Abstract
The inflammatory bowel diseases are chronic, relapsing disorders characterized by inflammation and ulceration in part of or the entire gastrointestinal tract. IBD affects people worldwide but is most prevalent in northern Europe and North America. Etiologically, the current consensus is that the intestinal inflammation is largely caused by an aberrant and excessive immune response to environmental triggers (intestinal bacterial infection, medications, or other agents) in genetically susceptible individuals. IBD exerts a heavy toll on patients’ quality of life and imposes a considerable economic burden on the healthcare system. Some forms of IBD lead to severe complications such as formation of fistulae and intestinal strictures, for which management options are very limited. Moreover, many IBD patients develop drug tolerance and toxic responses, which severely compromise the disease control. Over the past decade, modern genetics has led to a new era of IBD research. Up to 163 genes have been identified to be associated with IBD. A growing number of new diagnostic tools and therapeutic agents resulted from the IBD genetics have already been implemented in the management of IBD; however, unmet needs persist. By utilizing new experimental tools such as powerful next-generation DNA sequencing machines along with accessing large cohorts of IBD patients, genetic studies will lead to a better understanding of the causes of individual IBD, more diagnostic tools to aid in evaluating the disease course and responsiveness to treatment, more novel targets to be identified for new drug development, and ultimately the most desirable strategies for IBD prevention.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Silverberg MS, Satsangi J, Ahmad T, Arnott ID, Bernstein CN, Brant SR et al (2005) Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: Report of a Working Party of the 2005 Montreal World Congress of Gastroenterology. Can J Gastroenterol 9(Suppl 1):5–36
Molodecky NA, Soon IS, Rabi DM, Ghali WA, Ferris M, Chernoff G et al (2012) Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology 142(1):46–54, e42; quiz e30
Podolsky DK (2002) The current future understanding of inflammatory bowel disease. Best Pract Res Clin Gastroenterol 16(6):933–943
Fiocchi C (1998) Inflammatory bowel disease: etiology and pathogenesis. Gastroenterology 115(1):182–205
Farmer RG, Michener WM, Mortimer EA (1980) Studies of family history among patients with inflammatory bowel disease. Clin Gastroenterol 9(2):271–277
Tysk C, Lindberg E, Jarnerot G, Floderus-Myrhed B (1988) 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 29(7):990–996
Sonnenberg A, McCarty DJ, Jacobsen SJ (1991) Geographic variation of inflammatory bowel disease within the United States. Gastroenterology 100(1):143–149
Loftus EV Jr (2004) Clinical epidemiology of inflammatory bowel disease: Incidence, prevalence, and environmental influences. Gastroenterology 126(6):1504–1517
Sokol H, Seksik P, Rigottier-Gois L, Lay C, Lepage P, Podglajen I et al (2006) Specificities of the fecal microbiota in inflammatory bowel disease. Inflamm Bowel Dis 12(2):106–111
Logan RF, Edmond M, Somerville KW, Langman MJ (1984) Smoking and ulcerative colitis. Br Med J (Clin Res Ed) 288(6419):751–753
Somerville KW, Logan RF, Edmond M, Langman MJ (1984) Smoking and Crohn’s disease. Br Med J (Clin Res Ed) 289(6450):954–956
Pullan RD, Rhodes J, Ganesh S, Mani V, Morris JS, Williams GT et al (1994) Transdermal nicotine for active ulcerative colitis. N Eng J Med 330(12):811–815
Ananthakrishnan AN, Higuchi LM, Huang ES, Khalili H, Richter JM, Fuchs CS et al (2012) Aspirin, nonsteroidal anti-inflammatory drug use, and risk for Crohn disease and ulcerative colitis: a cohort study. Ann Intern Med 156(5):350–359, Epub 2012/03/07
Schroeder KW, Tremaine WJ, Ilstrup DM (1987) Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis. A randomized study. N Eng J Med 317(26):1625–1629
Podolsky DK (2002) Inflammatory bowel disease. N Eng J Med 347(6):417–429
Wagtmans MJ, Verspaget HW, Lamers CB, van Hogezand RA (1997) Clinical aspects of Crohn’s disease of the upper gastrointestinal tract: a comparison with distal Crohn’s disease. Am J Gastroenterol 92(9):1467–1471
de Vlam K, Mielants H, Cuvelier C, De Keyser F, Veys EM, De Vos M (2000) Spondyloarthropathy is underestimated in inflammatory bowel disease: prevalence and HLA association. J Rheumatol 27(12):2860–2865
Ghosh S, Cowen S, Hannan WJ, Ferguson A (1994) Low bone mineral density in Crohn’s disease, but not in ulcerative colitis, at diagnosis. Gastroenterology 107(4):1031–1039
Lebwohl M, Lebwohl O (1998) Cutaneous manifestations of inflammatory bowel disease. Inflamm Bowel Dis 4(2):142–148
Mintz R, Feller ER, Bahr RL, Shah SA (2004) Ocular manifestations of inflammatory bowel disease. Inflamm Bowel Dis 10(2):135–139
Nikolaus S, Schreiber S (2007) Diagnostics of inflammatory bowel disease. Gastroenterology 133(5):1670–1689
Ahmad J, Slivka A (2002) Hepatobiliary disease in inflammatory bowel disease. Gastroenterol Clin North Am 31(1):329–345
Talwalkar JA, Lindor KD (2005) Primary sclerosing cholangitis. Inflamm Bowel Dis 11(1):62–72
Farmer RG, Hawk WA, Turnbull RB Jr (1975) Clinical patterns in Crohn’s disease: a statistical study of 615 cases. Gastroenterology 68(4 Pt 1):627–635
Gasche C, Scholmerich J, Brynskov J, D’Haens G, Hanauer SB, Irvine EJ et al (2000) A simple classification of Crohn’s disease: report of the working party for the world congresses of gastroenterology, Vienna 1998. Inflamm Bowel Dis 6(1):8–15
Farmer RG, Whelan G, Fazio VW (1985) Long-term follow-up of patients with Crohn’s disease. Relationship between the clinical pattern and prognosis. Gastroenterology 88(6):1818–1825
Cosnes J, Cattan S, Blain A, Beaugerie L, Carbonnel F, Parc R et al (2002) Long-term evolution of disease behavior of Crohn’s disease. Inflamm Bowel Dis 8(4):244–250
Mekhjian HS, Switz DM, Melnyk CS, Rankin GB, Brooks RK (1979) Clinical features and natural history of Crohn’s disease. Gastroenterology 77(4 Pt 2):898–906
Lapidus A, Bernell O, Hellers G, Lofberg R (1998) Clinical course of colorectal Crohn’s disease: a 35-year follow-up study of 507 patients. Gastroenterology 114(6):1151–1160
Martland GT, Shepherd NA (2007) Indeterminate colitis: definition, diagnosis, implications and a plea for nosological sanity. Histopathology 50(1):83–96, Epub 2007/01/06
Tremaine WJ (2012) Is indeterminate colitis determinable? Curr Gastroenterol Rep 14(2):162–165, Epub 2012/02/09
Murrell ZA, Melmed GY, Ippoliti A, Vasiliauskas EA, Dubinsky M, Targan SR et al (2009) A prospective evaluation of the long-term outcome of ileal pouch-anal anastomosis in patients with inflammatory bowel disease-unclassified and indeterminate colitis. Dis Colon Rectum 52(5):872–878, Epub 2009/06/09
Prenzel F, Uhlig HH (2009) Frequency of indeterminate colitis in children and adults with IBD—a metaanalysis. J Crohns Colitis 3(4):277–281
Chetty R, Govender D (2012) Lymphocytic and collagenous colitis: an overview of so-called microscopic colitis. Nat Rev Gastroenterol Hepatol 9(4):209–218, Epub 2012/02/22
Geraghty JM, Talbot IC (1991) Diversion colitis: histological features in the colon and rectum after defunctioning colostomy. Gut 32(9):1020–1023
Lamps LW, Knapple WL (2007) Diverticular disease-associated segmental colitis. Clin Gastroenterol Hepatol 5(1):27–31, Epub 2007/01/20
Rameshshanker R, Arebi N (2012) Endoscopy in inflammatory bowel disease when and why. World J Gastrointest Endosc 4(6):201–211
Kornbluth A, Sachar DB, Practice Parameters Committee of the American College of Gastroenterology (2010) Ulcerative colitis practice guidelines in adults: American College Of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol 105(3):501–523
Nostrant TT, Kumar NB, Appelman HD (1987) Histopathology differentiates acute self-limited colitis from ulcerative colitis. Gastroenterology 92(2):318–328
Sands BE (2004) From symptom to diagnosis: clinical distinctions among various forms of intestinal inflammation. Gastroenterology 126(6):1518–1532
Hanauer SB, Sandborn WJ, Kornbluth A, Katz S, Safdi M, Woogen S et al (2005) Delayed-release oral mesalamine at 4.8 g/day (800 mg tablet) for the treatment of moderately active ulcerative colitis: the ASCEND II trial. Am J Gastroenterol 100(11):2478–2485
Marteau P, Probert CS, Lindgren S, Gassul M, Tan TG, Dignass A et al (2005) Combined oral and enema treatment with Pentasa (mesalazine) is superior to oral therapy alone in patients with extensive mild/moderate active ulcerative colitis: a randomised, double blind, placebo controlled study. Gut 54(7):960–965
Truelove SC, Watkinson G, Draper G (1962) Comparison of corticosteroid and sulphasalazine therapy in ulcerative colitis. Br Med J 2(5321):1708–1711
Rutgeerts P, Sandborn WJ, Feagan BG, Reinisch W, Olson A, Johanns J et al (2005) Infliximab for induction and maintenance therapy for ulcerative colitis. N Eng J Med 353(23):2462–2476
Oussalah A, Laclotte C, Chevaux JB, Bensenane M, Babouri A, Serre AA et al (2008) Long-term outcome of adalimumab therapy for ulcerative colitis with intolerance or lost response to infliximab: a single-centre experience. Aliment Pharmacol Ther 28(8):966–972
Shibolet O, Regushevskaya E, Brezis M, Soares-Weiser K (2005) Cyclosporine A for induction of remission in severe ulcerative colitis. Cochrane Database Syst Rev 1, CD004277
Perrier C, Rutgeerts P (2012) New Drug Therapies on the Horizon for IBD. Dig Dis 30(Suppl 1):100–105
Lichtenstein GR, Hanauer SB, Sandborn WJ, Practice Parameters Committee of American College of Gastroenterology (2009) Management of Crohn’s disease in adults. Am J Gastroenterol 104(2):465–483; quiz 4, 84
Rutgeerts P, Hiele M, Geboes K, Peeters M, Penninckx F, Aerts R et al (1995) Controlled trial of metronidazole treatment for prevention of Crohn’s recurrence after ileal resection. Gastroenterology 108(6):1617–1621
Thia KT, Mahadevan U, Feagan BG, Wong C, Cockeram A, Bitton A et al (2009) Ciprofloxacin or metronidazole for the treatment of perianal fistulas in patients with Crohn’s disease: a randomized, double-blind, placebo-controlled pilot study. Inflamm Bowel Dis 15(1):17–24
Benchimol EI, Seow CH, Steinhart AH, Griffiths AM (2008) Traditional corticosteroids for induction of remission in Crohn’s disease. Cochrane Database Syst Rev 2, CD006792
Seow CH, Benchimol EI, Griffiths AM, Otley AR, Steinhart AH (2008) Budesonide for induction of remission in Crohn’s disease. Cochrane Database Syst Rev 3, CD000296
Lichtenstein GR, Bengtsson B, Hapten-White L, Rutgeerts P (2009) Oral budesonide for maintenance of remission of Crohn’s disease: a pooled safety analysis. Aliment Pharmacol Ther 29(6):643–653
Prefontaine E, Macdonald JK, Sutherland LR (2009) Azathioprine or 6-mercaptopurine for induction of remission in Crohn’s disease. Cochrane Database Syst Rev 4, CD000545
Prefontaine E, Sutherland LR, Macdonald JK, Cepoiu M (2009) Azathioprine or 6-mercaptopurine for maintenance of remission in Crohn’s disease. Cochrane Database Syst Rev 1, CD000067
Feagan BG, Rochon J, Fedorak RN, Irvine EJ, Wild G, Sutherland L et al (1995) Methotrexate for the treatment of Crohn’s disease. The North American Crohn’s Study Group Investigators. N Eng J Med 332(5):292–297
Vavricka SR, Schoepfer AM, Bansky G, Binek J, Felley C, Geyer M et al (2011) Efficacy and safety of certolizumab pegol in an unselected Crohn’s disease population: 26-week data of the FACTS II survey. Inflamm Bowel Dis 17(7):1530–1539
Rutgeerts P (2004) Review article: treatment of perianal fistulizing Crohn’s disease. Aliment Pharmacol Ther 20(Suppl 4):106–110
Colombel JF, Sandborn WJ, Rutgeerts P, Enns R, Hanauer SB, Panaccione R et al (2007) Adalimumab for maintenance of clinical response and remission in patients with Crohn’s disease: the CHARM trial. Gastroenterology 132(1):52–65
Sinh P, Barrett TA, Yun L (2011) Clostridium difficile Infection and Inflammatory Bowel Disease: A Review. Gastroenterol Res Pract 2011:136064, Epub 2011/09/15
Afif W, Loftus EV Jr, Faubion WA, Kane SV, Bruining DH, Hanson KA et al (2010) Clinical utility of measuring infliximab and human anti-chimeric antibody concentrations in patients with inflammatory bowel disease. Am J Gastroenterol 105(5):1133–1139
Targan SR, Feagan BG, Fedorak RN, Lashner BA, Panaccione R, Present DH et al (2007) Natalizumab for the treatment of active Crohn’s disease: results of the ENCORE Trial. Gastroenterology 132(5):1672–1683
Sandborn WJ (2009) The future of inflammatory bowel disease care. Rev Gastroenterol Disord 9(3):E69–E77
Jostins L, Ripke S, Weersma RK, Duerr RH, McGovern DP, Hui KY et al (2012) Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491(7422):119–124, Epub 2012/11/07
Lees CW, Barrett JC, Parkes M, Satsangi J (2011) New IBD genetics: common pathways with other diseases. Gut 60(12):1739–1753, Epub 2011/02/09
Cho JH, Brant SR (2011) Recent insights into the genetics of inflammatory bowel disease. Gastroenterology 140(6):1704–1712
Brand S, Staudinger T, Schnitzler F, Pfennig S, Hofbauer K, Dambacher J et al (2005) The role of Toll-like receptor 4 Asp299Gly and Thr399Ile polymorphisms and CARD15/NOD2 mutations in the susceptibility and phenotype of Crohn’s disease. Inflamm Bowel Dis 11(7):645–652
Sehgal R, Berg A, Hegarty JP, Kelly AA, Lin Z, Poritz LS et al (2010) NOD2/CARD15 mutations correlate with severe pouchitis after ileal pouch-anal anastomosis. Dis Colon Rectum 53(11):1487–1494
Christodoulou K, Wiskin AE, Gibson J, Tapper W, Willis C (2012) Afzal NA, et al. Next generation exome sequencing of paediatric inflammatory bowel disease patients identifies rare and novel variants in candidate genes, Gut
Russell RK, Drummond HE, Nimmo EE, Anderson N, Smith L, Wilson DC et al (2005) Genotype-phenotype analysis in childhood-onset Crohn’s disease: NOD2/CARD15 variants consistently predict phenotypic characteristics of severe disease. Inflamm Bowel Dis 11(11):955–964
Babusukumar U, Wang T, McGuire E, Broeckel U, Kugathasan S (2006) Contribution of OCTN variants within the IBD5 locus to pediatric onset Crohn’s disease. Am J Gastroenterol 101(6):1354–1361
Reinhard C, Rioux JD (2006) Role of the IBD5 susceptibility locus in the inflammatory bowel diseases. Inflamm Bowel Dis 12(3):227–238
Mirza MM, Fisher SA, King K, Cuthbert AP, Hampe J, Sanderson J et al (2003) Genetic evidence for interaction of the 5q31 cytokine locus and the CARD15 gene in Crohn disease. Am J Hum Genet 72(4):1018–1022
Moran CJ, Walters TD, Guo CH, Kugathasan S, Klein C, Turner D et al (2012) IL-10R polymorphisms are associated with very-early-onset ulcerative colitis. Inflamm Bowel Dis 19(1):115–123
Kotlarz D, Beier R, Murugan D, Diestelhorst J, Jensen O, Boztug K et al (2012) Loss of interleukin-10 signaling and infantile inflammatory bowel disease: implications for diagnosis and therapy. Gastroenterology 143(2):347–355
Muise AM, Xu W, Guo CH, Walters TD, Wolters VM, Fattouh R et al (2012) NADPH oxidase complex and IBD candidate gene studies: identification of a rare variant in NCF2 that results in reduced binding to RAC2. Gut 61(7):1028–1035
Worthey EA, Mayer AN, Syverson GD, Helbling D, Bonacci BB, Decker B et al (2011) Making a definitive diagnosis: successful clinical application of whole exome sequencing in a child with intractable inflammatory bowel disease. Genet Med 13(3):255–262
Latiano A, Palmieri O, Cucchiara S, Castro M, D’Inca R, Guariso G et al (2009) Polymorphism of the IRGM gene might predispose to fistulizing behavior in Crohn’s disease. Am J Gastroenterol 104(1):110–116
de Ridder L, Weersma RK, Dijkstra G, van der Steege G, Benninga MA, Nolte IM et al (2007) Genetic susceptibility has a more important role in pediatric-onset Crohn’s disease than in adult-onset Crohn’s disease. Inflamm Bowel Dis 13(9):1083–1092
Lichtenstein GR, Targan SR, Dubinsky MC, Rotter JI, Barken DM, Princen F et al (2011) Combination of genetic and quantitative serological immune markers are associated with complicated Crohn’s disease behavior. Inflamm Bowel Dis 17(12):2488–2496
Glas J, Konrad A, Schmechel S, Dambacher J, Seiderer J, Schroff F et al (2008) The ATG16L1 gene variants rs2241879 and rs2241880 (T300A) are strongly associated with susceptibility to Crohn’s disease in the German population. Am J Gastroenterol 103(3):682–691
Simms LA, Doecke JD, Roberts RL, Fowler EV, Zhao ZZ, McGuckin MA et al (2010) KCNN4 gene variant is associated with ileal Crohn’s Disease in the Australian and New Zealand population. Am J Gastroenterol 105(10):2209–2217
Henckaerts L, Van Steen K, Verstreken I, Cleynen I, Franke A, Schreiber S et al (2009) Genetic risk profiling and prediction of disease course in Crohn’s disease patients. Clin Gastroenterol Hepatol 7(9):972–980, e2
Marrakchi R, Moussa A, Ouerhani S, Bougatef K, Bouhaha R, Messai Y et al (2009) Interleukin 10 promoter region polymorphisms in inflammatory bowel disease in Tunisian population. Inflamm Res 58(3):155–160
Koslowski MJ, Kubler I, Chamaillard M, Schaeffeler E, Reinisch W, Wang G et al (2009) Genetic variants of Wnt transcription factor TCF-4 (TCF7L2) putative promoter region are associated with small intestinal Crohn’s disease. PLoS One 4(2):e4496
Brand S (2012) Homozygosity for the NOD2 p.Leu1007fsX1008 variant is the main genetic predictor for fibrostenotic Crohn’s disease. Inflamm Bowel Dis 18(2):393–394
Ippoliti A, Devlin S, Mei L, Yang H, Papadakis KA, Vasiliauskas EA et al (2010) Combination of innate and adaptive immune alterations increased the likelihood of fibrostenosis in Crohn’s disease. Inflamm Bowel Dis 16(8):1279–1285
Weersma RK, Zhernakova A, Nolte IM, Lefebvre C, Rioux JD, Mulder F et al (2008) ATG16L1 and IL23R are associated with inflammatory bowel diseases but not with celiac disease in the Netherlands. Am J Gastroenterol 103(3):621–627
Seiderer J, Dambacher J, Leistner D, Tillack C, Glas J, Niess JH et al (2008) Genotype-phenotype analysis of the CXCL16 p.Ala181Val polymorphism in inflammatory bowel disease. Clin Immunol 127(1):49–55
Hume GE, Fowler EV, Lincoln D, Eri R, Templeton D, Florin TH et al (2006) Angiotensinogen and transforming growth factor beta1: novel genes in the pathogenesis of Crohn’s disease. J Med Genet 43(10):e51
Eglinton TW, Barclay ML, Gearry RB, Frizelle FA (2012) The spectrum of perianal Crohn’s disease in a population-based cohort. Dis Colon Rectum 55(7):773–777
Sehgal R, Berg A, Polinski JI, Hegarty JP, Lin Z, McKenna KJ et al (2012) Mutations in IRGM are associated with more frequent need for surgery in patients with ileocolonic Crohn’s disease. Dis Colon Rectum 55(2):115–121
Vermeire S, Pierik M, Hlavaty T, Claessens G, van Schuerbeeck N, Joossens S et al (2005) Association of organic cation transporter risk haplotype with perianal penetrating Crohn’s disease but not with susceptibility to IBD. Gastroenterology 129(6):1845–1853
Santana G, Bendicho MT, Santana TC, Reis LB, Lemaire D, Lyra AC (2011) The TNF-alpha -308 polymorphism may affect the severity of Crohn’s disease. Clinics 66(8):1373–1378
Moon CM, Cheon JH, Kim SW, Shin DJ, Kim ES, Shin ES et al (2010) Association of signal transducer and activator of transcription 4 genetic variants with extra-intestinal manifestations in inflammatory bowel disease. Life Sci 86(17–18):661–667
Orchard TR, Chua CN, Ahmad T, Cheng H, Welsh KI, Jewell DP (2002) Uveitis and erythema nodosum in inflammatory bowel disease: clinical features and the role of HLA genes. Gastroenterology 123(3):714–718, Epub 2002/08/29
Ellinghaus E, Stuart PE, Ellinghaus D, Nair RP, Debrus S, Raelson JV et al (2012) Genome-wide meta-analysis of psoriatic arthritis identifies susceptibility locus at REL. J Invest Dermatol 132(4):1133–1140
Parkes J (2011) on behalf of the authors. Validating non-invasive markers of fibrosis: the need for a new histological reference standard—The Authors’ response. Gut
Gelbmann CM, Rogler G, Gierend M, Gross V, Scholmerich J, Andus T (2001) Association of HLA-DR genotypes and IL-1ra gene polymorphism with treatment failure of budesonide and disease patterns in Crohn’s disease. Eur J Gastroenterol Hepatol 13(12):1431–1437
Toedter G, Li K, Marano C, Ma K, Sague S, Huang CC et al (2011) Gene expression profiling and response signatures associated with differential responses to infliximab treatment in ulcerative colitis. Am J Gastroenterol 106(7):1272–1280
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2013 Springer Science+Business Media New York
About this chapter
Cite this chapter
Zhu, X.C., MacDermott, R.P. (2013). A Primer on IBD: Phenotypes, Diagnosis, Treatment, and Clinical Challenges. In: D'Amato, M., Rioux, J. (eds) Molecular Genetics of Inflammatory Bowel Disease. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-8256-7_1
Download citation
DOI: https://doi.org/10.1007/978-1-4614-8256-7_1
Published:
Publisher Name: Springer, New York, NY
Print ISBN: 978-1-4614-8255-0
Online ISBN: 978-1-4614-8256-7
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)