Genetics and phenotypes in inflammatory bowel disease
Authors: Joana Torres, Jean-Frédéric Colombel
Journal: The Lancet (2015)

Inflammatory bowel diseases, encompassing Crohn's disease and ulcerative colitis, have long been recognised as very heterogeneous diseases at the clinical level. Farmer and colleagues1Farmer RG Hawk WA Turnbull Jr, RB Clinical patterns in Crohn's disease: a statistical study of 615 cases.Gastroenterology. 1975; 68: 627-635Summary Full Text PDF PubMed Scopus (568) Google Scholar were among the first to report that location of disease was a major driver for disease presentation, complications, and rates of surgery. More recently, the Montreal and Paris classifications (ie, modified Montreal classification for use in paediatric inflammatory bowel disease) have tried to standardise clinical phenotypes further, acknowledging that age at diagnosis, and location and extent of disease in Crohn's disease and ulcerative colitis, and disease behaviour in Crohn's disease, are the main factors affecting disease course and prognosis.2Silverberg MS Satsangi J Ahmad T et al.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. 2005; 19: 5A-36ACrossref PubMed Scopus (2503) Google Scholar, 3Levine A Griffiths A Markowitz J et al.Pediatric modification of the Montreal classification for inflammatory bowel disease: the Paris classification.Inflamm Bowel Dis. 2011; 17: 1314-1321Crossref PubMed Scopus (992) Google Scholar For example, younger age at diagnosis is generally associated with more extensive and aggressive disease in both Crohn's disease and ulcerative colitis; ileal (L1) and ileocolonic (L3) Crohn's disease are more frequently associated with stenosing and fistulising complications and need for surgery than is colonic Crohn's disease (L2); and in ulcerative colitis, extensive disease (E3) usually has higher therapeutic requirements, risk of colorectal cancer, and rates of hospital admission and surgery than does non-extensive disease (E1 and E2).2Silverberg MS Satsangi J Ahmad T et al.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. 2005; 19: 5A-36ACrossref PubMed Scopus (2503) Google Scholar The phenotypic concordance reported in familial cases of inflammatory bowel disease and in monozygotic twins with inflammatory bowel disease has long served as an argument that shared environmental and genetic factors shape disease phenotype.4Colombel JF Grandbastien B Gower-Rousseau C et al.Clinical characteristics of Crohn's disease in 72 families.Gastroenterology. 1996; 111: 604-607Summary Full Text Full Text PDF PubMed Scopus (174) Google Scholar, 5Halfvarson 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: 1767-1773Summary Full Text Full Text PDF PubMed Scopus (313) Google Scholar Beginning with the early linkage studies, and continuing through identification of the NOD2 gene until the most recent era of genome-wide association studies, progress has been enormous, culminating in the identification of 163 independent loci associated with inflammatory bowel disease.6Jostins L Ripke S Weersma RK et al.Host–microbe interactions have shaped the genetic architecture of inflammatory bowel disease.Nature. 2012; 491: 119-124Crossref PubMed Scopus (3320) Google Scholar We have learned that Crohn's disease and ulcerative colitis share several disease susceptibility loci, many of which are implicated in other immune-mediated diseases.6Jostins L Ripke S Weersma RK et al.Host–microbe interactions have shaped the genetic architecture of inflammatory bowel disease.Nature. 2012; 491: 119-124Crossref PubMed Scopus (3320) Google Scholar Furthermore, the discoveries of genes related to T-helper-17 cell differentiation and function, and genes influencing innate immunity and microbial immune response, have brought major insights into disease pathogenesis, pointing to altered bacterial handling as a key factor in disease pathogenesis.7Colombel J-F Decade in review—IBD: IBD genes, bacteria and new therapeutic strategies.Nat Rev Gastroenterol Hepatol. 2014; 11: 652-654Crossref PubMed Scopus (12) Google Scholar Clearly, the next logical step would be to dissect genotype–phenotype relations, in the hope of identifying inflammatory bowel disease subtypes that could be translated into the clinic. In The Lancet, Isabelle Cleynen and colleagues8Cleynen I Boucher G Jostins L et al.Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: a genetic association study.Lancet. 2015; (published online Oct 19.)http://dx.doi.org/10.1016/S0140-6736(15)00465-1Google Scholar report the largest genotype–phenotype study ever undertaken in inflammatory bowel disease. The investigators are to be congratulated for the enormous international collaborative effort, with detailed phenotypic data gathered for many patients with inflammatory bowel disease, and for their meticulous and well designed statistical methodology. Overall, 29 838 patients with inflammatory bowel disease were genotyped with the Immunochip array (designed to capture almost 200 different loci associated with common autoimmune diseases), and variants in the MHC were imputed. That important phenotypic conclusions would be drawn from such a well powered study might be expected; unfortunately, this was not the case. The major findings were, first, that the previously proposed relation between NOD2 and stenosing disease is not a true one; rather, it is driven by NOD2 association with young age at diagnosis and ileal location; and second, that colonic disease location (L2) for Crohn's disease was better predicted by the HLA susceptibility alleles of ulcerative colitis than by the susceptibility alleles of Crohn's disease. To investigate this finding further, the researchers resorted to predictive models of disease location and showed that colonic Crohn's disease is genetically intermediate between ileal Crohn's disease and ulcerative colitis. Cleynen and colleagues8Cleynen I Boucher G Jostins L et al.Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: a genetic association study.Lancet. 2015; (published online Oct 19.)http://dx.doi.org/10.1016/S0140-6736(15)00465-1Google Scholar conclude that colonic Crohn's disease is genetically distinct from ileal Crohn's disease, and propose a new nomenclature for inflammatory bowel disease (however, L3 disease—the most common disease location—is inexplicably left out). Only three main loci (NOD2, MHC, and 3p21/MST1) achieved genome-wide significance for association with clinical phenotypes in Cleynen and colleagues study,8Cleynen I Boucher G Jostins L et al.Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: a genetic association study.Lancet. 2015; (published online Oct 19.)http://dx.doi.org/10.1016/S0140-6736(15)00465-1Google Scholar but when combined in a predictive model with clinical–demographic factors, these loci were unable to explain disease variance. Next to NOD2, age at diagnosis and smoking were the main drivers for disease location in adult Crohn's disease, whereas, for ulcerative colitis, age at diagnosis was the most important determinant of disease extent, albeit of modest effect. The feeble tone of our criticism merely reflects our disappointment that, in essence, Cleynen and colleagues' strongly powered study,8Cleynen I Boucher G Jostins L et al.Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: a genetic association study.Lancet. 2015; (published online Oct 19.)http://dx.doi.org/10.1016/S0140-6736(15)00465-1Google Scholar which focused mainly on genetic factors, provides only limited new phenotypic insights. No genetic loci associated with perianal disease, upper gastrointestinal disease, or extra-intestinal manifestations were identified. No genetic predictors of disease progression in Crohn's disease, or of disease extent or proximal extension in ulcerative colitis, could be detected (figure). So how should we interpret the results? As pointed out by Cleynen and colleagues, the analysis was restricted to the known variants determining disease risk, and therefore it is possible that important loci influencing disease course remain to be identified. For example, rare variants with larger effects could have a profound effect in disease subphenotypes. Novel approaches such as whole-genome and exome sequencing will perhaps bring additional insight. Fundamentally, it is clear that gene–environment connections need to be more systematically interrogated. Epigenetic factors, mediating the interactions between genetics and complex environmental exposures such as the microbiome, could potentially provide new clues to disease pathogenesis in the years to come.9Fraga MF Ballestar E Paz MF et al.Epigenetic differences arise during the lifetime of monozygotic twins.Proc Natl Acad Sci USA. 2005; 102: 10604-10609Crossref PubMed Scopus (2722) Google Scholar, 10Ventham NT Kennedy NA Nimmo ER Satsangi J Beyond gene discovery in inflammatory bowel disease: the emerging role of epigenetics.Gastroenterology. 2013; 145: 293-308Summary Full Text Full Text PDF PubMed Scopus (219) Google Scholar Importantly, many of the classic clinical and epidemiological findings—such as the relation with smoking, the macroscopic distribution of disease, and the mesenteric fat hypertrophy in Crohn's disease—remain to be explained.11Colombel JF Watson AJ Neurath MF The 10 remaining mysteries of inflammatory bowel disease.Gut. 2008; 57: 429-433Crossref PubMed Scopus (57) Google Scholar Cleynen and colleagues' study highlights the urgent need for innovative thinking and the development of a new research roadmap that systematically integrates genetic with non-genetic factors. JT has served as a consultant for AbbVie and as a speaker for Ferring and Falk. J-FC has served as consultant or advisory board member for AbbVie, AB Science, Amgen, Bristol-Myers Squibb, Celltrion, Danone, Ferring, Genentech, Giuliani SpA, Given Imaging, Janssen, Immune Pharmaceuticals, MedImmune, Merck & Co, Millennium Pharmaceuticals, Neovacs, Nutrition Science Partners Ltd, Pfizer, Prometheus Laboratories, Protagonist, Receptos, Sanofi, Schering-Plough, Second Genome, Shire, Takeda, Teva Pharmaceuticals, TiGenix, UCB Pharma, Vertex, and Dr August Wolff GmbH & Co. J-FC has also served as speaker for AbbVie, Ferring, Janssen, Merck & Co, Nutrition Science Partners Ltd, and Takeda. Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: a genetic association studyOur data support a continuum of disorders within inflammatory bowel disease, much better explained by three groups (ileal Crohn's disease, colonic Crohn's disease, and ulcerative colitis) than by Crohn's disease and ulcerative colitis as currently defined. Disease location is an intrinsic aspect of a patient's disease, in part genetically determined, and the major driver to changes in disease behaviour over time. Full-Text PDF Open Access