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Background & AimsClinical presentation at diagnosis and disease course of Crohn's disease (CD) are heterogeneous and variable over time. Early introduction of immunomodulators and/or biologicals might be justified in patients at risk for disease progression, so it is important to identify these patients as soon as possible. We examined the influence of recently discovered CD-associated susceptibility loci on changes in disease behavior and evaluated whether a genetic risk model for disease progression could be generated. MethodsComplete medical data were available for 875 CD patients (median follow-up time, 14 years; interquartile range, 7–22). Fifty CD-associated polymorphisms were genotyped. Kaplan–Meier survival analyses, multiple logistic regression, and generalized multifactor dimensionality reduction analyses (GMDR) were performed, correcting for follow-up time. ResultsHomozygosity for the rs1363670 G-allele in a gene encoding a hypothetical protein near the IL12B gene was independently associated with stricturing disease behavior (odds ratio [OR], 5.48; 95% confidence interval [CI], 1.60–18.83; P = .007) and with shorter time to strictures (P = .01), especially in patients with ileal involvement (P = .0002). Male patients carrying at least one rs12704036 T-allele in a gene desert had the shortest time to non-perianal fistula (P < .0001). The presence of a C-allele at the CDKAL1 single nucleotide polymorphism rs6908425 and the absence of NOD2 variants were independently associated with development of perianal fistula (OR, 8.86; 95% CI, 1.13–69.78; P = .04 and OR, 0.56; 95% CI, 0.38–0.83; P = .004, respectively), particularly when colonic involvement and active smoking were present. ConclusionsCD-associated polymorphisms play a role in disease progression and might be useful in identifying patients who could benefit from an early top-down treatment approach. Abbreviations used in this paper: CD, Crohn's disease, CI, confidence interval, CV, cross-validation, GWAS, genome-wide association study, GMDR, generalized MDR, MDR, multifactor dimensionality reduction, OR, odds ratio, SNP, single nucleotide polymorphism, WTCCC, Wellcome Trust Case Control Consortium ⁎ Department of Medicine, Gastroenterology Section, Catholic University of Leuven, Leuven, Belgium ‡ Montefiore Institute, Department of Electrical Engineering and Computer Science/Bioinformatics, University of Liège, Liège, Belgium § StepGen cvba, Merelbeke, Belgium ∥ Department of Human Genetics, Catholic University of Leuven, Leuven, Belgium ¶ Department of Laboratory Medicine, Catholic University of Leuven, Leuven, Belgium # Institute for Clinical Molecular Biology, University Hospital Schleswig-Holstein, Christian-Albrechts-University, Kiel, Germany ⁎⁎ Department of General Internal Medicine, University Hospital Schleswig-Holstein, Christian-Albrechts-University, Kiel, Germany
Conflicts of interest The authors disclose no conflicts. Funding L. Henckaerts is a doctoral fellow and S. Vermeire is a clinical researcher of the Fund for Scientific Research (FWO), Flanders, Belgium. A. Franke was supported by the German Ministry of Education and Research (BMBF) through the National Genome Research Network (NGFN) and received infrastructure support through the DFG excellence cluster “Inflammation at Interfaces.” PII: S1542-3565(09)00435-2 doi:10.1016/j.cgh.2009.05.001 © 2009 AGA Institute. Published by Elsevier Inc. All rights reserved.
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ABSTRACT
Genetic Risk Profiling and Prediction of Disease Course in Crohn's Disease Patients
Analysis of HLA and Non-HLA Alleles Can Identify Individuals at High Risk for Celiac Disease
