Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: a genetic association study.
Cast your vote
You can rate an item by clicking the amount of stars they wish to award to this item.
When enough users have cast their vote on this item, the average rating will also be shown.
Your vote was cast
Thank you for your feedback
Thank you for your feedback
Schumm, L Philip
Andrews, Jane M
Brant, Steven R
Cho, Judy H
Daly, Mark J
Duerr, Richard H
Ferguson, Lynnette R
Gearry, Richard B
Hov, Johannes R
Kennedy, Nicholas A
Lawrance, Ian C
Lee, James C
van der Meulen-de Jong, Andrea E
Weersma, Rinse K
Wilson, David C
Rioux, John D
Silverberg, Mark S
McGovern, Dermot P B
Barrett, Jeffrey C
Lees, Charlie W
MetadataShow full item record
AbstractCrohn's disease and ulcerative colitis are the two major forms of inflammatory bowel disease; treatment strategies have historically been determined by this binary categorisation. Genetic studies have identified 163 susceptibility loci for inflammatory bowel disease, mostly shared between Crohn's disease and ulcerative colitis. We undertook the largest genotype association study, to date, in widely used clinical subphenotypes of inflammatory bowel disease with the goal of further understanding the biological relations between diseases. This study included patients from 49 centres in 16 countries in Europe, North America, and Australasia. We applied the Montreal classification system of inflammatory bowel disease subphenotypes to 34,819 patients (19,713 with Crohn's disease, 14,683 with ulcerative colitis) genotyped on the Immunochip array. We tested for genotype-phenotype associations across 156,154 genetic variants. We generated genetic risk scores by combining information from all known inflammatory bowel disease associations to summarise the total load of genetic risk for a particular phenotype. We used these risk scores to test the hypothesis that colonic Crohn's disease, ileal Crohn's disease, and ulcerative colitis are all genetically distinct from each other, and to attempt to identify patients with a mismatch between clinical diagnosis and genetic risk profile. After quality control, the primary analysis included 29,838 patients (16,902 with Crohn's disease, 12,597 with ulcerative colitis). Three loci (NOD2, MHC, and MST1 3p21) were associated with subphenotypes of inflammatory bowel disease, mainly disease location (essentially fixed over time; median follow-up of 10·5 years). Little or no genetic association with disease behaviour (which changed dramatically over time) remained after conditioning on disease location and age at onset. The genetic risk score representing all known risk alleles for inflammatory bowel disease showed strong association with disease subphenotype (p=1·65 × 10(-78)), even after exclusion of NOD2, MHC, and 3p21 (p=9·23 × 10(-18)). Predictive models based on the genetic risk score strongly distinguished colonic from ileal Crohn's disease. Our genetic risk score could also identify a small number of patients with discrepant genetic risk profiles who were significantly more likely to have a revised diagnosis after follow-up (p=6·8 × 10(-4)). Our 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.
- Contribution of genes of the major histocompatibility complex to susceptibility and disease phenotype in inflammatory bowel disease.
- Authors: Satsangi J, Welsh KI, Bunce M, Julier C, Farrant JM, Bell JI, Jewell DP
- Issue date: 1996 May 4
- Genetic determinants associated with early age of diagnosis of IBD.
- Authors: Connelly TM, Berg AS, Harris L 3rd, Brinton D, Deiling S, Koltun WA
- Issue date: 2015 Mar
- Autophagy and inflammatory bowel disease: Association between variants of the autophagy-related IRGM gene and susceptibility to Crohn's disease.
- Authors: Rufini S, Ciccacci C, Di Fusco D, Ruffa A, Pallone F, Novelli G, Biancone L, Borgiani P
- Issue date: 2015 Sep
- Molecular prediction of disease risk and severity in a large Dutch Crohn's disease cohort.
- Authors: Weersma RK, Stokkers PC, van Bodegraven AA, van Hogezand RA, Verspaget HW, de Jong DJ, van der Woude CJ, Oldenburg B, Linskens RK, Festen EA, van der Steege G, Hommes DW, Crusius JB, Wijmenga C, Nolte IM, Dijkstra G, Dutch Initiative on Crohn and Colitis (ICC)
- Issue date: 2009 Mar
- CARD15 in inflammatory bowel disease and Crohn's disease phenotypes: an association study and pooled analysis.
- Authors: Oostenbrug LE, Nolte IM, Oosterom E, van der Steege G, te Meerman GJ, van Dullemen HM, Drenth JP, de Jong DJ, van der Linde K, Jansen PL, Kleibeuker JH
- Issue date: 2006 Nov