The Genetics of Inflammatory Bowel Disease

Chapter
First Online:

Abstract

Through rapid advances, genome-wide association studies (GWAS) have identified almost 100 susceptibility genes which confer an increased risk of developing inflammatory bowel disorders (IBD). This review focuses on recent advances in our understanding of the genetics of IBD. We discuss the role of key loci or genes in IBD pathophysiology. Some of the genes implicated have highlighted key pathways including bacterial recognition (NOD2), autophagy (ATG16L1, IRGM) in Crohn’s disease. Other loci including CDH, HNF4A, LAMB1, and ECM1 are significantly associated with ulcerative colitis (UC) and have been linked to modulating epithelial barrier function. Nearly one-third of the described loci or genes are common to both Crohn’s disease and ulcerative colitis. Several of these are involved in the IL23 signaling pathway (IL23R, IL12B, JAK2, and STAT3). These findings highlight the importance of genetic variability and its interactions with the immune system, gut microbiota, and environmental factors in determining pathogenesis of IBD.

Keywords

Crohn’s disease Ulcerative colitis Interleukin 23 Autophagy Innate immunity Epithelial defense Intestinal microbiome 
This is a preview of subscription content, log in to check access.

References

  1. 1.
    Kugathasan S, Judd RH, Hoffmann RG, et al. Epidemiologic and clinical characteristics of children with newly diagnosed inflammatory bowel disease in Wisconsin: a statewide population-based study. J Pediatr. 2003;143(4):525–31.PubMedCrossRefGoogle Scholar
  2. 2.
    Cho JH. The genetics and immunopathogenesis of inflammatory bowel disease. Nat Rev Immunol. 2008;8(6):458–66.PubMedCrossRefGoogle Scholar
  3. 3.
    Korn T, Bettelli E, Oukka M, Kuchroo VK. IL-17 and Th17 cells. Annu Rev Immunol. 2009;27:485–517.PubMedCrossRefGoogle Scholar
  4. 4.
    Kappelman MD, Rifas-Shiman SL, Porter CQ, et al. Direct health care costs of Crohn’s disease and ulcerative colitis in US children and adults. Gastroenterology. 2008;135(6):1907–13.PubMedCrossRefGoogle Scholar
  5. 5.
    Shanahan F, Bernstein CN. The evolving epidemiology of inflammatory bowel disease. Curr Opin Gastroenterol. 2009;25(4):301–5.PubMedCrossRefGoogle Scholar
  6. 6.
    Benchimol EI, Fortinsky KJ, Gozdyra P, Van den Heuvel M, Van Limbergen J, Griffiths AM. Epidemiology of pediatric inflammatory bowel disease: a systematic review of international trends. Inflamm Bowel Dis. 2011;17(1):423–39.PubMedCrossRefGoogle Scholar
  7. 7.
    Sewell JL, Inadomi JM, Yee Jr HF. Race and inflammatory bowel disease in an urban healthcare system. Dig Dis Sci. 2010;55(12):3479–87.PubMedCrossRefGoogle Scholar
  8. 8.
    Bernstein CN. Epidemiologic clues to inflammatory bowel disease. Curr Gastroenterol Rep. 2010;12(6):495–501.PubMedCrossRefGoogle Scholar
  9. 9.
    Okada H, Kuhn C, Feillet H, Bach JF. The ‘hygiene hypothesis’ for autoimmune and allergic diseases: an update. Clin Exp Immunol. 2010;160(1):1–9.PubMedCrossRefGoogle Scholar
  10. 10.
    Fumagalli M, Pozzoli U, Cagliani R, et al. Parasites represent a major selective force for interleukin genes and shape the genetic predisposition to autoimmune conditions. J Exp Med. 2009;206(6):1395–408.PubMedCrossRefGoogle Scholar
  11. 11.
    Tlaskalova-Hogenova H, Stepankova R, Hudcovic T, et al. Commensal bacteria (normal microflora), mucosal immunity and chronic inflammatory and autoimmune diseases. Immunol Lett. 2004;93(2–3):97–108.PubMedCrossRefGoogle Scholar
  12. 12.
    Ley RE, Lozupone CA, Hamady M, Knight R, Gordon JI. Worlds within worlds: evolution of the vertebrate gut microbiota. Nat Rev Microbiol. 2008;6(10):776–88.PubMedCrossRefGoogle Scholar
  13. 13.
    Hansen J, Gulati A, Sartor RB. The role of mucosal immunity and host genetics in defining intestinal commensal bacteria. Curr Opin Gastroenterol. 2010;26(6):564–71.PubMedCrossRefGoogle Scholar
  14. 14.
    Lee YK, Mazmanian SK. Has the microbiota played a critical role in the evolution of the adaptive immune ­system? Science. 2010;330(6012):1768–73.PubMedCrossRefGoogle Scholar
  15. 15.
    Walker AW, Sanderson JD, Churcher C, et al. High-throughput clone library analysis of the mucosa-associated microbiota reveals dysbiosis and differences between inflamed and non-inflamed regions of the intestine in inflammatory bowel disease. BMC Microbiol. 2011;11(1):7.PubMedCrossRefGoogle Scholar
  16. 16.
    Frank DN, St Amand AL, Feldman RA, Boedeker EC, Harpaz N, Pace NR. Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proc Natl Acad Sci USA. 2007;104(34):13780–5.PubMedCrossRefGoogle Scholar
  17. 17.
    Sokol H, Seksik P, Furet JP, et al. Low counts of Faecalibacterium prausnitzii in colitis microbiota. Inflamm Bowel Dis. 2009;15(8):1183–9.PubMedCrossRefGoogle Scholar
  18. 18.
    Barnich N, Carvalho FA, Glasser AL, et al. CEACAM6 acts as a receptor for adherent-invasive E. coli, supporting ileal mucosa colonization in Crohn disease. J Clin Invest. 2007;117(6):1566–74.PubMedCrossRefGoogle Scholar
  19. 19.
    Jick H, Walker AM. Cigarette smoking and ulcerative colitis. N Engl J Med. 1983;308(5):261–3.PubMedCrossRefGoogle Scholar
  20. 20.
    Tobin MV, Logan RF, Langman MJ, McConnell RB, Gilmore IT. Cigarette smoking and inflammatory bowel disease. Gastroenterology. 1987;93(2):316–21.PubMedGoogle Scholar
  21. 21.
    van der Heide F, Dijkstra A, Weersma RK, et al. Effects of active and passive smoking on disease course of Crohn’s disease and ulcerative colitis. Inflamm Bowel Dis. 2009;15(8):1199–207.PubMedCrossRefGoogle Scholar
  22. 22.
    Lindberg E, Jarnerot G, Huitfeldt B. Smoking in Crohn’s disease: effect on localisation and clinical course. Gut. 1992;33(6):779–82.PubMedCrossRefGoogle Scholar
  23. 23.
    Cosnes J, Carbonnel F, Carrat F, Beaugerie L, Cattan S, Gendre J. Effects of current and former cigarette smoking on the clinical course of Crohn’s disease. Aliment Pharmacol Ther. 1999;13(11):1403–11.PubMedCrossRefGoogle Scholar
  24. 24.
    Odes HS, Fich A, Reif S, et al. Effects of current cigarette smoking on clinical course of Crohn’s disease and ulcerative colitis. Dig Dis Sci. 2001;46(8):1717–21.PubMedCrossRefGoogle Scholar
  25. 25.
    Barclay AR, Russell RK, Wilson ML, Gilmour WH, Satsangi J, Wilson DC. Systematic review: the role of breastfeeding in the development of pediatric inflammatory bowel disease. J Pediatr. 2009;155(3):421–6.PubMedCrossRefGoogle Scholar
  26. 26.
    Shaw SY, Blanchard JF, Bernstein CN. Association between the use of antibiotics in the first year of life and pediatric inflammatory bowel disease. Am J Gastroenterol. 2010;105(12):2687–92.PubMedCrossRefGoogle Scholar
  27. 27.
    Jantchou P, Morois S, Clavel-Chapelon F, Boutron-Ruault MC, Carbonnel F. Animal protein intake and risk of inflammatory bowel disease: The E3N prospective study. Am J Gastroenterol. 2010;105(10):2195–201.PubMedCrossRefGoogle Scholar
  28. 28.
    Orholm M, Munkholm P, Langholz E, Nielsen OH, Sorensen TI, Binder V. Familial occurrence of inflammatory bowel disease. N Engl J Med. 1991;324(2):84–8.PubMedCrossRefGoogle Scholar
  29. 29.
    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. 1988;29(7):990–6.PubMedCrossRefGoogle Scholar
  30. 30.
    Thompson NP, Driscoll R, Pounder RE, Wakefield AJ. Genetics versus environment in inflammatory bowel disease: results of a British twin study. BMJ. 1996;312(7023):95–6.PubMedCrossRefGoogle Scholar
  31. 31.
    Jess T, Riis L, Jespersgaard C, et al. Disease concordance, zygosity, and NOD2/CARD15 status: follow-up of a population-based cohort of Danish twins with inflammatory bowel disease. Am J Gastroenterol. 2005;100(11):2486–92.PubMedCrossRefGoogle Scholar
  32. 32.
    Halfvarson J, Jess T, Magnuson A, et al. Environmental factors in inflammatory bowel disease: a co-twin control study of a Swedish-Danish twin population. Inflamm Bowel Dis. 2006;12(10):925–33.PubMedCrossRefGoogle Scholar
  33. 33.
    Spehlmann ME, Begun AZ, Burghardt J, Lepage P, Raedler A, Schreiber S. Epidemiology of inflammatory bowel disease in a German twin cohort: results of a nationwide study. Inflamm Bowel Dis. 2008;14(7):968–76.PubMedCrossRefGoogle Scholar
  34. 34.
    Halfvarson J. Genetics in twins with Crohn’s disease: Less pronounced than previously believed? Inflamm Bowel Dis. 2010. doi: 10.1002/ibd.21295.
  35. 35.
    Binder V. Genetic epidemiology in inflammatory bowel disease. Dig Dis. 1998;16(6):351–5.PubMedCrossRefGoogle Scholar
  36. 36.
    Hugot JP, Chamaillard M, Zouali H, et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature. 2001;411(6837):599–603.PubMedCrossRefGoogle Scholar
  37. 37.
    Ogura Y, Bonen DK, Inohara N, et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature. 2001;411(6837):603–6.PubMedCrossRefGoogle Scholar
  38. 38.
    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(3):246–52.PubMedCrossRefGoogle Scholar
  39. 39.
    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(12):1118–25.PubMedCrossRefGoogle Scholar
  40. 40.
    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(8):955–62.PubMedCrossRefGoogle Scholar
  41. 41.
    Girardin SE, Boneca IG, Viala J, et al. Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection. J Biol Chem. 2003;278(11):8869–72.PubMedCrossRefGoogle Scholar
  42. 42.
    Inohara N, Ogura Y, Fontalba A, et al. Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Crohn’s disease. J Biol Chem. 2003;278(8):5509–12.PubMedCrossRefGoogle Scholar
  43. 43.
    Kobayashi KS, Chamaillard M, Ogura Y, et al. Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science. 2005;307(5710):731–4.PubMedCrossRefGoogle Scholar
  44. 44.
    Economou M, Trikalinos TA, Loizou KT, Tsianos EV, Ioannidis JP. Differential effects of NOD2 variants on Crohn’s disease risk and phenotype in diverse populations: a metaanalysis. Am J Gastroenterol. 2004;99(12):2393–404.PubMedCrossRefGoogle Scholar
  45. 45.
    Bonen DK, Ogura Y, Nicolae DL, et al. Crohn’s disease-associated NOD2 variants share a signaling defect in response to lipopolysaccharide and peptidoglycan. Gastroenterology. 2003;124(1):140–6.PubMedCrossRefGoogle Scholar
  46. 46.
    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. 2002;47(9):469–72.PubMedCrossRefGoogle Scholar
  47. 47.
    Croucher PJ, Mascheretti S, Hampe J, et al. Haplotype structure and association to Crohn’s disease of CARD15 mutations in two ethnically divergent populations. Eur J Hum Genet. 2003;11(1):6–16.PubMedCrossRefGoogle Scholar
  48. 48.
    Leong RW, Armuzzi A, Ahmad T, et al. NOD2/CARD15 gene polymorphisms and Crohn’s disease in the Chinese population. Aliment Pharmacol Ther. 2003;17(12):1465–70.PubMedCrossRefGoogle Scholar
  49. 49.
    Kugathasan S, Loizides A, Babusukumar U, et al. Comparative phenotypic and CARD15 mutational analysis among African American, Hispanic, and White children with Crohn’s disease. Inflamm Bowel Dis. 2005;11(7):631–8.PubMedCrossRefGoogle Scholar
  50. 50.
    Arnott ID, Nimmo ER, Drummond HE, et al. NOD2/CARD15, TLR4 and CD14 mutations in Scottish and Irish Crohn’s disease patients: evidence for genetic heterogeneity within Europe? Genes Immun. 2004;5(5):417–25.PubMedCrossRefGoogle Scholar
  51. 51.
    Coulombe F, Divangahi M, Veyrier F, et al. Increased NOD2-mediated recognition of N-glycolyl muramyl dipeptide. J Exp Med. 2009;206(8):1709–16.PubMedCrossRefGoogle Scholar
  52. 52.
    Zhang FR, Huang W, Chen SM, et al. Genomewide association study of leprosy. N Engl J Med. 2009;361(27):2609–18.PubMedCrossRefGoogle Scholar
  53. 53.
    Yamazaki K, McGovern D, Ragoussis J, et al. Single nucleotide polymorphisms in TNFSF15 confer susceptibility to Crohn’s disease. Hum Mol Genet. 2005;14(22):3499–506.PubMedCrossRefGoogle Scholar
  54. 54.
    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(2):207–11.PubMedCrossRefGoogle Scholar
  55. 55.
    Baldassano RN, Bradfield JP, Monos DS, et al. Association of the T300A non-synonymous variant of the ATG16L1 gene with susceptibility to paediatric Crohn’s disease. Gut. 2007;56(8):1171–3.PubMedCrossRefGoogle Scholar
  56. 56.
    Prescott NJ, Fisher SA, Franke A, et al. A nonsynonymous SNP in ATG16L1 predisposes to ileal Crohn’s disease and is independent of CARD15 and IBD5. Gastroenterology. 2007;132(5):1665–71.PubMedCrossRefGoogle Scholar
  57. 57.
    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(5):596–604.PubMedCrossRefGoogle Scholar
  58. 58.
    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(1):90–7.PubMedCrossRefGoogle Scholar
  59. 59.
    Homer CR, Richmond AL, Rebert NA, Achkar JP, McDonald C. ATG16L1 and NOD2 interact in an autophagy-dependent antibacterial pathway implicated in Crohn’s disease pathogenesis. Gastroenterology. 2010;139(5):1630–41. e1632.PubMedCrossRefGoogle Scholar
  60. 60.
    Cadwell K, Liu JY, Brown SL, et al. A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells. Nature. 2008;456(7219):259–63.PubMedCrossRefGoogle Scholar
  61. 61.
    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(7):830–2.PubMedCrossRefGoogle Scholar
  62. 62.
    WTCCC. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature. 2007;447(7145):661–78.CrossRefGoogle Scholar
  63. 63.
    Bekpen C, Hunn JP, Rohde C, et al. The interferon-inducible p47 (IRG) GTPases in vertebrates: loss of the cell autonomous resistance mechanism in the human lineage. Genome Biol. 2005;6(11):R92.PubMedCrossRefGoogle Scholar
  64. 64.
    Bekpen C, Marques-Bonet T, Alkan C, et al. Death and resurrection of the human IRGM gene. PLoS Genet. 2009;5(3):e1000403.PubMedCrossRefGoogle Scholar
  65. 65.
    Henry SC, Daniell X, Indaram M, et al. Impaired macrophage function underscores susceptibility to Salmonella in mice lacking Irgm1 (LRG-47). J Immunol. 2007;179(10):6963–72.PubMedGoogle Scholar
  66. 66.
    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(9):1107–12.PubMedCrossRefGoogle Scholar
  67. 67.
    Prescott NJ, Dominy KM, Kubo M, et al. Independent and population-specific association of risk variants at the IRGM locus with Crohn’s disease. Hum Mol Genet. 2010;19(9):1828–39.PubMedCrossRefGoogle Scholar
  68. 68.
    Duerr RH, Taylor KD, Brant SR, et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science. 2006;314(5804):1461–3.PubMedCrossRefGoogle Scholar
  69. 69.
    Cargill M, Schrodi SJ, Chang 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. 2007;80(2):273–90.PubMedCrossRefGoogle Scholar
  70. 70.
    Burton PR, Clayton DG, Cardon LR, et al. Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat Genet. 2007;39(11):1329–37.PubMedCrossRefGoogle Scholar
  71. 71.
    Parham C, Chirica M, Timans J, et al. A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rbeta1 and a novel cytokine receptor subunit, IL-23R. J Immunol. 2002;168(11):5699–708.PubMedGoogle Scholar
  72. 72.
    Oppmann B, Lesley R, Blom B, et al. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity. 2000;13(5):715–25.PubMedCrossRefGoogle Scholar
  73. 73.
    Cua DJ, Sherlock J, Chen Y, et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature. 2003;421(6924):744–8.PubMedCrossRefGoogle Scholar
  74. 74.
    Murphy CA, Langrish CL, Chen Y, et al. Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J Exp Med. 2003;198(12):1951–7.PubMedCrossRefGoogle Scholar
  75. 75.
    Chan JR, Blumenschein W, Murphy E, et al. IL-23 stimulates epidermal hyperplasia via TNF and IL-20R2-dependent mechanisms with implications for psoriasis pathogenesis. J Exp Med. 2006;203(12):2577–87.PubMedCrossRefGoogle Scholar
  76. 76.
    Yen D, Cheung J, Scheerens H, et al. IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. J Clin Invest. 2006;116(5):1310–6.PubMedCrossRefGoogle Scholar
  77. 77.
    Kullberg MC, Jankovic D, Feng CG, et al. IL-23 plays a key role in Helicobacter hepaticus-induced T cell-dependent colitis. J Exp Med. 2006;203(11):2485–94.PubMedCrossRefGoogle Scholar
  78. 78.
    Sandborn WJ, Feagan BG, Fedorak RN, et al. A randomized trial of Ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with moderate-to-severe Crohn’s disease. Gastroenterology. 2008;135(4):1130–41.PubMedCrossRefGoogle Scholar
  79. 79.
    Fuss IJ, Neurath M, Boirivant M, et al. Disparate CD4+ lamina propria (LP) lymphokine secretion profiles in inflammatory bowel disease. Crohn’s disease LP cells manifest increased secretion of IFN-gamma, whereas ulcerative colitis LP cells manifest increased secretion of IL-5. J Immunol. 1996;157(3):1261–70.PubMedGoogle Scholar
  80. 80.
    Plevy SE, Landers CJ, Prehn J, et al. A role for TNF-alpha and mucosal T helper-1 cytokines in the pathogenesis of Crohn’s disease. J Immunol. 1997;159(12):6276–82.PubMedGoogle Scholar
  81. 81.
    Kobayashi T, Okamoto S, Hisamatsu T, et al. IL23 differentially regulates the Th1/Th17 balance in ulcerative colitis and Crohn’s disease. Gut. 2008;57(12):1682–9.PubMedCrossRefGoogle Scholar
  82. 82.
    Ferguson LR, Han DY, Fraser AG, et al. Genetic factors in chronic inflammation: single nucleotide polymorphisms in the STAT-JAK pathway, susceptibility to DNA damage and Crohn’s disease in a New Zealand population. Mutat Res. 2010;690(1–2):108–15.PubMedGoogle Scholar
  83. 83.
    Kan SH, Mancini G, Gallagher G. Identification and characterization of multiple splice forms of the human interleukin-23 receptor alpha chain in mitogen-activated leukocytes. Genes Immun. 2008;9(7):631–9.PubMedCrossRefGoogle Scholar
  84. 84.
    Morahan G, Huang D, Ymer SI, et al. Linkage disequilibrium of a type 1 diabetes susceptibility locus with a regulatory IL12B allele. Nat Genet. 2001;27(2):218–21.PubMedCrossRefGoogle Scholar
  85. 85.
    Fuss IJ, Becker C, Yang Z, 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. 2006;12(1):9–15.PubMedCrossRefGoogle Scholar
  86. 86.
    Levy DE, Darnell Jr JE. Stats: transcriptional control and biological impact. Nat Rev Mol Cell Biol. 2002;3(9):651–62.PubMedCrossRefGoogle Scholar
  87. 87.
    Horvath CM. STAT proteins and transcriptional responses to extracellular signals. Trends Biochem Sci. 2000;25(10):496–502.PubMedCrossRefGoogle Scholar
  88. 88.
    Ivanov II, McKenzie BS, Zhou L, et al. The orphan nuclear receptor ROR gamma t directs the differentiation program of proinflammatory IL-17(+) T helper cells. Cell. 2006;126(6):1121–33.PubMedCrossRefGoogle Scholar
  89. 89.
    Laurence A, Tato CM, Davidson TS, et al. Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity. 2007;26(3):371–81.PubMedCrossRefGoogle Scholar
  90. 90.
    Harris TJ, Grosso JF, Yen HR, et al. Cutting edge: an in vivo requirement for STAT3 signaling in TH17 development and TH17-dependent autoimmunity. J Immunol. 2007;179(7):4313–7.PubMedGoogle Scholar
  91. 91.
    Yang XO, Panopoulos AD, Nurieva R, et al. STAT3 regulates cytokine-mediated generation of inflammatory helper T cells. J Biol Chem. 2007;282(13):9358–63.PubMedCrossRefGoogle Scholar
  92. 92.
    Zhou L, Ivanov II, Spolski R, et al. IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat Immunol. 2007;8(9):967–74.PubMedCrossRefGoogle Scholar
  93. 93.
    Watford WT, Hissong BD, Bream JH, Kanno Y, Muul L, O’Shea JJ. Signaling by IL-12 and IL-23 and the immunoregulatory roles of STAT4. Immunol Rev. 2004;202:139–56.PubMedCrossRefGoogle Scholar
  94. 94.
    O’Malley JT, Eri RD, Stritesky GL, et al. STAT4 isoforms differentially regulate Th1 cytokine production and the severity of inflammatory bowel disease. J Immunol. 2008;181(7):5062–70.PubMedGoogle Scholar
  95. 95.
    McGovern DP, Gardet A, Torkvist L, et al. Genome-wide association identifies multiple ulcerative colitis ­susceptibility loci. Nat Genet. 2010;42(4):332–7.PubMedCrossRefGoogle Scholar
  96. 96.
    Franke A, Balschun T, Karlsen TH, et al. Replication of signals from recent studies of Crohn’s disease identifies previously unknown disease loci for ulcerative colitis. Nat Genet. 2008;40(6):713–5.PubMedCrossRefGoogle Scholar
  97. 97.
    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(6):710–2.PubMedCrossRefGoogle Scholar
  98. 98.
    Chan I, Liu L, Hamada T, Sethuraman G, McGrath JA. The molecular basis of lipoid proteinosis: mutations in extracellular matrix protein 1. Exp Dermatol. 2007;16(11):881–90.PubMedCrossRefGoogle Scholar
  99. 99.
    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(9010):1212–7.PubMedCrossRefGoogle Scholar
  100. 100.
    Silverberg MS, Cho JH, Rioux JD, et al. Ulcerative colitis-risk loci on chromosomes 1p36 and 12q15 found by genome-wide association study. Nat Genet. 2009;41(2):216–20.PubMedCrossRefGoogle Scholar
  101. 101.
    Kuhn R, Lohler J, Rennick D, Rajewsky K, Muller W. Interleukin-10-deficient mice develop chronic enterocolitis. Cell. 1993;75(2):263–74.PubMedCrossRefGoogle Scholar
  102. 102.
    Uhlig HH, Coombes J, Mottet C, et al. Characterization of Foxp3+CD4+CD25+ and IL-10-secreting CD4+CD25+ T cells during cure of colitis. J Immunol. 2006;177(9):5852–60.PubMedGoogle Scholar
  103. 103.
    Sellon RK, Tonkonogy S, Schultz M, et al. Resident enteric bacteria are necessary for development of spontaneous colitis and immune system activation in interleukin-10-deficient mice. Infect Immun. 1998;66(11):5224–31.PubMedGoogle Scholar
  104. 104.
    Schreiber S, Nikolaus S, Hampe J. Activation of nuclear factor kappa B inflammatory bowel disease. Gut. 1998;42(4):477–84.PubMedCrossRefGoogle Scholar
  105. 105.
    Schreiber S, Fedorak RN, Nielsen OH, et al. Safety and efficacy of recombinant human interleukin 10 in chronic active Crohn’s disease. Crohn’s Disease IL-10 Cooperative Study Group. Gastroenterology. 2000;119(6):1461–72.PubMedCrossRefGoogle Scholar
  106. 106.
    Colombel JF, Rutgeerts P, Malchow H, et al. Interleukin 10 (Tenovil) in the prevention of postoperative recurrence of Crohn’s disease. Gut. 2001;49(1):42–6.PubMedCrossRefGoogle Scholar
  107. 107.
    Erdman SE, Rao VP, Poutahidis T, et al. CD4(+)CD25(+) regulatory lymphocytes require interleukin 10 to interrupt colon carcinogenesis in mice. Cancer Res. 2003;63(18):6042–50.PubMedGoogle Scholar
  108. 108.
    Glocker EO, Kotlarz D, Boztug K, et al. Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N Engl J Med. 2009;361(21):2033–45.PubMedCrossRefGoogle Scholar
  109. 109.
    Glocker EO, Frede N, Perro M, et al. Infant colitis – it’s in the genes. Lancet. 2010;376(9748):1272.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Division of Pediatric GastroenterologyStonybrook University HospitalStonybrookUSA
  2. 2.Department of Internal Medicine, Digestive Diseases, GeneticsYale University School of MedicineNew HavenUSA

Personalised recommendations