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Genetic risk factors predict disease progression in Crohn's disease patients of the Swiss inflammatory bowel disease cohort.

ABSTRACT: Background: Crohn's disease (CD) may progress from an inflammatory to a stricturing or penetrating disease phenotype. The aim of our study was to identify single nucleotide polymorphisms (SNPs) that predict disease progression in patients of the Swiss IBD Cohort Study (SIBDCS).

Methods: We applied a multi-state Markov model for progression behavior of CD with three behavioral states according to the Montreal classification. The model considered transition from B1 to B2/B3 or from B2 to B3 stage. Model dynamics were summarized with transition intensities by including the effect of SNPs and calculating transition intensities for each SNP.

Results: We included 1276 CD patients [669 (52.4%) B1, 248 (19.4%) B2, 359 (28.1%) B3 patients] with a median follow-up of 6.8 (interquartile range?=?3.6-9.1; range 0-11.6) years. Probability for a B1 patient to develop a stenosis (B1 to B2, q?=?0.033) was twice as much as compared to developing a penetrating complication (B3) during the disease course. In contrast, the probability of entering B3 stage was similar regardless of whether antecedent stricture was present (B2 to B3, q?=?0.016) or not (B1 to B3, q?=?0.016). We identified SNPs within the gene loci encoding ZMIZ1, LOC105373831 and KSR1 as carrying the highest risk for progression to B3, while the presence of SNPs within gene loci TNFSF15 and CEBPB-PTPN1 protected from progression to B2 or B3.

Conclusion: We identified new genetic risk factors that can predict disease course in CD patients. A closer understanding on the functional impact of these genetic variations might improve our treatment options finally to prevent disease progression in CD patients.

SUBMITTER: Ditrich F

PROVIDER: S-EPMC7686597 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Genetic risk factors predict disease progression in Crohn's disease patients of the Swiss inflammatory bowel disease cohort.

Ditrich Felicitas F Blümel Sena S Biedermann Luc L Fournier Nicolas N Rossel Jean-Benoit JB Ellinghaus David D Franke Andre A Stange Eduard F EF Rogler Gerhard G Scharl Michael M

Therapeutic advances in gastroenterology 20201119

<h4>Background</h4>Crohn's disease (CD) may progress from an inflammatory to a stricturing or penetrating disease phenotype. The aim of our study was to identify single nucleotide polymorphisms (SNPs) that predict disease progression in patients of the Swiss IBD Cohort Study (SIBDCS).<h4>Methods</h4>We applied a multi-state Markov model for progression behavior of CD with three behavioral states according to the Montreal classification. The model considered transition from B1 to B2/B3 or from B2 ...[more]

PMID: 33281934

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Project description:BackgroundInflammatory bowel diseases (IBDs) are complex, multifactorial disorders that comprise Crohn's disease (CD) and ulcerative colitis (UC). Recent discoveries have brought much attention to the genetic predisposition of patients with IBD. Here we evaluate the interaction between IBD genetic risk factors susceptibility and CD occurrence in an IBD pediatric patient population, performing a clinical exome survey.MethodsFrom February 2018 to April 2019, we collected blood samples from 7 pediatric patients with IBD concerns from several collaborating health centers and/or hospitals. Blood samples were processed by extracting and sequencing DNA for a clinical exome survey. Shophia-DDM-v3-4 platform allowed sequenced reads alignment on hg19 genome as well as genetic variant calling. Both IBD risk and pathogenic genetic variants covered by at least 20 reads were selected for subjacent analysis.ResultsNormality and Bartlett tests of both risk and pathogenic genetic variants suggested random and heterogeneous distribution of these variants in this group of IBD pediatric patients. P value clustering analysis by processing 157 IBD risk factors revealed genetic heterogeneity in IBD population and suggested two pathways influencing IBD development. In particular, (1) genetic variants associated with autoimmune and (2) metabolic diseases and CD risk factors (rs2066844 and rs2241880 single nucleotide polymorphism variants, respectively, of genes NOD2 and ATG16L) were identified in distinct clusters of IBD patients (P < .05). Moreover, the heterogeneous distribution of the following variants rs10065172 (IRGM), rs1805010 (IL4R), rs5030737 (MBL2), and rs33995883 (LRRK2) in this group of IBD patients was consistent with their random distribution in that population.ConclusionOur study revealed specific genetic variants linked to CD susceptibility, autoimmune and/or innate immunodeficiency as well as to metabolic defects, as favoring factors of IBD, suggesting the valuable role of next generation sequencing (NGS) approaches in IBD molecular diagnostic procedures.

Dataset Information

Genetic risk factors predict disease progression in Crohn's disease patients of the Swiss inflammatory bowel disease cohort.

Publications

Genetic risk factors predict disease progression in Crohn's disease patients of the Swiss inflammatory bowel disease cohort.

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