Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

Genetic factors in inflammatory bowel disease

Scott B Snapper, MD, PhD
Dermot P B McGovern, MD, PhD, FRCP(Lon)
Section Editor
Paul Rutgeerts, MD, PhD, FRCP
Deputy Editor
Shilpa Grover, MD, MPH


Inflammatory bowel disease (IBD) is comprised of two major disorders: ulcerative colitis (UC) and Crohn disease (CD) with more than 1.4 million affected people in the United States [1]. These disorders have both distinct and overlapping pathologic and clinical characteristics. (See "Definition, epidemiology, and risk factors in inflammatory bowel disease".)

The pathogenesis of UC and CD are not well understood. The role of genetic factors will be reviewed here. Immune and microbial mechanisms are discussed separately. (See "Immune and microbial mechanisms in the pathogenesis of inflammatory bowel disease".)


There are two issues related to genetic factors in IBD: factors that increase the susceptibility to IBD, which will be reviewed here; and genetic syndromes that are associated with an increased risk of IBD. However, more than 85 percent of patients with Crohn disease (CD) have no family history of IBD [2].

Genetic susceptibility — A number of observations in both humans and animal models suggest that genetically determined factors contribute to IBD susceptibility [3].

 Animal models — The ability to delete or modify genes selectively (such as interleukin [IL]-10) in animal models has contributed to the understanding of the genetic loci that may be involved in IBD pathogenesis [4,5]. These experiments have revealed several important observations:


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Sep 2016. | This topic last updated: Jul 14, 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2016 UpToDate, Inc.
  1. Loftus EV Jr. Clinical epidemiology of inflammatory bowel disease: Incidence, prevalence, and environmental influences. Gastroenterology 2004; 126:1504.
  2. Orholm M, Munkholm P, Langholz E, et al. Familial occurrence of inflammatory bowel disease. N Engl J Med 1991; 324:84.
  3. Satsangi J, Jewell DP, Bell JI. The genetics of inflammatory bowel disease. Gut 1997; 40:572.
  4. Mizoguchi A, Mizoguchi E. Animal models of IBD: linkage to human disease. Curr Opin Pharmacol 2010; 10:578.
  5. Saleh M, Elson CO. Experimental inflammatory bowel disease: insights into the host-microbiota dialog. Immunity 2011; 34:293.
  6. 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.
  7. Thompson NP, Driscoll R, Pounder RE, Wakefield AJ. Genetics versus environment in inflammatory bowel disease: results of a British twin study. BMJ 1996; 312:95.
  8. Orholm M, Binder V, Sørensen TI, et al. Concordance of inflammatory bowel disease among Danish twins. Results of a nationwide study. Scand J Gastroenterol 2000; 35:1075.
  9. Halfvarson J, Bodin L, Tysk C, et al. Inflammatory bowel disease in a Swedish twin cohort: a long-term follow-up of concordance and clinical characteristics. Gastroenterology 2003; 124:1767.
  10. Laharie D, Debeugny S, Peeters M, et al. Inflammatory bowel disease in spouses and their offspring. Gastroenterology 2001; 120:816.
  11. Roth MP, Petersen GM, McElree C, et al. Familial empiric risk estimates of inflammatory bowel disease in Ashkenazi Jews. Gastroenterology 1989; 96:1016.
  12. Monsén U, Broström O, Nordenvall B, et al. Prevalence of inflammatory bowel disease among relatives of patients with ulcerative colitis. Scand J Gastroenterol 1987; 22:214.
  13. Fielding JF. The relative risk of inflammatory bowel disease among parents and siblings of Crohn's disease patients. J Clin Gastroenterol 1986; 8:655.
  14. Yang H, McElree C, Roth MP, et al. Familial empirical risks for inflammatory bowel disease: differences between Jews and non-Jews. Gut 1993; 34:517.
  15. Satsangi J, Grootscholten C, Holt H, Jewell DP. Clinical patterns of familial inflammatory bowel disease. Gut 1996; 38:738.
  16. Bayless TM, Tokayer AZ, Polito JM 2nd, et al. Crohn's disease: concordance for site and clinical type in affected family members--potential hereditary influences. Gastroenterology 1996; 111:573.
  17. Colombel JF, Grandbastien B, Gower-Rousseau C, et al. Clinical characteristics of Crohn's disease in 72 families. Gastroenterology 1996; 111:604.
  18. Polito JM 2nd, Childs B, Mellits ED, et al. Crohn's disease: influence of age at diagnosis on site and clinical type of disease. Gastroenterology 1996; 111:580.
  19. Peeters M, Nevens H, Baert F, et al. Familial aggregation in Crohn's disease: increased age-adjusted risk and concordance in clinical characteristics. Gastroenterology 1996; 111:597.
  20. Henckaerts L, Van Steen K, Verstreken I, et al. Genetic risk profiling and prediction of disease course in Crohn's disease patients. Clin Gastroenterol Hepatol 2009; 7:972.
  21. Annese V, Andreoli A, Astegiano M, et al. Clinical features in familial cases of Crohn's disease and ulcerative colitis in Italy: a GISC study. Italian Study Group for the Disease of Colon and Rectum. Am J Gastroenterol 2001; 96:2939.
  22. Grandbastien B, Peeters M, Franchimont D, et al. Anticipation in familial Crohn's disease. Gut 1998; 42:170.
  23. Lee JC, Lennard-Jones JE. Inflammatory bowel disease in 67 families each with three or more affected first-degree relatives. Gastroenterology 1996; 111:587.
  24. Lee JC, Bridger S, McGregor C, et al. Why children with inflammatory bowel disease are diagnosed at a younger age than their affected parent. Gut 1999; 44:808.
  25. Picco MF, Goodman S, Reed J, Bayless TM. Methodologic pitfalls in the determination of genetic anticipation: the case of Crohn disease. Ann Intern Med 2001; 134:1124.
  26. Abraham C, Cho JH. Inflammatory bowel disease. N Engl J Med 2009; 361:2066.
  27. Kaser A, Zeissig S, Blumberg RS. Inflammatory bowel disease. Annu Rev Immunol 2010; 28:573.
  28. Jostins L, Ripke S, Weersma RK, et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 2012; 491:119.
  29. 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.
  30. Fisher SA, Tremelling M, Anderson CA, et al. Genetic determinants of ulcerative colitis include the ECM1 locus and five loci implicated in Crohn's disease. Nat Genet 2008; 40:710.
  31. Rioux JD, Xavier RJ, Taylor KD, et al. Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nat Genet 2007; 39:596.
  32. Hugot JP, Chamaillard M, Zouali H, et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 2001; 411:599.
  33. Ogura Y, Bonen DK, Inohara N, et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 2001; 411:603.
  34. Cuthbert AP, Fisher SA, Mirza MM, et al. The contribution of NOD2 gene mutations to the risk and site of disease in inflammatory bowel disease. Gastroenterology 2002; 122:867.
  35. Vermeire S, Wild G, Kocher K, et al. CARD15 genetic variation in a Quebec population: prevalence, genotype-phenotype relationship, and haplotype structure. Am J Hum Genet 2002; 71:74.
  36. Hampe J, Grebe J, Nikolaus S, et al. Association of NOD2 (CARD 15) genotype with clinical course of Crohn's disease: a cohort study. Lancet 2002; 359:1661.
  37. Abreu MT, Taylor KD, Lin YC, et al. Mutations in NOD2 are associated with fibrostenosing disease in patients with Crohn's disease. Gastroenterology 2002; 123:679.
  38. Kugathasan S, Collins N, Maresso K, et al. CARD15 gene mutations and risk for early surgery in pediatric-onset Crohn's disease. Clin Gastroenterol Hepatol 2004; 2:1003.
  39. Rioux JD, Silverberg MS, Daly MJ, et al. Genomewide search in Canadian families with inflammatory bowel disease reveals two novel susceptibility loci. Am J Hum Genet 2000; 66:1863.
  40. Rioux JD, Daly MJ, Silverberg MS, et al. Genetic variation in the 5q31 cytokine gene cluster confers susceptibility to Crohn disease. Nat Genet 2001; 29:223.
  41. Kugathasan S, Baldassano RN, Bradfield JP, et al. Loci on 20q13 and 21q22 are associated with pediatric-onset inflammatory bowel disease. Nat Genet 2008; 40:1211.
  42. Glocker EO, Kotlarz D, Boztug K, et al. Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N Engl J Med 2009; 361:2033.
  43. Duerr RH, Taylor KD, Brant SR, et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 2006; 314:1461.
  44. Forcione DG, Sands B, Isselbacher KJ, et al. An increased risk of Crohn's disease in individuals who inherit the HLA class II DRB3*0301 allele. Proc Natl Acad Sci U S A 1996; 93:5094.
  45. Hampe J, Franke A, Rosenstiel P, et al. A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat Genet 2007; 39:207.
  46. Parkes M, Barrett JC, Prescott NJ, et al. Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn's disease susceptibility. Nat Genet 2007; 39:830.
  47. Noble CL, Nimmo ER, Drummond H, et al. The contribution of OCTN1/2 variants within the IBD5 locus to disease susceptibility and severity in Crohn's disease. Gastroenterology 2005; 129:1854.
  48. Franke A, Balschun T, Sina C, et al. Genome-wide association study for ulcerative colitis identifies risk loci at 7q22 and 22q13 (IL17REL). Nat Genet 2010; 42:292.
  49. Franke A, McGovern DP, 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.
  50. Anderson CA, Boucher G, Lees CW, et al. Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nat Genet 2011; 43:246.
  51. Imielinski M, Baldassano RN, Griffiths A, et al. Common variants at five new loci associated with early-onset inflammatory bowel disease. Nat Genet 2009; 41:1335.
  52. Rivas MA, Beaudoin M, Gardet A, et al. Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease. Nat Genet 2011; 43:1066.
  53. McCarroll SA, Huett A, Kuballa P, et al. Deletion polymorphism upstream of IRGM associated with altered IRGM expression and Crohn's disease. Nat Genet 2008; 40:1107.
  54. Cooney R, Baker J, Brain O, et al. NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation. Nat Med 2010; 16:90.
  55. Travassos LH, Carneiro LA, Ramjeet M, et al. Nod1 and Nod2 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry. Nat Immunol 2010; 11:55.
  56. UK IBD Genetics Consortium, Barrett JC, Lee JC, et al. Genome-wide association study of ulcerative colitis identifies three new susceptibility loci, including the HNF4A region. Nat Genet 2009; 41:1330.
  57. Kaser A, Lee AH, Franke A, et al. XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell 2008; 134:743.
  58. VanDussen KL, Liu TC, Li D, et al. Genetic variants synthesize to produce paneth cell phenotypes that define subtypes of Crohn's disease. Gastroenterology 2014; 146:200.
  59. Danzé PM, Colombel JF, Jacquot S, et al. Association of HLA class II genes with susceptibility to Crohn's disease. Gut 1996; 39:69.
  60. Mathew CG, Easton DF, Lennard-Jones JE. HLA and inflammatory bowel disease. Lancet 1996; 348:68.
  61. Reinshagen M, Loeliger C, Kuehnl P, et al. HLA class II gene frequencies in Crohn's disease: a population based analysis in Germany. Gut 1996; 38:538.
  62. 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 1996; 347:1212.
  63. Nakajima A, Matsuhashi N, Kodama T, et al. HLA-linked susceptibility and resistance genes in Crohn's disease. Gastroenterology 1995; 109:1462.
  64. De La Concha EG, Fernandez-Arquero M, Santa-Cruz S, et al. Positive and negative associations of distinct HLA-DR2 subtypes with ulcerative colitis (UC). Clin Exp Immunol 1997; 108:392.
  65. Duerr RH, Neigut DA. Molecularly defined HLA-DR2 alleles in ulcerative colitis and an antineutrophil cytoplasmic antibody-positive subgroup. Gastroenterology 1995; 108:423.
  66. Sugimura K, Asakura H, Mizuki N, et al. Analysis of genes within the HLA region affecting susceptibility to ulcerative colitis. Hum Immunol 1993; 36:112.
  67. Kobayashi K, Atoh M, Konoeda Y, et al. HLA-DR, DQ and T cell antigen receptor constant beta genes in Japanese patients with ulcerative colitis. Clin Exp Immunol 1990; 80:400.
  68. Asakura H, Tsuchiya M, Aiso S, et al. Association of the human lymphocyte-DR2 antigen with Japanese ulcerative colitis. Gastroenterology 1982; 82:413.
  69. Bouma G, Oudkerk Pool M, Crusius JB, et al. Evidence for genetic heterogeneity in inflammatory bowel disease (IBD); HLA genes in the predisposition to suffer from ulcerative colitis (UC) and Crohn's disease (CD). Clin Exp Immunol 1997; 109:175.
  70. Hesresbach D, Alizadeh M, Bretagne JF, et al. Investigation of the association of major histocompatibility complex genes, including HLA class I, class II and TAP genes, with clinical forms of Crohn's disease. Eur J Immunogenet 1996; 23:141.
  71. Smolen JS, Gangl A, Polterauer P, et al. HLA antigens in inflammatory bowel disease. Gastroenterology 1982; 82:34.
  72. Zetterquist H, Broomé U, Einarsson K, Olerup O. HLA class II genes in primary sclerosing cholangitis and chronic inflammatory bowel disease: no HLA-DRw52a association in Swedish patients with sclerosing cholangitis. Gut 1992; 33:942.
  73. Biemond I, Burnham WR, D'Amaro J, Langman MJ. HLA-A and -B antigens in inflammatory bowel disease. Gut 1986; 27:934.
  74. Toyoda H, Wang SJ, Yang HY, et al. Distinct associations of HLA class II genes with inflammatory bowel disease. Gastroenterology 1993; 104:741.
  75. Okada Y, Yamazaki K, Umeno J, et al. HLA-Cw*1202-B*5201-DRB1*1502 haplotype increases risk for ulcerative colitis but reduces risk for Crohn's disease. Gastroenterology 2011; 141:864.
  76. Ballester V, Guo X, Vendrell R, et al. Association of NOD2 and IL23R with inflammatory bowel disease in Puerto Rico. PLoS One 2014; 9:e108204.
  77. Asano K, Matsushita T, Umeno J, et al. A genome-wide association study identifies three new susceptibility loci for ulcerative colitis in the Japanese population. Nat Genet 2009; 41:1325.
  78. Yang SK, Hong M, Choi H, et al. Immunochip analysis identification of 6 additional susceptibility loci for Crohn's disease in Koreans. Inflamm Bowel Dis 2015; 21:1.
  79. Kenny EE, Pe'er I, Karban A, et al. A genome-wide scan of Ashkenazi Jewish Crohn's disease suggests novel susceptibility loci. PLoS Genet 2012; 8:e1002559.
  80. Yang SK, Hong M, Zhao W, et al. Genome-wide association study of Crohn's disease in Koreans revealed three new susceptibility loci and common attributes of genetic susceptibility across ethnic populations. Gut 2014; 63:80.
  81. Inoue N, Tamura K, Kinouchi Y, et al. Lack of common NOD2 variants in Japanese patients with Crohn's disease. Gastroenterology 2002; 123:86.
  82. Uhlig HH, Schwerd T, Koletzko S, et al. The diagnostic approach to monogenic very early onset inflammatory bowel disease. Gastroenterology 2014; 147:990.
  83. Moran CJ, Klein C, Muise AM, Snapper SB. Very early-onset inflammatory bowel disease: gaining insight through focused discovery. Inflamm Bowel Dis 2015; 21:1166.
  84. Price WH. A high incidence of chronic inflammatory bowel disease in patients with Turner's syndrome. J Med Genet 1979; 16:263.
  85. Weinrieb IJ, Fineman RM, Spiro HM. Turner syndrome and inflammatory bowel disease. N Engl J Med 1976; 294:1221.
  86. Hayward PA, Satsangi J, Jewell DP. Inflammatory bowel disease and the X chromosome. QJM 1996; 89:713.
  87. Schinella RA, Greco MA, Cobert BL, et al. Hermansky-Pudlak syndrome with granulomatous colitis. Ann Intern Med 1980; 92:20.
  88. Gahl WA, Brantly M, Kaiser-Kupfer MI, et al. Genetic defects and clinical characteristics of patients with a form of oculocutaneous albinism (Hermansky-Pudlak syndrome). N Engl J Med 1998; 338:1258.
  89. Visser G, Rake JP, Fernandes J, et al. Neutropenia, neutrophil dysfunction, and inflammatory bowel disease in glycogen storage disease type Ib: results of the European Study on Glycogen Storage Disease type I. J Pediatr 2000; 137:187.
  90. Roe TF, Coates TD, Thomas DW, et al. Brief report: treatment of chronic inflammatory bowel disease in glycogen storage disease type Ib with colony-stimulating factors. N Engl J Med 1992; 326:1666.
  91. Vaughan D, Drumm B. Treatment of fistulas with granulocyte colony-stimulating factor in a patient with Crohn's disease. N Engl J Med 1999; 340:239.