Skip to main content

Impact of Genes and the Environment on the Pathogenesis and Disease Course of Inflammatory Bowel Disease

Abstract

Crohn’s disease and ulcerative colitis constitute two major subgroups of inflammatory bowel diseases (IBD), a group of complex polygenic diseases characterized by chronic and progressive inflammation in the gastrointestinal tract. In recent years, methodological advances in genetic analysis have greatly expanded our understanding of the genetic background of IBD. So far, more than 240 genetic risk loci have been identified for IBD. However, these risk alleles explain less than 30% of the susceptibility to disease development, suggesting that environmental factors contribute considerably. The increasing occurrence of IBD in Eastern countries following their ‘westernization’, as well as the increased risk of disease among those who migrate to high-incidence regions, also suggest that the environment is key in the pathogenesis of IBD. In this review, we summarize the current evidence on the role of genetic and environmental factors in the susceptibility to, and disease course of, IBD, and we suggest how these findings might be applied to clinical practice.

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

References

  1. 1.

    Orholm M, Fonager K, Sørensen HT. Risk of ulcerative colitis and Crohnʼs disease among offspring of patients with chronic inflammatory bowel disease. Am J Gastroenterol. 1999;94:3236–3238.

    Article  CAS  PubMed  Google Scholar 

  2. 2.

    Moller FT, Andersen V, Wohlfahrt J, Jess T. Familial risk of inflammatory bowel disease: a population-based cohort study 1977–2011. Am J Gastroenterol. 2015;110:564–571.

    Article  PubMed  Google Scholar 

  3. 3.

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Franke A, McGovern DPB, Barrett JC, et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn’s disease susceptibility loci. Nat Genet. 2010;42:1118–1125.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Barrett JC, Hansoul S, Nicolae DL, et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn’s disease. Nat Genet. 2008;40:955–962.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Zhernakova A, van Diemen CC, Wijmenga C. Detecting shared pathogenesis from the shared genetics of immune-related diseases. Nat Rev Genet. 2009;10:43–55.

    Article  CAS  PubMed  Google Scholar 

  7. 7.

    Burisch J, Jess T, Egeberg A. Incidence of immune-mediated inflammatory diseases among patients with inflammatory bowel diseases in denmark. Clin Gastroenterol Hepatol. https://doi.org/10.1016/j.cgh.2019.03.040.

  8. 8.

    Davies JM, Abreu MT. The innate immune system and inflammatory bowel disease. Scand J Gastroenterol. 2015;50:24–33.

    Article  CAS  PubMed  Google Scholar 

  9. 9.

    Cleynen I, González JR, Figueroa C, et al. Genetic factors conferring an increased susceptibility to develop Crohn’s disease also influence disease phenotype: results from the IBDchip European Project. Gut. 2013;62:1556–1565.

    Article  CAS  PubMed  Google Scholar 

  10. 10.

    Franchimont D, Vermeire S, El Housni H, et al. Deficient host-bacteria interactions in inflammatory bowel disease? The toll-like receptor (TLR)-4 Asp299gly polymorphism is associated with Crohn’s disease and ulcerative colitis. Gut. 2004;53:987–992.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Bank S, Skytt Andersen P, Burisch 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. Heimesaat MM, ed. PLoS One. 2014;9:e98815.

  12. 12.

    Heliö T, Halme L, Lappalainen M, et al. CARD15/NOD2 gene variants are associated with familially occurring and complicated forms of Crohn’s disease. Gut. 2003;52:558–562.

    Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Cleynen I, Boucher G, Jostins L, et al. Inherited determinants of Crohn’s disease and ulcerative colitis phenotypes: a genetic association study. Lancet. 2016;387:156–167.

    Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Weersma RK, Zhernakova A, Nolte IM, et al. ATG16L1 and IL23R are associated with inflammatory bowel diseases but not with celiac disease in the Netherlands. Am J Gastroenterol. 2008;103:621–627.

    Article  CAS  PubMed  Google Scholar 

  15. 15.

    Wang C, Yuan X, Ma E, et al. NOD2 is dispensable for ATG16L1 deficiency-mediated resistance to urinary tract infection. Autophagy. 2014;10:331–338.

    Article  CAS  PubMed  Google Scholar 

  16. 16.

    Glas J, Konrad A, Schmechel S, et al. The ATG16L1 gene variants rs2241879 and rs2241880 (T300A) are strongly associated with susceptibility to Crohn’s disease in the german population. Am J Gastroenterol. 2008;103:682–691.

    Article  CAS  PubMed  Google Scholar 

  17. 17.

    Ng SC, Tsoi KKF, Kamm MA, et al. Genetics of inflammatory bowel disease in Asia: systematic review and meta-analysis. Inflamm Bowel Dis. 2012;18:1164–1176.

    Article  PubMed  Google Scholar 

  18. 18.

    Irvine EJ, Marshall JK. Increased intestinal permeability precedes the onset of Crohn’s disease in a subject with familial risk. Gastroenterology. 2000;119:1740–1744.

    Article  CAS  PubMed  Google Scholar 

  19. 19.

    Muise AM, Walters TD, Glowacka WK, et al. Polymorphisms in E-cadherin (CDH1) result in a mis-localised cytoplasmic protein that is associated with Crohn’s disease. Gut. 2009;58:1121–1127.

    Article  CAS  PubMed  Google Scholar 

  20. 20.

    Elding H, Lau W, Swallow DM, Maniatis N. Dissecting the genetics of complex inheritance: linkage disequilibrium mapping provides insight into Crohn disease. Am J Hum Genet. 2011;89:798–805.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Diaz-Gallo L-M, Espino-Paisán L, Fransen K, et al. Differential association of two PTPN22 coding variants with Crohnʼs disease and ulcerative colitis. Inflamm Bowel Dis. 2011;17:2287–2294.

    Article  Google Scholar 

  22. 22.

    Van der Sluis M, De Koning BAE, De Bruijn ACJM, et al. Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection. Gastroenterology. 2006;131:117–129.

    Article  CAS  Google Scholar 

  23. 23.

    Niv Y. Mucin gene expression in the intestine of ulcerative colitis patients. Eur J Gastroenterol Hepatol. 2016;28:1241–1245.

    Article  CAS  PubMed  Google Scholar 

  24. 24.

    Momozawa Y, Mni M, Nakamura K, et al. Resequencing of positional candidates identifies low frequency IL23R coding variants protecting against inflammatory bowel disease. Nat Genet. 2011;43:43–47.

    Article  CAS  PubMed  Google Scholar 

  25. 25.

    Craddock N, Hurles ME, Cardin N, et al. Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls. Nature. 2010;464:713–720.

    Article  CAS  PubMed  Google Scholar 

  26. 26.

    Dubinsky MC, Kugathasan S, Kwon S, et al. Multidimensional prognostic risk assessment identifies association between IL12B variation and surgery in Crohn’s disease. Inflamm Bowel Dis. 2013;19:1662–1670.

    Article  PubMed  Google Scholar 

  27. 27.

    Simon EG, Ghosh S, Iacucci M, Moran GW. Ustekinumab for the treatment of Crohn’s disease: can it find its niche? Therap Adv Gastroenterol. 2016;9:26–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Sandborn WJ, Su C, Sands BE, et al. Tofacitinib as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2017;376:1723–1736.

    Article  CAS  PubMed  Google Scholar 

  29. 29.

    Pigneur B, Escher J, Elawad M, et al. Phenotypic characterization of very early-onset IBD due to mutations in the IL10, IL10 receptor alpha or beta gene: a survey of the Genius Working Group. Inflamm Bowel Dis. 2013;19:2820–2828.

    Article  PubMed  Google Scholar 

  30. 30.

    Glocker E-O, Kotlarz D, Boztug K, et al. Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N Engl J Med. 2009;361:2033–2045.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Kalla R, Ventham NT, Kennedy NA, et al. MicroRNAs: new players in IBD. Gut. 2015;64:504–513.

    Article  CAS  PubMed  Google Scholar 

  32. 32.

    Imhann F, Vich Vila A, Bonder MJ, et al. Interplay of host genetics and gut microbiota underlying the onset and clinical presentation of inflammatory bowel disease. Gut. 2018;67:108–119.

    Article  CAS  PubMed  Google Scholar 

  33. 33.

    Knights D, Lassen KG, Xavier RJ. Advances in inflammatory bowel disease pathogenesis: linking host genetics and the microbiome. Gut. 2013;62:1505–1510.

    Article  CAS  PubMed  Google Scholar 

  34. 34.

    Kostic AD, Xavier RJ, Gevers D. The microbiome in inflammatory bowel diseases: current status and the future ahead. Gastroenterology. 2014;146:1489.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Bager P, Simonsen J, Nielsen NM, Frisch M. Cesarean section and offspringʼs risk of inflammatory bowel disease: a national cohort study. Inflamm Bowel Dis. 2012;18:857–862.

    Article  PubMed  Google Scholar 

  36. 36.

    Bruce A, Black M, Bhattacharya S. Mode of delivery and risk of inflammatory bowel disease in the offspring: systematic review and meta-analysis of observational studies. Inflamm Bowel Dis. 2014;20:1217–1226.

    Article  PubMed  Google Scholar 

  37. 37.

    van den Elsen LWJ, Garssen J, Burcelin R, Verhasselt V. Shaping the gut microbiota by breastfeeding: the gateway to allergy prevention? Front Pediatr. 2019;7:47.

    Article  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Gearry RB, Richardson AK, Frampton CM, Dodgshun AJ, Barclay ML. Population-based cases control study of inflammatory bowel disease risk factors. J Gastroenterol Hepatol. 2010;25:325–333.

    Article  PubMed  Google Scholar 

  39. 39.

    Hansen TS, Jess T, Vind I, et al. Environmental factors in inflammatory bowel disease: a case-control study based on a Danish inception cohort. J Crohn’s Colitis. 2011;5:577–584.

    Article  Google Scholar 

  40. 40.

    Xu L, Lochhead P, Ko Y, et al. Systematic review with meta-analysis: breastfeeding and the risk of Crohn’s disease and ulcerative colitis. Aliment Pharmacol Ther. 2017;46:780–789.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Ng SC, Tang W, Leong RW, et al. Environmental risk factors in inflammatory bowel disease: a population-based case-control study in Asia-Pacific. Gut. 2015;64:1063–1071.

    Article  PubMed  Google Scholar 

  42. 42.

    Cholapranee A, Ananthakrishnan AN. Environmental hygiene and risk of inflammatory bowel diseases: a systematic review and meta-analysis. Inflamm Bowel Dis. 2016;22:2191–2199.

    Article  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Wu X-W, Ji H-Z, Yang M-F, Wu L, Wang F-Y. Helicobacter pylori infection and inflammatory bowel disease in Asians: a meta-analysis. World J Gastroenterol. 2015;21:4750–4756.

    Article  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Lin K-D, Chiu G-F, Waljee AK, et al. Effects of anti-helicobacter pylori therapy on incidence of autoimmune diseases, including inflammatory bowel diseases. Clin Gastroenterol Hepatol. https://doi.org/10.1016/j.cgh.2018.12.014.

  45. 45.

    Lakatos PL, Vegh Z, Lovasz BD, et al. Is Current smoking still an important environmental factor in inflammatory bowel diseases? Results from a population-based incident cohort. Inflamm Bowel Dis. 2013;19:1010–1017.

    Article  PubMed  Google Scholar 

  46. 46.

    To N, Ford AC, Gracie DJ. Systematic review with meta-analysis: the effect of tobacco smoking on the natural history of ulcerative colitis. Aliment Pharmacol Ther. 2016;44:117–126.

    Article  CAS  PubMed  Google Scholar 

  47. 47.

    Bergers J, Stockbrugger R, Brummer R, et al. Appendectomy and the risk of developing ulcerative colitis or Crohn’s disease: Results of a large case-control study. South Limburg Inflammatory Bowel Disease Study Group. Gastroenterology. 2005;113:337–382.

  48. 48.

    Biedermann L, Brülisauer K, Zeitz J, et al. Smoking cessation alters intestinal microbiota: insights from quantitative investigations on human fecal samples using FISH. Inflamm Bowel Dis. 2014;20:1496–1501.

    Article  PubMed  Google Scholar 

  49. 49.

    Parian A, Limketkai B, Koh J, et al. Appendectomy does not decrease the risk of future colectomy in UC: results from a large cohort and meta-analysis. Gut. 2017;66:1390–1397.

    Article  CAS  PubMed  Google Scholar 

  50. 50.

    Myrelid P, Landerholm K, Nordenvall C, Pinkney TD, Andersson RE. Appendectomy and the risk of colectomy in ulcerative colitis: a national cohort study. Am J Gastroenterol. 2017;112:1311–1319.

    Article  PubMed  Google Scholar 

  51. 51.

    Radford-Smith GL, Edwards JE, Purdie DM, et al. Protective role of appendicectomy on onset and severity of ulcerative colitis and Crohn’s disease. Gut. 2002;51:808–813.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Andersson RE, Olaison G, Tysk C, Ekbom A. Appendectomy and protection against ulcerative colitis. N Engl J Med. 2001;344:808–814.

    Article  CAS  PubMed  Google Scholar 

  53. 53.

    Kaplan GG, Pedersen BV, Andersson RE, Sands BE, Korzenik J, Frisch M. The risk of developing Crohn’s disease after an appendectomy: a population-based cohort study in Sweden and Denmark. Gut. 2007;56:1387–1392.

    Article  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Hviid A, Svanstrom H, Frisch M. Antibiotic use and inflammatory bowel diseases in childhood. Gut. 2011;60:49–54.

    Article  PubMed  Google Scholar 

  55. 55.

    Theochari NA, Stefanopoulos A, Mylonas KS, Economopoulos KP. Antibiotics exposure and risk of inflammatory bowel disease: a systematic review. Scand J Gastroenterol. 2018;53:1–7.

    Article  CAS  PubMed  Google Scholar 

  56. 56.

    Khalili H, Higuchi LM, Ananthakrishnan AN, et al. Oral contraceptives, reproductive factors and risk of inflammatory bowel disease. Gut. 2013;62:1153–1159.

    Article  CAS  PubMed  Google Scholar 

  57. 57.

    Owczarek D, Rodacki T, Domagała-Rodacka R, Cibor D, Mach T. Diet and nutritional factors in inflammatory bowel diseases. World J Gastroenterol. 2016;22:895–905.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Ananthakrishnan AN, Khalili H, Konijeti GG, et al. Long-term intake of dietary fat and risk of ulcerative colitis and Crohn’s disease. Gut. 2014;63:776–784.

    Article  CAS  PubMed  Google Scholar 

  59. 59.

    Martinez-Medina M, Denizot J, Dreux N, et al. Western diet induces dysbiosis with increased E. coli in CEABAC10 mice, alters host barrier function favouring AIEC colonisation. Gut. 2014;63:116–124.

    Article  CAS  PubMed  Google Scholar 

  60. 60.

    Ananthakrishnan AN, Khalili H, Konijeti GG, et al. A prospective study of long-term intake of dietary fiber and risk of Crohn’s disease and ulcerative colitis. Gastroenterology. 2013;145:970–977.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. 61.

    Andersen V, Chan S, Luben R, et al. Fibre intake and the development of inflammatory bowel disease: A European prospective multi-centre cohort study (EPIC-IBD). J Crohn’s Colitis. 2018;12:129–136.

    Article  Google Scholar 

  62. 62.

    Torres J, Caprioli F, Katsanos KH, et al. Predicting outcomes to optimize disease management in inflammatory bowel diseases. J Crohns Colitis. 2016;10:1385–1394.

    Article  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Cosnes J, Gower-Rousseau C, Seksik P, Cortot A. Epidemiology and natural history of inflammatory bowel diseases. Gastroenterology. 2011;140:1785.e4–1794.e4.

    Article  Google Scholar 

  64. 64.

    Adler J, Rangwalla SC, Dwamena BA, Higgins PD. The prognostic power of the NOD2 genotype for complicated Crohn’s disease: a meta-analysis. Am J Gastroenterol. 2011;106:699–712.

    Article  CAS  PubMed  Google Scholar 

  65. 65.

    Annese V, Lombardi G, Perri F, et al. Variants of CARD15 are associated with an aggressive clinical course of Crohn’s disease—an IG-IBD study. Am J Gastroenterol. 2005;100:84–92.

    Article  CAS  PubMed  Google Scholar 

  66. 66.

    Henckaerts L, Van Steen K, Verstreken I, et al. Genetic risk profiling and prediction of disease course in Crohn’s disease patients. YJCGH. 2009;7:972.e2–980.e2.

    Google Scholar 

  67. 67.

    Weersma RK, Stokkers PCF, Van Bodegraven AA, et al. Molecular prediction of disease risk and severity in a large Dutch Crohn’ s disease cohort. Gut. 2009;58:388–395.

    Article  CAS  PubMed  Google Scholar 

  68. 68.

    Zhao M, Lo BZS, Vester-Andersen MK, Vind I, Bendtsen F, Burisch J. A 10-year follow-up study of the natural history of perianal Crohn’s disease in a Danish population-based inception cohort. Inflamm Bowel Dis. https://doi.org/10.1093/ibd/izy374.

  69. 69.

    Ryan JD, Silverberg MS, Xu W, et al. Predicting complicated Crohn’s disease and surgery: phenotypes, genetics, serology and psychological characteristics of a population-based cohort. Aliment Pharmacol Ther. 2013;38:274–283.

    Article  CAS  PubMed  Google Scholar 

  70. 70.

    Roussomoustakaki M, Satsangi J, Welsh K, et al. Genetic markers may predict disease behavior in patients with ulcerative colitis. Gastroenterology. 1997;112:1845–1853.

    Article  CAS  PubMed  Google Scholar 

  71. 71.

    Satsangi J, Welsh KI, Bunce M, et al. Contribution of genes of the major histocompatibility complex to susceptibility and disease phenotype in inflammatory bowel disease. Lancet (London, England). 1996;347:1212–1217.

    Article  CAS  Google Scholar 

  72. 72.

    Cravo ML, Ferreira PA, Sousa P, et al. IL23R polymorphisms influence phenotype and response to therapy in patients with ulcerative colitis. Eur J Gastroenterol Hepatol. 2014;26:26–32.

    Article  CAS  PubMed  Google Scholar 

  73. 73.

    Ho G-T, Nimmo ER, Tenesa A, et al. Allelic variations of the multidrug resistance gene determine susceptibility and disease behavior in ulcerative colitis. Gastroenterology. 2005;128:288–296.

    Article  CAS  PubMed  Google Scholar 

  74. 74.

    Annese V, Piepoli A, Latiano A, et al. HLA-DRB1 alleles may influence disease phenotype in patients with inflammatory bowel disease: a critical reappraisal with review of the literature. Dis Colon Rectum. 2005;48:57–64-5.

  75. 75.

    Karlsen TH, Franke A, Melum E, et al. Genome-wide association analysis in primary sclerosing cholangitis. Gastroenterology. 2010;138:1102–1111.

    Article  PubMed  Google Scholar 

  76. 76.

    Ran Kim E, Kyung Chang Eun Ran Kim D, Kyung Chang D. Colorectal cancer in inflammatory bowel disease: The risk, pathogenesis, prevention and diagnosis. World J Gastroenterol. 2014;20:9872–9881.

  77. 77.

    Li H, Jin Z, Li X, Wu L, Jin J. Associations between single-nucleotide polymorphisms and inflammatory bowel disease-associated colorectal cancers in inflammatory bowel disease patients: a meta-analysis. Clin Transl Oncol. 2017;19:1018–1027.

    Article  CAS  PubMed  Google Scholar 

  78. 78.

    Sehgal R, Berg A, Polinski JI, et al. Mutations in IRGM are associated with more frequent need for surgery in patients with ileocolonic Crohnʼs disease. Dis Colon Rectum. 2012;55:115–121.

    Article  PubMed  Google Scholar 

  79. 79.

    Fowler SA, Ananthakrishnan AN, Gardet A, et al. SMAD3 gene variant is a risk factor for recurrent surgery in patients with Crohn’s disease. J Crohns Colitis. 2014;8:845–851.

    Article  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Germain A, Guéant R-M, Chamaillard M, Bresler L, Guéant J-L, Peyrin-Biroulet L. CARD8 gene variant is a risk factor for recurrent surgery in patients with Crohn’s disease. Dig Liv Dis. 2015;47:938–942.

    Article  CAS  Google Scholar 

  81. 81.

    Maconi G, Colombo E, Sampietro GM, et al. CARD15 gene variants and risk of reoperation in Crohn’s disease patients. Am J Gastroenterol. 2009;104:2483–2491.

    Article  CAS  PubMed  Google Scholar 

  82. 82.

    Fischer S, Kövesdi E, Magyari L, et al. IL23R single nucleotide polymorphisms could be either beneficial or harmful in ulcerative colitis. World J Gastroenterol. 2017;23:447.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. 83.

    Haritunians T, Taylor KD, Targan SR, et al. Genetic predictors of medically refractory ulcerative colitis. Inflamm Bowel Dis. 2010;16:1830–1840.

    Article  PubMed  PubMed Central  Google Scholar 

  84. 84.

    To N, Gracie DJ, Ford AC. Systematic review with meta-analysis: the adverse effects of tobacco smoking on the natural history of Crohn’s disease. Aliment Pharmacol Ther. 2016;43:549–561.

    Article  CAS  PubMed  Google Scholar 

  85. 85.

    Inamdar S, Volfson A, Rosen L, Sunday S, Katz S, Sultan K. Smoking and early infliximab response in Crohn’s disease: a meta-analysis. J Crohn’s Colitis. 2015;9:140–146.

    Article  Google Scholar 

  86. 86.

    Höie O, Wolters F, Riis L, et al. Ulcerative colitis: patient characteristics may predict 10-yr disease recurrence in a European-wide population-based cohort. Am J Gastroenterol. 2007;102:1692–1701.

    Article  PubMed  Google Scholar 

  87. 87.

    Timmer A, Sutherland LR, Martin F. Oral contraceptive use and smoking are risk factors for relapse in Crohn’s disease. The Canadian Mesalamine for Remission of Crohn’s Disease Study Group. Gastroenterology. 1998;114:1143–1150.

  88. 88.

    Khalili H, Granath F, Smedby KE, et al. Association between long-term oral contraceptive use and risk of Crohn’s disease complications in a nationwide study. Gastroenterology. 2016;150:1561.e1–1567.e1.

    Article  CAS  Google Scholar 

  89. 89.

    Takeuchi K, Smale S, Premchand P, et al. Prevalence and mechanism of nonsteroidal anti-inflammatory drug-induced clinical relapse in patients with inflammatory bowel disease. Clin Gastroenterol Hepatol. 2006;4:196–202.

    Article  CAS  PubMed  Google Scholar 

  90. 90.

    Tasson L, Canova C, Vettorato MG, Savarino E, Zanotti R. Influence of diet on the course of inflammatory bowel disease. Dig Dis Sci. 2017;62:2087–2094. https://doi.org/10.1007/s10620-017-4620-0.

    CAS  Article  PubMed  Google Scholar 

  91. 91.

    Brotherton CS, Martin CA, Long MD, Kappelman MD, Sandler RS. Avoidance of fiber is associated with greater risk of Crohn’s disease flare in a 6-month period. Clin Gastroenterol Hepatol. 2016;14:1130–1136.

    Article  PubMed  Google Scholar 

  92. 92.

    Hou JK, Abraham B, El-Serag H. Dietary intake and risk of developing inflammatory bowel disease: a systematic review of the literature. Am J Gastroenterol. 2011;106:563–573.

    Article  CAS  PubMed  Google Scholar 

  93. 93.

    Gubatan J, Mitsuhashi S, Zenlea T, Rosenberg L, Robson S, Moss AC. Low serum vitamin d during remission increases risk of clinical relapse in patients with ulcerative colitis. Clin Gastroenterol Hepatol. 2017;15:240.e1–246.e1.

    Google Scholar 

  94. 94.

    Ananthakrishnan AN, Khalili H, Higuchi LM, et al. Higher predicted vitamin D status is associated with reduced risk of Crohn’s disease. Gastroenterology. 2012;142:482–489.

    Article  CAS  PubMed  Google Scholar 

  95. 95.

    Ananthakrishnan AN, Cagan A, Gainer VS, et al. Normalization of plasma 25-hydroxy vitamin D is associated with reduced risk of surgery in Crohn’s disease. J Crohn’s Colitis. 2012;50:152–156.

    Google Scholar 

  96. 96.

    Torres J, Burisch J, Riddle M, Dubinsky M, Colombel J-F. Preclinical disease and preventive strategies in IBD: perspectives, challenges and opportunities. Gut. 2016;65:1061–1069.

    Article  CAS  PubMed  Google Scholar 

  97. 97.

    Nunes T, Etchevers MJ, García-Sánchez V, et al. Impact of smoking cessation on the clinical course of Crohn’s disease under current therapeutic algorithms: a multicenter prospective study. Am J Gastroenterol. 2016;111:411–419.

    Article  CAS  PubMed  Google Scholar 

  98. 98.

    Cosnes J, Beaugerie L, Carbonnel F, Gendre J-P. Smoking cessation and the course of Crohn’s disease: an intervention study. Gastroenterology. 2001;120:1093–1099.

    Article  CAS  PubMed  Google Scholar 

  99. 99.

    Jørgensen SP, Agnholt J, Glerup H, et al. Clinical trial: vitamin D3 treatment in Crohn’s disease—a randomized double-blind placebo-controlled study. Aliment Pharmacol Ther. 2010;32:377–383.

    Article  CAS  PubMed  Google Scholar 

  100. 100.

    Durães C, Machado JC, Portela F, et al. Phenotype–genotype profiles in Crohnʼs disease predicted by genetic markers in autophagy-related genes (GOIA Study II). Inflamm Bowel Dis. 2013;19:230–239.

    Article  PubMed  Google Scholar 

  101. 101.

    Hlavaty T, Pierik M, Henckaerts L, et al. Polymorphisms in apoptosis genes predict response to infliximab therapy in luminal and fistulizing Crohn’s disease. Aliment Pharmacol Ther. 2005;22:613–626.

    Article  CAS  PubMed  Google Scholar 

  102. 102.

    Netz U, Carter JV, Eichenberger MR, et al. Genetic polymorphisms predict response to anti-tumor necrosis factor treatment in Crohn’s disease. World J Gastroenterol. 2017;23:4958.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. 103.

    Vermeire S, Louis E, Rutgeerts P, et al. NOD2/CARD15 does not influence response to infliximab in Crohn’s disease. Gastroenterology. 2002;123:106–111.

    Article  CAS  PubMed  Google Scholar 

  104. 104.

    Jürgens M, Laubender RP, Hartl F, et al. Disease activity, ANCA and IL23R genotype status determine early response to infliximab in patients with ulcerative colitis. Am J Gastroenterol. 2010;105:1811–1819.

    Article  CAS  PubMed  Google Scholar 

  105. 105.

    Bek S, Nielsen JV, Bojesen AB, et al. Systematic review: genetic biomarkers associated with anti-TNF treatment response in inflammatory bowel diseases. Aliment Pharmacol Ther. 2016;44:554–567.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. 106.

    Arijs I, Li K, Toedter G, et al. Mucosal gene signatures to predict response to infliximab in patients with ulcerative colitis. Gut. 2009;58:1612–1619.

    Article  CAS  Google Scholar 

  107. 107.

    Bank S, Andersen PS, Burisch J, et al. Associations between functional polymorphisms in the NF k B signaling pathway and response to anti-TNF treatment in Danish patients with inflammatory bowel disease. Pharmacogenomics J. 2014;14:526–534.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Johan Burisch.

Ethics declarations

Conflict of interest

The authors declare that there is no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Zhao, M., Burisch, J. Impact of Genes and the Environment on the Pathogenesis and Disease Course of Inflammatory Bowel Disease. Dig Dis Sci 64, 1759–1769 (2019). https://doi.org/10.1007/s10620-019-05648-w

Download citation

Keywords

  • Inflammatory bowel disease
  • Crohn’s disease
  • Ulcerative colitis
  • Pathogenesis
  • Risk factors
  • Genetics
  • Environment