory bowel disease Russell RK, Wilson DC, Satsangi J. Unravelling the complex genetics of inflammatory bowel disease. Archives of disease in childhood. 2004 Jul 1; 89(7):598-603.
  18. Moazzami B, Moazzami K, Rezaei N. Early-onset inflammatory bowel disease: manifestations, genetics, and diagnosis. Turkish Journal of Pediatrics. 2019 Sep 1; 61(5).
  19. Satsangi J, Parkes M, Louis E, Hashimoto L, Kato N, Welsh K, Terwilliger JD, Lathrop GM, Bell JI, Jewell DP. Two-stage genome- wide search in inflammatory bowel disease provides evidence for susceptibility loci on chromosomes 3, 7, and 12. Nat Genet 1996; 14:199–202
  20. Rioux JD, Silverberg MS, Daly MJ, Steinhart AH, McLeod RS, Grifiths AM, Green T, Brettin TS, Stone V, Bull SB, Bitton A, Williams CN, Greenberg GR, Cohen Z, Lander ES, Hudson TJ, Siminovitch KA. Genome wide search in Canadian families with inflammatory bowel disease reveals two novel susceptibility loci. Am J Hum Genet 2000; 66: 1863– 70.
  21. Hampe J, Schreiber S, Shaw SH, Lau KF, Bridger S, Macpherson AJ, Hampe J, Schreiber S, Shaw SH, Lau KF, Bridger S, Macpherson AJ, Cardon LR, Sakul H, Harris TJ, Buckler A, Hall J, Stokkers P, van Deventer SJ, Nürnberg P, Mirza MM, Lee JC, Lennard-Jones JE, Mathew CG, Curran ME. A genome wide analysis provides evidence for novel linkages in inflammatory bowel disease in a large European cohort. Am J Hum Genet 1999; 64: 808– 16.
  22. Yang H, Plevy SE, Taylor K, Tyan D, Fischel-Ghodsian N, McElree C, Targan SR, Rotter JI. Linkage of Crohn’s disease to the major histocompatibility complex region is detected by multiple nonparametric analyses. Gut 1999; 44: 519–26.
  23. Szymanska E, Wierzbicka A, Dadalski M, Kierkus J. Fecal Zonulin as a noninvasive biomarker of intestinal permeability in pediatric patients with inflammatory bowel diseases—correlation with disease activity and fecal calprotectin. Journal of Clinical Medicine. 2021 Aug 30; 10(17):3905.
  24. Basaldella F, Della Paolera S, Vuch J, Tommasini A, Martelossi S, Crovella S, Bianco AM. Genetic profile of patients with early onset inflammatory bowel disease. Gene. 2018 Mar 1; 645:18-29.
  25. Mikhailov TA, Furner SE. Breastfeeding and genetic factors in the etiology of inflammatory bowel disease in children. World journal of gastroenterology: WJG. 2009 Jan 1; 15(3):270
  26. Kammermeier J, Drury S, James CT, Dziubak R, Ocaka L, Elawad M, Beales P, Lench N, Uhlig HH, Bacchelli C, Shah N. Targeted gene panel sequencing in children with very early onset inflammatory bowel disease—evaluation and prospective analysis. Journal of medical genetics. 2014 Nov 1; 51(11):748-55.
  27. Binder V. Genetic epidemiology in inflammatory bowel disease. Digestive Diseases. 1998;16(6):351-5
  28. Christodoulou K, Wiskin AE, Gibson J, Tapper W, Willis C, Afzal NA, Upstill-Goddard R, Holloway JW, Simpson MA, Beattie RM, Collins A. Next generation exome sequencing of pediatric inflammatory bowel disease patients identifies rare and novel variants in candidate genes. Gut. 2013 Jul 1; 62(7):977-84.
  29. Thapar N, Shah N, Ramsay AD, Lindley KJ, Milla PJ. Long-term outcome of intractable ulcerating enterocolitis of infancy. J Pediatr Gastroenterol Nutr 2005; 40:582–588.
  30. Cannioto Z, Berti I, Martelossi S, Bruno I, Giurici N, Crovella S, Ventura A. IBD and IBD mimicking enterocolitis in children younger than 2 years of age. Eur J Pediatr 2009; 168:149–155.
  31. Parente P, Macciomei MC, Buccoliero AM, Santoro L, Cafferata B, Bifano D, Ferro J, Vanoli A, Fassan M, Angerilli V, Alaggio R. Application of a pattern‐based approach to histological diagnosis in very early onset IBD (VEO‐IBD) in a multicentric cohort of children with emphasis on monogenic disease with IBD‐like morphology. Histopathology. 2023 Oct 30.
  32. Ouahed J, Spencer E, Kotlarz D, Shouval DS, Kowalik M, Peng K, Field M, Grushkin-Lerner L, Pai SY, Bousvaros A, Cho J. Very early onset inflammatory bowel disease: a clinical approach with a focus on the role of genetics and underlying immune deficiencies. Inflammatory bowel diseases. 2020 May 12; 26(6):820-42.
  33. Uhlig HH, Schwerd T, Koletzko S, Shah N, Kammermeier J, Elkadri A, Ouahed J, Wilson DC, Travis SP, Turner D, Klein C, Snapper SB, Muise AM; COLORS in IBD Study Group and NEOPICS. The diagnostic approach to monogenic very early onset inflammatory bowel disease. Gastroenterology. 2014 Nov; 147(5):990-1007.e3. doi: 10.1053/j.gastro.2014.07.023. Epub 2014 Jul 21. PMID: 25058236; PMCID: PMC5376484.
  34. Kelsen, J.R., Dawany, N., Moran, C.J., Petersen, B.S., Sarmady, M., Sasson, A., Pauly-Hubbard, H., Martinez, A., Maurer, K., Soong, J. and Rappaport, E., 2015. Exome sequencing analysis reveals variants in primary immunodeficiency genes in patients with very early onset inflammatory bowel disease. Gastroenterology, 149(6), pp.1415-1424.
  35. Heyman, M.B., Kirschner, B.S., Gold, B.D., Ferry, G., Baldassano, R., Cohen, S.A., winter, H.S., Fain, P., King, C., Smith, T. and El-Serag, H.B., 2005. Children with early-onset inflammatory bowel disease (IBD): analysis of a pediatric IBD consortium registry. The Journal of pediatrics, 146(1), pp.35-40.
  36. Russell RK, Wilson DC, Satsangi J. Unravelling the complex genetics of inflammatory bowel disease. Archives of disease in childhood. 2004 Jul 1; 89(7):598-603.
  37. Brant SR, Panhuysen CI, Bailey-Wilson JE, Rohal PM, Lee S, Mann J, Ravenhill G, Kirschner BS, Hanauer S|B, Cho JH, Bayless TM. Linkage heterogeneity for the IBD1 locus in Crohn’s disease pedigrees by disease onset and severity. Gastroenterology 2000; 119:1483–90.
  38. Rioux JD, Silverberg MS, Daly MJ, Steinhart AH, McLeod RS, Grifiths AM, Green T, Brettin TS, Stone V, Bull SB, Bitton A, Williams CN, Greenberg GR, Cohen Z, Lander ES, Hudson TJ, Siminovitch KA. Genome-wide search in Canadian families with inflammatory bowel disease reveals two novel susceptibility loci. Am J Hum Genet 2000; 66: 1863–70.
  39. Imielinski M, Baldassano RN, Griffiths A, Russell RK, Annese V, Dubinsky M, Kugathasan S, Bradfield JP, Walters TD, Sleiman P, Kim CE. Common variants at five new loci associated with early-onset inflammatory bowel disease. Nature genetics. 2009 Dec; 41(12):1335-40.
  40. Girardelli M, Basaldella F, Della Paolera S, Vuch J, Tommasini A, Martelossi S, Crovella S, Bianco AM. Genetic profile of patients with early onset inflammatory bowel disease. Gene. 2018 Mar 1; 645:18-29.
  41. Xiao Y, Wang XQ, Yu Y, Guo Y, Xu X, Gong L, Zhou T, Li XQ, Xu CD. Comprehensive mutation screening for 10 genes in Chinese patients suffering very early onset inflammatory bowel disease. World journal of gastroenterology. 2016 Jun 6; 22(24):5578.
  42. Karaky M, Boucher G, Mola S, Foisy S, Beauchamp C, Rivard ME, Burnette M, Gosselin H, iGenoMed Consortium, Bitton A, Charron G. Prostaglandins and calprotectin are genetically and functionally linked to the Inflammatory Bowel Diseases. PLoS genetics. 2022 Sep 26; 18(9):e1010189.
  43. Molavi M, Fakheri H, Bahari A, Vossoughinia H, Bari Z, Esmaeelzadeh A, Ganji A, Hashemi M, Khajedaluee M, Bahari G, Amin B. Evaluating the association between genetic polymorphisms of calprotectin and inflammatory bowel diseases. Medical journal of Mashhad University of Medical Sciences. 2015 Mar 21; 58(1):13-20.
  44. Leach ST, Yang Z, Messina I, Song C, Geczy CL, Cunningham AM, Day AS. Serum and mucosal S100 proteins, calprotectin (S100A8/S100A9), and S100A12 are elevated at diagnosis in children with inflammatory bowel disease. Scandinavian journal of gastroenterology. 2007 Jan 1;42(11):1321-31
  45. Szymanska E, Wierzbicka A, Dadalski M, Kierkus J. Fecal Zonulin as a noninvasive biomarker of intestinal permeability in pediatric patients with inflammatory bowel diseases—correlation with disease activity and fecal calprotectin. Journal of Clinical Medicine. 2021 Aug 30; 10(17):3905.
  46. Wang X, Memon AA, Palmér K, Hedelius A, Sundquist J, Sundquist K. The association of zonulin-related proteins with prevalent and incident inflammatory bowel disease. BMC gastroenterology. 2022 Dec; 22:1-8.
  47. Kushlinskii NE, Gershtein ES, Zybina NN, Tsarapaev PV, Salyanova EP, Korotkova EA, Nikonov EL, Mamedli ZZ, Bozhenko VK, Stilidi IS. Blood Serum Zonulin in Colorectal Cancer, Autoimmune Bowel Diseases, and Irritable Bowel Syndrome. Bulletin of Experimental Biology and Medicine. 2022 Jul; 173(3):376-9.
  48. Yildiz M, Adrovic A, Tasdemir E, Baba-Zada K, Aydin M, Koker O, Sahin S, Barut K, Kasapcopur O. Evaluation of co-existing diseases in children with familial Mediterranean fever. Rheumatology international. 2020 Jan; 40(1):57-64.
  49. Urgancı N, Ozgenc F, Kuloğlu Z, Yüksekkaya H, Sarı S, Erkan T, Önal Z, Çaltepe G, Akçam M, Arslan D, Arslan N, Artan R, Aydoğan A, Balamtekin N, Baran M, Baysoy G, Çakır M, Dalgıç B, Doğan Y, Durmaz Ö, Ecevıt Ç, Eren M, Gökçe S, Gülerman F, Gürakan F, Hızlı S, Işık I, Kalaycı AG, Kansu A, Kutlu T, Karabiber H, Kasırga E, Kutluk G, Özbay Hoşnut F, Özen H, Özkan T, Öztürk Y, Bekem Soylu Ö, Tutar E, Tümgör G, Ünal F, Ugraş M, Üstündağ G, Yaman A, Study Group TI. Familial Mediterranean Fever Mutation Analysis in Pediatric Patients With İnflammatory Bowel Disease: A Multicenter Study. Turk J Gastroenterol. 2021 Mar; 32(3):248-250. doi: 10.5152/tjg.2021.20057. PMID: 34160354; PMCID: PMC8975365.
  50. Sonoyama K, Ohsaka F. Role of microRNAs in the crosstalk between the gut microbiota and intestinal immune system. Bioscience of Microbiota, Food and Health. 2023.
  51. Yuan X, Berg N, Lee JW, Le T, Neudecker V, Jing N, Eltzschig H. MicroRNA miR-223 as regulator of innate immunity. Journal of Leukocyte Biology. 2018; 104: 515–524.
  52. El Sabbagh E, Shaker O, Kassem AM, Khairy A. Role of circulating microRNA146b‐5p and microRNA-106a in diagnosing and predicting the severity of inflammatory bowel disease. Egyptian Journal of Chemistry. 2023 Mar 28.
  53. Alexandru V. Olaru, MD and others, Dynamic changes in the expression of microRNA-31 during inflammatory bowel disease-associated neoplastic transformation, Inflammatory Bowel Diseases, Volume 17, Issue 1, 1 January 2011, Pages 221–231
  54. Zhang, M.M.; Bahal, R.; Rasmussen, T.P.; Manautou, J.E.; Zhong, X.B. The growth of siRNA-based therapeutics: Updated clinical studies. Biochem. Pharm. 2021, 189, 114432
  55. Imhann F, Vila AV, Bonder MJ, Fu J, Gevers D, Visschedijk MC, Spekhorst LM, Alberts R, Franke L, Van Dullemen HM, Ter Steege RW. The interplay of host genetics and gut microbiota underlying the onset and clinical presentation of inflammatory bowel disease. Gut. 2018 Jan 1; 67(1):108-19.
  56. Jostins, L., Ripke, S., Weersma, R.K., Duerr, R.H., McGovern, D.P., Hui, K.Y., Lee, J.C., Philip Schumm, L., Sharma, Y., Anderson, C.A. and Essers, J., 2012. Host–microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature, 491(7422), pp.119-124.
  57. Kalla R, Adams AT, Ventham NT, Kennedy NA, White R, Clarke C, Ivens A, Bergemalm D, Vatn S, Lopez-Jimena B; IBD Character Consortium; P Ricanek, Vatn MH, Söderholm JD, Gomollón F, Nowak JK, Jahnsen J, Halfvarson J, McTaggart S, Ho GT, Buck A, Satsangi J. Whole blood profiling of T-cell-derived microRNA allows the development of prognostic models in inflammatory bowel disease. J. Crohn’s Colitis 2020, 14, 1724–1733.
  58. Liu JZ, Van Sommeren S, Huang H, Ng SC, Alberts R, Takahashi A, Ripke S, Lee JC, Jostins L, Shah T, Abedian S. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nature genetics. 2015 Sep; 47(9):979-86.
  59. Thomas, J.P; Ölbei, M.; Brooks-Warburton, J.; Korcsmaros, T.; Modos, D. Analysing MiRNA-target gene networks in inflammatory bowel disease and other complex diseases using transcriptomic data. Genes 2022, 13, 370.
  60. Bianco AM, Girardelli M, Tommasini A. Genetics of inflammatory bowel disease from multifactorial to monogenic forms. World journal of gastroenterology. 2015 Nov 11; 21(43):12296.
  61. Noble AJ, Nowak JK, Adams AT, Uhlig HH, Satsangi J. Defining interactions between the genome, epigenome, and the environment in inflammatory bowel disease: progress and prospects. Gastroenterology. 2023 Apr 14.
  62. Wu Y, Gettler K, Kars ME, Giri M, Li D, Bayrak CS, Zhang P, Jain A, Maffucci P, Sabic K, Van Vleck T. Identifying high-impact variants and genes in exomes of Ashkenazi Jewish inflammatory bowel disease patients. Nature communications. 2023 Apr 20; 14(1):2256.
  63. Christodoulou K, Wiskin AE, Gibson J, Tapper W, Willis C, Afzal NA, Upstill-Goddard R, Holloway JW, Simpson MA, Beattie RM, Collins A. Next generation exome sequencing of pediatric inflammatory bowel disease patients identifies rare and novel variants in candidate genes. Gut. 2013 Jul 1; 62(7):977-84.
  64. Imhann F, Vila AV, Bonder MJ, Fu J, Gevers D, Visschedijk MC, Spekhorst LM, Alberts R, Franke L, Van Dullemen HM, Ter Steege RW. Interplay of host genetics and gut microbiota underlying the onset and clinical presentation of inflammatory bowel disease. Gut. 2018 Jan 1; 67(1):108-19.
  65. Serra EG, Schwerd T, Moutsianas L, Cavounidis A, Fachal L, Pandey S, Kammermeier J, Croft NM, Posovszky C, Rodrigues A, Russell RK. Somatic mosaicism and common genetic variation contribute to the risk of very-early-onset inflammatory bowel disease. Nature communications. 2020 Feb 21; 11(1):995.
  66. Kamaraj B, Ahmad K, Matavalam NR, Mosli MH, Elango R. Background: Inflammatory bowel disease (IBD) is a chronic autoimmune disorder characterized by severe inflammation and mucosal destruction of the intestine. The specific, complex molecular processes underlying IBD pathogenesis are not well understood. Therefore, this study is aimed at identifying and uncovering the role of key genetic factors in IBD. Computational genomics and structural bioinformatics in personalized medicines, volume II. 2023 Nov 6:105.
  67. Finocchi A, Pacillo L, Chiriaco M, Di Matteo Gi, Francalanci P, Angelino G, Caldaro T, Rivalta B, O'Mara M, Zhang S, Lepri FR. Neonatal-onset Inflammatory Bowel Disease Due To Novel Compound Heterozygous Mutation In Duox2. Frontiers in Genetics.; 14:1276697.
  68. Kyodo R, Takeuchi I, Narumi S, Shimizu H, Hata K, Yoshioka T, Tanase-Nakao K, Shimizu T, Arai K. Novel biallelic mutations in the DUOX2 gene underlying very early-onset inflammatory bowel disease: A case report. Clinical Immunology. 2022 May 1; 238:109015.
Journal of Pediatric Perspectives
Volume 12, Issue 2
February 2024
Pages 18530-18546

Files

Share

How to cite

Statistics