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Genetics Suggest Three IBD Types Rather Than Ulcerative Colitis, Crohn’s Binary
The largest genotype association study of inflammatory bowel disease to date showed the disease may be better explained by a spectrum of three main disease types — ileal Crohn’s, colonic Crohn’s and ulcerative colitis — rather than the current binary categorization. Researchers said this data provides a better understanding of IBD progression and could lead to more effective treatments.
“This new research strongly suggests that we are dealing [with] a number of different diseases hidden within Crohn’s disease and ulcerative colitis, constituting a large spectrum of inflammatory bowel disease,” Dermot McGovern, MD, PhD, MRCP(UK), director of translational medicine in the F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute at Cedars-Sinai, said in a press release. “We have very effective therapies for IBD if we use them sooner in the disease, especially for those patients who are at risk for developing a serious form of illness. We want to understand what the important, singular, genetic signature is for each individual patient because they may respond to available therapies very differently, even with the same IBD diagnosis.”
Dermot McGovern
McGovern and colleagues acquired phenotype data on 19,713 patients with Crohn’s disease and 14,683 with ulcerative colitis from 49 centers in 16 countries across Europe, North America and Australasia, all of whom were genotyped with the Immunochip array. They tested for genotype-phenotype associations spanning 156,154 genetic variants, and combined previously identified associations to generate genetic risk scores, which were used to determine if ileal and colonic Crohn’s and ulcerative colitis are genetically distinct, and to identify patients with discrepancies between their risk score and clinical diagnosis.
The primary analysis included 29,838 patients after quality control. They found that three genetic loci were associated with IBD subphenotypes (primarily disease location) with genome-wide significance — NOD2, MHC, and MST1 3p21. They also found the genetic risk score was strongly associated with IBD subphenotype, and predictive models showed that “ileal and colonic Crohn’s disease are at least as genetically distinct from each other as they are from ulcerative colitis.” Moreover, the genetic risk score was able to identify small numbers of misclassified patients.
The researchers concluded that IBD “is better classified into [these] three distinct groups … and we would recommend that clinicians adopt this nomenclature in regular practice. We also show that, although genetic risk scores do not yet have widespread clinical use, they are already valuable in some contexts in [IBD], and their study in other complex disease phenotypes is warranted.”
Jean-Frédéric Colombel
“For many of our patients, these new genetic insights could be very beneficial,” McGovern said in the press release. “But we also need to look more closely at some of the sickest IBD patients in hopes of providing more effective treatment and disease management.”
“That important phenotypic conclusions would be drawn from such a well powered study might be expected; unfortunately, this was not the case,” Joanna Torres, MD, and Jean-Frédéric Colombel, MD, from the Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, wrote in an accompanying commentary. The study, “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.” They concluded that because the analysis was restricted to known IBD genetic variants, other important loci may remain unidentified. – by Adam Leitenberger
Disclosures: McGovern reports no relevant financial disclosures. Please see the full study for a list of all other researchers’ relevant financial disclosures. Torres reports she has served as a consultant for AbbVie and as a speaker for Ferring and Falk. Colombel reports he 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. Colombel reports he has also served as speaker for AbbVie, Ferring, Janssen, Merck & Co, Nutrition Science Partners Ltd, and Takeda.