Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The genetics and immunopathogenesis of inflammatory bowel disease

Nature Reviews Immunology volume 8, pages 458–466 (2008)Cite this article

Key Points

  • The central challenge of the intestinal immune system is balancing the need to respond to pathogens while co-existing with commensal bacteria and food antigens. Data from genome-wide association (GWA) studies support the concept that dysregulation of the normally controlled immune responses to commensal gut bacteria in a genetically susceptible individual drives the development of inflammatory bowel disease.

  • GWA studies provide a broad view of the relative contributions of various genomic loci to common human diseases and involve genotyping a large number of single-nucleotide polymorphisms (SNPs) that sample human genetic variation throughout the genome.

  • Crohn's disease, but not ulcerative colitis, is associated with functional polymorphisms in the NOD2 (nucleotide-binding oligomerization domain protein 2), ATG16L1 (autophagy related 16-like protein 1) and IRGM (immunity-related GTPase family, M) gene regions. These genes have been implicated in the innate immune system and intracellular processing of bacterial components.

  • Crohn's disease-associated polymorphisms in NOD2 are associated with a decreased ability of the NOD2 protein to appropriately sense bacterial peptidoglycan and activate nuclear factor-κB and mitogen-activated protein kinase pathways. Further studies assessing the altered function of ATG16L1 and IRGM polymorphisms associated with Crohn's disease will be important in establishing the extent to which Crohn's disease occurs as a result of a primary defect in bacterial sensing by the innate immune system.

  • Consistent with previous epidemiological observations, several genes are associated with both Crohn's disease and ulcerative colitis, notably IL23R (encoding interleukin-13 receptor), IL12B (encoding the p40 subunit for IL-12 and IL-23) and STAT3 (encoding signal transducer and activator of transcription 3), all of which are involved in IL-23R signalling. The homeodomain-containing transcription factor NKX2-3 (NK2 transcription factor related, locus 3), which is involved in lymphocyte development, differentiation and organization, is also associated with both Crohn's disease and ulcerative colitis.

  • Within the IL23R gene region, there are multiple independent signals showing association with inflammatory bowel disease and similar patterns of association have been observed in psoriasis and ankylosing spondylitis. The contributions of the IL23R region polymorphisms to intestinal inflammation are complex, reflecting contributions from both the innate and adaptive immune systems.

Abstract

Genome-wide association studies efficiently and powerfully assay common genetic variation. The application of these studies to Crohn's disease has provided insight into the immunopathogenesis of this disease, implicating a role for genes of the innate and adaptive immune systems. In this Review, I discuss our current understanding of the genetics and immunopathogenesis of Crohn's disease and ulcerative colitis. Crohn's disease, but not ulcerative colitis, is associated with genetic variation in NOD2 and an autophagy gene, ATG16L1, both of which affect the intracellular processing of bacterial components. By contrast, variation in the gene encoding the interleukin-23 (IL-23) receptor subunit, as well as in the IL12B, STAT3 and NKX2-3 gene regions, is associated with both Crohn's disease and ulcerative colitis. Comparative analyses of gene associations between these two inflammatory bowel diseases reveal common and unique mechanisms of their immunopathogenesis.

Access through your institution
Buy or subscribe

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

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Key features of the intestinal immune system.
Figure 2: Variation in multiple genes in the IL-23R pathway is associated with Crohn's disease.

Similar content being viewed by others

References

  1. Podolsky, D. K. Inflammatory bowel disease. N. Engl. J. Med. 347, 417–429 (2002).

    Article  CAS  PubMed  Google Scholar 

  2. Loftus, E. V. Jr Clinical epidemiology of inflammatory bowel disease: incidence, prevalence, and environmental influences. Gastroenterology 126, 1504–1517 (2004).

    Article  PubMed  Google Scholar 

  3. Xavier, R. J. & Podolsky, D. K. Unravelling the pathogenesis of inflammatory bowel disease. Nature 448, 427–434 (2007).

    Article  CAS  PubMed  Google Scholar 

  4. Elson, C. O. et al. Experimental models of inflammatory bowel disease reveal innate, adaptive, and regulatory mechanisms of host dialogue with the microbiota. Immunol. Rev. 206, 260–276 (2005).

    Article  PubMed  Google Scholar 

  5. Frazer, K. A. et al. A second generation human haplotype map of over 3.1 million SNPs. Nature 449, 851–861 (2007). Data from the HapMap project provided the basis for the advent of GWA studies.

    Article  CAS  PubMed  Google Scholar 

  6. Wang, W. Y., Barratt, B. J., Clayton, D. G. & Todd, J. A. Genome-wide association studies: theoretical and practical concerns. Nature Rev. Genet. 6, 109–118 (2005).

    Article  CAS  PubMed  Google Scholar 

  7. Hirschhorn, J. N. & Daly, M. J. Genome-wide association studies for common diseases and complex traits. Nature Rev. Genet. 6, 95–108 (2005).

    Article  CAS  PubMed  Google Scholar 

  8. Cho, J. H. & Weaver, C. T. The genetics of inflammatory bowel disease. Gastroenterology 133, 1327–1339 (2007).

    Article  CAS  PubMed  Google Scholar 

  9. Binder, V. Genetic epidemiology in inflammatory bowel disease. Digest. Dis. 16, 351–355 (1998).

    Article  CAS  Google Scholar 

  10. Fisher, S. A. et al. Genetic determinants of ulcerative colitis include the ECM1 locus and five loci implicated in Crohn's disease. Nature Genet. 27 April 2008 (doi:10.1038/ng.145).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Franke, A. et al. Replication of signals from recent studies of Crohn's disease identifies previously unknown disease loci for ulcerative colitis. Nature Genet. 27 April 2008 (doi:10.1038/ng.148). Together with reference 10, this study identifies an overlap between susceptibility loci in Crohn's disease and ulcerative colitis.

    Article  CAS  PubMed  Google Scholar 

  12. The Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678 (2007). A landmark article defining the GWAs for seven common diseases, including Crohn's disease.

  13. Tarlinton, D., Light, A., Metcalf, D., Harvey, R. P. & Robb, L. Architectural defects in the spleens of Nkx2-3-deficient mice are intrinsic and associated with defects in both B cell maturation and T cell-dependent immune responses. J. Immunol. 170, 4002–4010 (2003).

    Article  CAS  PubMed  Google Scholar 

  14. Hugot, J. P. et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 411, 599–603 (2001).

    Article  CAS  PubMed  Google Scholar 

  15. Ogura, Y. et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 411, 603–606 (2001).

    Article  CAS  PubMed  Google Scholar 

  16. Girardin, S. E. et al. Peptidoglycan molecular requirements allowing detection by Nod1 and Nod2. J. Biol. Chem. 278, 41702–41708 (2003).

    Article  CAS  PubMed  Google Scholar 

  17. Inohara, N. et al. Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Crohn's disease. J. Biol. Chem. 278, 5509–5512 (2003).

    Article  CAS  PubMed  Google Scholar 

  18. Kobayashi, K. S. et al. Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science 307, 731–734 (2005).

    Article  CAS  PubMed  Google Scholar 

  19. Croucher, P. J. et al. Haplotype structure and association to Crohn's disease of CARD15 mutations in two ethnically divergent populations. Eur. J. Hum. Genet. 11, 6–16 (2003).

    Article  CAS  PubMed  Google Scholar 

  20. Leong, R. W. et al. NOD2/CARD15 gene polymorphisms and Crohn's disease in the Chinese population. Aliment Pharmacol. Ther. 17, 1465–1470 (2003).

    Article  CAS  PubMed  Google Scholar 

  21. Yamazaki, K., Takazoe, M., Tanaka, T., Kazumori, T. & Nakamura, Y. Absence of mutation in the NOD2/CARD15 gene among 483 Japanese patients with Crohn's disease. J. Hum. Genet. 47, 469–472 (2002).

    Article  CAS  PubMed  Google Scholar 

  22. Kugathasan, S. et al. Comparative phenotypic and CARD15 mutational analysis among African American, Hispanic, and White children with Crohn's disease. Inflamm. Bowel Dis. 11, 631–638 (2005).

    Article  PubMed  Google Scholar 

  23. Economou, M., Trikalinos, T. A., Loizou, K. T., Tsianos, E. V. & Ioannidis, J. P. Differential effects of NOD2 variants on Crohn's disease risk and phenotype in diverse populations: a metaanalysis. Am. J. Gastroenterol. 99, 2393–2404 (2004).

    Article  CAS  PubMed  Google Scholar 

  24. Abraham, C. & Cho, J. H. Functional consequences of NOD2 (CARD15) mutations. Inflamm. Bowel Dis. 12, 641–650 (2006).

    Article  PubMed  Google Scholar 

  25. Hugot, J. P. et al. Prevalence of CARD15/NOD2 mutations in caucasian healthy people. Am. J. Gastroenterol. 102, 1259–1267 (2007).

    Article  CAS  PubMed  Google Scholar 

  26. Pauleau, A. L. & Murray, P. J. Role of nod2 in the response of macrophages to Toll-like receptor agonists. Mol. Cell Biol. 23, 7531–7539 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Schreiber, S., Nikolaus, S. & Hampe, J. Activation of nuclear factor κB inflammatory bowel disease. Gut 42, 477–484 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Hedl, M., Li, J., Cho, J. H. & Abraham, C. Chronic stimulation of Nod2 mediates tolerance to bacterial products. Proc. Natl Acad. Sci. USA 104, 19440–19445 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Watanabe, T. et al. Muramyl dipeptide activation of nucleotide-binding oligomerization domain 2 protects mice from experimental colitis. J. Clin. Invest. 118, 545–559 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Hisamatsu, T. et al. CARD15/NOD2 functions as an anti-bacterial factor in human intestinal epithelial cells. Gastroenterology 124, 993–1000 (2003).

    Article  CAS  PubMed  Google Scholar 

  31. Kim, Y. G. et al. The cytosolic sensors Nod1 and Nod2 are critical for bacterial recognition and host defense after exposure to Toll-like receptor ligands. Immunity 28, 246–257 (2008).

    Article  CAS  PubMed  Google Scholar 

  32. Wehkamp, J. et al. Reduced Paneth cell α-defensins in ileal Crohn's disease. Proc. Natl Acad. Sci. USA 102, 18129–18134 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Darfeuille-Michaud, A. et al. High prevalence of adherent-invasive Escherichia coli associated with ileal mucosa in Crohn's disease. Gastroenterology 127, 412–421 (2004).

    Article  PubMed  Google Scholar 

  34. Simms, L. A. et al. Reduced α-defensin expression is associated with inflammation and not NOD2 mutation status in ileal Crohn's disease. Gut 27 February 2008 (doi:10.1136/gut.2007.142588).

    Article  CAS  PubMed  Google Scholar 

  35. Hampe, J. et al. A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nature Genet. 39, 207–211 (2007).

    Article  CAS  PubMed  Google Scholar 

  36. Mizushima, N. et al. Mouse Apg16L, a novel WD-repeat protein, targets to the autophagic isolation membrane with the Apg12–Apg5 conjugate. J. Cell Sci. 116, 1679–1688 (2003).

    Article  CAS  PubMed  Google Scholar 

  37. Rioux, J. D. et al. Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nature Genet. 39, 596–604 (2007).

    Article  CAS  PubMed  Google Scholar 

  38. Levine, B. & Deretic, V. Unveiling the roles of autophagy in innate and adaptive immunity. Nature Rev. Immunol. 7, 767–777 (2007).

    Article  CAS  Google Scholar 

  39. Amano, A., Nakagawa, I. & Yoshimori, T. Autophagy in innate immunity against intracellular bacteria. J. Biochem. 140, 161–166 (2006).

    Article  CAS  PubMed  Google Scholar 

  40. Parkes, M. et al. Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn's disease susceptibility. Nature Genet. 39, 830–832 (2007).

    Article  CAS  PubMed  Google Scholar 

  41. Collazo, C. M. et al. Inactivation of LRG-47 and IRG-47 reveals a family of interferon γ-inducible genes with essential, pathogen-specific roles in resistance to infection. J. Exp. Med. 194, 181–188 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Singh, S. B., Davis, A. S., Taylor, G. A. & Deretic, V. Human IRGM induces autophagy to eliminate intracellular mycobacteria. Science 313, 1438–1441 (2006).

    CAS  PubMed  Google Scholar 

  43. Fuss, I. J. et al. Disparate CD4+ lamina propria (LP) lymphokine secretion profiles in inflammatory bowel disease. Crohn's disease LP cells manifest increased secretion of IFN-γ, whereas ulcerative colitis LP cells manifest increased secretion of IL-5. J. Immunol. 157, 1261–1270 (1996). A seminal article describing the distinct cytokine profiles that distinguish Crohn's disease from ulcerative colitis.

    CAS  PubMed  Google Scholar 

  44. Plevy, S. E. et al. A role for TNF-α and mucosal T helper-1 cytokines in the pathogenesis of Crohn's disease. J. Immunol. 159, 6276–6282 (1997).

    CAS  PubMed  Google Scholar 

  45. Duerr, R. H. et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314, 1461–3 (2006). Initial description of association of variants in IL23R with a common, complex inflammatory disorder.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Cargill, M. et al. A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. Am. J. Hum. Genet. 80, 273–290 (2007).

    Article  CAS  PubMed  Google Scholar 

  47. Burton, P. R. et al. Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nature Genet. 39, 1329–1337 (2007).

    Article  CAS  PubMed  Google Scholar 

  48. Fujino, S. et al. Increased expression of interleukin 17 in inflammatory bowel disease. Gut 52, 65–70 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Parham, C. et al. A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rβ1 and a novel cytokine receptor subunit, IL-23R. J. Immunol. 168, 5699–5708 (2002). A seminal article identifying IL23R , its expression, its signalling pathway and its relationship to IL-12R signalling pathways.

    Article  CAS  PubMed  Google Scholar 

  50. Mangan, P. R. et al. Transforming growth factor-β induces development of the TH17 lineage. Nature 441, 231–234 (2006).

    Article  CAS  PubMed  Google Scholar 

  51. Palmer, M. T. & Weaver, C. T. Immunology: narcissistic helpers. Nature 448, 416–418 (2007).

    Article  CAS  PubMed  Google Scholar 

  52. Ivanov, I. I. et al. The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126, 1121–1133 (2006).

    Article  CAS  PubMed  Google Scholar 

  53. Bettelli, E. et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441, 235–238 (2006).

    Article  CAS  PubMed  Google Scholar 

  54. Veldhoen, M., Hocking, R. J., Atkins, C. J., Locksley, R. M. & Stockinger, B. TGFβ in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24, 179–189 (2006).

    Article  CAS  PubMed  Google Scholar 

  55. Wiekowski, M. T. et al. Ubiquitous transgenic expression of the IL-23 subunit p19 induces multiorgan inflammation, runting, infertility, and premature death. J. Immunol. 166, 7563–7570 (2001).

    Article  CAS  PubMed  Google Scholar 

  56. Elson, C. O. et al. Monoclonal anti-interleukin 23 reverses active colitis in a T cell-mediated model in mice. Gastroenterology 132, 2359–2370 (2007).

    Article  CAS  PubMed  Google Scholar 

  57. Hue, S. et al. Interleukin-23 drives innate and T cell-mediated intestinal inflammation. J. Exp. Med. 203, 2473–2483 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Kullberg, M. C. et al. IL-23 plays a key role in Helicobacter hepaticus-induced T cell-dependent colitis. J. Exp. Med. 203, 2485–2494 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Uhlig, H. H. et al. Differential activity of IL-12 and IL-23 in mucosal and systemic innate immune pathology. Immunity 25, 309–318 (2006).

    Article  CAS  PubMed  Google Scholar 

  60. Yen, D. et al. IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. J. Clin. Invest. 116, 1310–1316 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Mannon, P. J. et al. Anti-interleukin-12 antibody for active Crohn's disease. N. Engl. J. Med. 351, 2069–2079 (2004).

    Article  CAS  PubMed  Google Scholar 

  62. Watford, W. T. et al. Signaling by IL-12 and IL-23 and the immunoregulatory roles of STAT4. Immunol. Rev. 202, 139–156 (2004).

    Article  CAS  PubMed  Google Scholar 

  63. Laurence, A. et al. Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity 26, 371–381 (2007).

    Article  CAS  PubMed  Google Scholar 

  64. Zhou, L. et al. IL-6 programs TH-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nature Immunol. 8, 967–974 (2007).

    Article  CAS  Google Scholar 

  65. Barrett, J. C. et al. Genome-wide association defines more than thirty distinct susceptibility loci for Crohn's disease. Nature Genet. (in the press).

  66. Fuss, I. J. et al. Both IL-12p70 and IL-23 are synthesized during active Crohn's disease and are down-regulated by treatment with anti-IL-12 p40 monoclonal antibody. Inflamm. Bowel Dis. 12, 9–15 (2006).

    Article  PubMed  Google Scholar 

  67. Schmidt, C. et al. Expression of interleukin-12-related cytokine transcripts in inflammatory bowel disease: elevated interleukin-23p19 and interleukin-27p28 in Crohn's disease but not in ulcerative colitis. Inflamm. Bowel Dis. 11, 16–23 (2005).

    Article  PubMed  Google Scholar 

  68. Stallmach, A. et al. Cytokine/chemokine transcript profiles reflect mucosal inflammation in Crohn's disease. Int. J. Colorectal Dis. 19, 308–315 (2004).

    Article  PubMed  Google Scholar 

  69. Takeda, K. et al. Enhanced Th1 activity and development of chronic enterocolitis in mice devoid of Stat3 in macrophages and neutrophils. Immunity 10, 39–49 (1999).

    Article  CAS  PubMed  Google Scholar 

  70. Wolk, K. et al. IL-22 induces lipopolysaccharide-binding protein in hepatocytes: a potential systemic role of IL-22 in Crohn's disease. J. Immunol. 178, 5973–5981 (2007).

    Article  CAS  PubMed  Google Scholar 

  71. Sugimoto, K. et al. IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis. J. Clin. Invest. 118, 534–544 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Becker, C. et al. Cutting Edge: IL-23 cross-regulates IL-12 production in T cell-dependent experimental colitis. J. Immunol. 177, 2760–2764 (2006).

    Article  CAS  PubMed  Google Scholar 

  73. Wilson, N. J. et al. Development, cytokine profile and function of human interleukin 17-producing helper T cells. Nature Immunol. 8, 950–957 (2007).

    Article  CAS  Google Scholar 

  74. Silverberg, M. S. et al. Refined genomic localization and ethnic differences observed for the IBD5 association with Crohn's disease. Eur. J. Hum. Genet. 15, 328–335 (2007).

    Article  CAS  PubMed  Google Scholar 

  75. Libioulle, C. et al. A novel susceptibility locus for Crohn's disease identified by whole genome association maps to a gene desert on chromosome 5p13.1 and modulates the level of expression of the prostaglandin receptor EP4. PLoS Genet. 3, e58 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Kabashima, K. et al. The prostaglandin receptor EP4 suppresses colitis, mucosal damage and CD4 cell activation in the gut. J. Clin. Invest. 109, 883–893 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Peltekova, V. D. et al. Functional variants of OCTN cation transporter genes are associated with Crohn disease. Nature Genet. 36, 471–475 (2004).

    Article  CAS  PubMed  Google Scholar 

  78. Altshuler, D. et al. The common PPARγ Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nature Genet. 26, 76–80 (2000).

    Article  CAS  PubMed  Google Scholar 

  79. Kontoyiannis, D., Pasparakis, M., Pizarro, T. T., Cominelli, F. & Kollias, G. Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: implications for joint and gut-associated immunopathologies. Immunity 10, 387–398 (1999).

    Article  CAS  PubMed  Google Scholar 

  80. Remmers, E. F. et al. STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N. Engl. J. Med. 357, 977–986 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Lowe, C. E. et al. Large-scale genetic fine mapping and genotype-phenotype associations implicate polymorphism in the IL2RA region in type 1 diabetes. Nature Genet. 39, 1074–82 (2007).

    Article  CAS  PubMed  Google Scholar 

  82. Hafler, D. A. et al. Risk alleles for multiple sclerosis identified by a genomewide study. N. Engl. J. Med. 357, 851–862 (2007).

    Article  CAS  PubMed  Google Scholar 

  83. Loftus, E. V. Jr et al. Crohn's disease in Olmsted County, Minnesota, 1940–1993: incidence, prevalence, and survival. Gastroenterology 114, 1161–1168 (1998).

    Article  PubMed  Google Scholar 

  84. Loftus, E. V. Jr et al. Ulcerative colitis in Olmsted County, Minnesota, 1940–1993: incidence, prevalence, and survival. Gut 46, 336–343 (2000).

    Article  PubMed  PubMed Central  Google Scholar 

  85. Bernstein, C. N., Blanchard, J. F., Rawsthorne, P. & Wajda, A. Epidemiology of Crohn's disease and ulcerative colitis in a central Canadian province: a population-based study. Am. J. Epidemiol. 149, 916–924 (1999).

    Article  CAS  PubMed  Google Scholar 

  86. Sandler, R. S. in Inflammatory bowel disease: from bench to bedside (eds Targan, S. R. & Shanahan, F.) 5–30 (Williams and Wilkins, Baltimore, 1994).

    Google Scholar 

  87. Calkins, B. M. & Mendelhoff, A. I. in Inflammatory Bowel Disease (eds Kirsner, J. B. & Shorter, R. G.) 31–68 (Williams & Wilkins, Baltimore, 1995).

    Google Scholar 

  88. Yang, H. & Rotter, J. I. in Inflammatory bowel disease: from bench to bedside (eds Targan, S. R. & Shanahan, F.) 32–64 (Williams and Wilkins, Baltimore, 1994).

    Google Scholar 

  89. Ogunbi, S. O., Ransom, J. A., Sullivan, K., Schoen, B. T. & Gold, B. D. Inflammatory bowel disease in African-American children living in Georgia. J. Pediatr. 133, 103–107 (1998).

    Article  CAS  PubMed  Google Scholar 

  90. Binder, V. Genetic epidemiology in inflammatory bowel disease. Digest. Dis. 16, 351–355 (1998).

    Article  CAS  Google Scholar 

  91. Yang, H. & Rotter, J. I. in Inflammatory Bowel Disease (eds Kirsner, J. B. & Shorter, R. G.) 301–331 (Williams & Wilkins, Baltimore, 1995).

    Google Scholar 

  92. Tysk, C., Lindberg, E., Jarnerot, G. & Floderus-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 29, 990–996 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Halfvarson, J., Bodin, L., Tysk, C., Lindberg, E. & Jarnerot, G. Inflammatory bowel disease in a Swedish twin cohort: a long-term follow-up of concordance and clinical characteristics. Gastroenterology 124, 1767–1773 (2003).

    Article  PubMed  Google Scholar 

  94. Thompson, N. P., Driscoll, R., Pounder, R. E. & Wakefield, A. J. Genetics versus environment in inflammatory bowel disease: results of a British twin study. BMJ 312, 95–96 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Orholm, M., Binder, V., Sorensen, T. I., Rasmussen, L. P. & Kyvik, K. O. Concordance of inflammatory bowel disease among Danish twins. Results of a nationwide study. Scand. J. Gastroenterol. 35, 1075–1081 (2000).

    Article  CAS  PubMed  Google Scholar 

  96. Gent, A. E., Hellier, M. D., Grace, R. H., Swarbrick, E. T. & Coggon, D. Inflammatory bowel disease and domestic hygiene in infancy. Lancet 343, 766–767 (1994).

    Article  CAS  PubMed  Google Scholar 

  97. Boyko, E. J., Koepsell, T. D., Perera, D. R. & Inui, T. S. Risk of ulcerative colitis among former and current cigarette smokers. N. Engl. J. Med. 316, 707–710 (1987).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The support of NIDDK (U01 DK62429, U01 DK62422, R01 DK072373), the Burroughs Wellcome Foundation, CCFA, Broad Medical Research Foundation and the CTSA are gratefully acknowledged.

Author information

Authors and Affiliations

  1. Inflammatory Bowel Disease Center, Section of Digestive Diseases, Yale University, 333 Cedar Street, LMP 1080, New Haven, 06520, Connecticut, USA

    Judy H. Cho

Authors
  1. Judy H. Cho
    View author publications

    You can also search for this author inPubMed Google Scholar

Related links

Related links

FURTHER INFORMATION

Judy Cho's homepage

Glossary

Arthalgias

Pain in the joints that may or may not be associated with inflammatory changes.

Gut lamina propria

The layer of mucosal tissue directly under the mucosal epithelial-cell surface of the gastrointestinal tract, in which effector immune cells for mucosal immunity reside.

Goblet cells

Mucus-producing cells found in the epithelial-cell lining of the intestine and lungs.

Crypts

Tubular invaginations of the intestinal epithelium. At the base of the crypts, there are Paneth cells, which produce bactericidal defensins, and stem cells, which continuously divide and are the source of all intestinal epithelial cells.

Defensins

A family of proteins exhibiting bactericidal properties. They are secreted by immune cells (particularly neutrophils), intestinal Paneth cells and epithelial cells.

Single-nucleotide polymorphisms

(SNPs). Bi-allelic (typically) base-pair substitutions, which are the most common forms of genetic polymorphism.

HapMap

A catalogue of common genetic variants that occur in humans. It describes what these variants are, where they occur in our DNA, and how they are distributed among people within populations and among populations in different parts of the world.

Minor allele frequency

The allelic frequency of the less common of the two alleles. Most single base-pair substitutions have only two alleles (bi-allelic).

Causal variant

A genetic polymorphism that directly exerts an effect on protein function and/or expression that is believed to underlie the observed statistical association.

Concordance

The occurrence of the same trait in both members of a pair of twins. Concordance might occur for diseases as well as for behaviours, such as smoking.

Autophagy

Any process involving degradative delivery of a portion of the cytoplasm to the lysosome that does not involve direct transport through the endocytic or vacuolar protein sorting pathways.

Meta-analysis

A statistical approach that combines results from multiple related studies to define a composite effect. When applied to genome-wide association studies, increased power to identify more modest association effects accrue.

Odds ratio

A measurement of association that is commonly used in case-control studies. It is defined as the odds of exposure to the susceptible genetic variant in individuals with disease compared with that in controls. If the odds ratio is significantly greater than one, then the genetic variant is associated with the disease.

Compound heterozygous

Two distinct, recessive alleles that combine to exert effects similar to a homozygous recessive mutation state.

Hygiene hypothesis

The theory that the lack of early childhood exposure to infectious agents, symbiotic microorganisms (for example, changes in gut microflora) and parasites increases susceptibility to allergic and autoimmune diseases by modulating immune system development.

Haplotype block

A chromosomal region in which groups of alleles at different genetic loci are inherited together more often than expected by chance.

Linkage disequilibrium

The non-random association of alleles from two independent loci, owing to their close physical proximity and a lack of recombination between them.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cho, J. The genetics and immunopathogenesis of inflammatory bowel disease. Nat Rev Immunol 8, 458–466 (2008). https://doi.org/10.1038/nri2340

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri2340

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing