Adolescent; Adult; Crohn Disease/epidemiology/genetics/pathology/prevention & control; Cyclin-Dependent Kinase 5/genetics; DNA Fingerprinting; Disease Progression; Disease Susceptibility; Female; Gene Frequency; Genetic Predisposition to Disease/genetics; Genetic Testing; Humans; Kaplan-Meiers Estimate; Logistic Models; Male; Models, Genetic; Nod2 Signaling Adaptor Protein/genetics; Polymorphism, Single Nucleotide; Predictive Value of Tests; Rectal Fistula/epidemiology/genetics/pathology/prevention & control; Sex Factors; Young Adult
Abstract :
[en] BACKGROUND & AIMS: Clinical 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. METHODS: Complete 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. RESULTS: Homozygosity 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. CONCLUSIONS: CD-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.
Disciplines :
Genetics & genetic processes
Author, co-author :
Henckaerts, Liesbet
Van Steen, Kristel ; Université de Liège - ULiège > Dép. d'électric., électron. et informat. (Inst.Montefiore) > Bioinformatique
Verstreken, Isabel
Cleynen, Isabelle
Franke, Andre
Schreiber, Stefan
Rutgeerts, Paul
Vermeire, Severine
Language :
English
Title :
Genetic risk profiling and prediction of disease course in Crohn's disease patients.
Cho J.H. The genetics and immunopathogenesis of inflammatory bowel disease. Nat Rev Immunol 8 (2008) 458-466
Beaugerie L., Seksik P., Nion-Larmurier I., et al. Predictors of Crohn's disease. Gastroenterology 130 (2006) 650-656
Loly C., Belaiche J., and Louis E. Predictors of severe Crohn's disease. Scand J Gastroenterol 4 (2008) 1-8
Walker L.J., Aldhous M.C., Drummond H.E., et al. Anti-Saccharomyces cerevisiae antibodies (ASCA) in Crohn's disease are associated with disease severity but not NOD2/CARD15 mutations. Clin Exp Immunol 135 (2004) 490-496
Annese V., Lombardi G., Perri F., et al. Variants of CARD 15 are associated with an aggressive clinical course of Crohn's disease: an IG-IBD study. Am J Gastroenterol 100 (2005) 84-92
Dubinsky M.C., Lin Y.C., Dutridge D., et al. Serum immune responses predict rapid disease progression among children with Crohn's disease: immune responses predict disease progression. Am J Gastroenterol 101 (2006) 360-367
Torok H.P., Glas J., Hollay H.C., et al. Serum antibodies in first-degree relatives of patients with IBD: a marker of disease susceptibility?. A follow-up pilot-study after 7 years. Digestion 72 (2005) 119-123
Papp M., Altorjay I., Norman G.L., et al. Seroreactivity to microbial components in Crohn's disease is associated with ileal involvement, noninflammatory disease behavior and NOD2/CARD15 genotype, but not with risk for surgery in a Hungarian cohort of IBD patients. Inflamm Bowel Dis 13 (2007) 984-992
Ferrante M., Henckaerts L., Joossens M., et al. New serological markers in inflammatory bowel disease are associated with complicated disease behaviour. Gut 56 (2007) 1394-1403
Mow W.S., Vasiliauskas E.A., Lin Y.C., et al. Association of antibody responses to microbial antigens and complications of small bowel Crohn's disease. Gastroenterology 126 (2004) 414-424
Alvarez-Lobos M., Arostegui J.I., Sans M., et al. Crohn's disease patients carrying Nod2/CARD15 gene variants have an increased and early need for first surgery due to stricturing disease and higher rate of surgical recurrence. Ann Surg 242 (2005) 693-700
Seiderer J., Brand S., Herrmann K.A., et al. Predictive value of the CARD15 variant 1007fs for the diagnosis of intestinal stenoses and the need for surgery in Crohn's disease in clinical practice: results of a prospective study. Inflamm Bowel Dis 12 (2006) 1114-1121
Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447 (2007) 661-678
Parkes M., Barrett J.C., Prescott N.J., et al. Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn's disease susceptibility. Nat Genet 39 (2007) 830-832
Libioulle C., Louis E., Hansoul S., et al. Novel Crohn disease locus identified by genome-wide association maps to a gene desert on 5p13.1 and modulates expression of PTGER4. PLos Genet 3 (2007) e58
Barrett J.C., Hansoul S., Nicolae D.L., et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat Genet 40 (2008) 955-962
Podolsky D.K. Inflammatory bowel disease. N Engl J Med 347 (2002) 417-429
Silverberg M.S., 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 19 Suppl A (2005) 5-36
Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447 (2007) 661-678
Duerr R.H., Taylor K.D., Brant S.R., et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314 (2006) 1461-1463
Hampe J., Franke A., Rosenstiel P., et al. A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat Genet 39 (2007) 207-211
Rioux J.D., Daly M.J., Silverberg M.S., et al. Genetic variation in the 5q31 cytokine gene cluster confers susceptibility to Crohn disease. Nat Genet 29 (2001) 223-228
Rioux J.D., Xavier R.J., Taylor K.D., et al. Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nat Genet 39 (2007) 596-604
Vermeire S., Pierik M., Hlavaty T., et al. Association of organic cation transporter risk haplotype with perianal penetrating Crohn's disease but not with susceptibility to IBD. Gastroenterology 129 (2005) 1845-1853
Esters N., Pierik M., Van Steen K., et al. Transmission of CARD15 (NOD2) variants within families of patients with inflammatory bowel disease. Am J Gastroenterol 99 (2004) 299-305
Franchimont D., Vermeire S., El Housni H., et al. Deficient host-bacteria interactions in inflammatory bowel disease?. The toll-like receptor (TLR)-4 Asp299gly polymorphism is associated with Crohn's disease and ulcerative colitis. Gut 53 (2004) 987-992
Tobler A.R., Short S., Andersen M.R., et al. The SNPlex genotyping system: a flexible and scalable platform for SNP genotyping. J Biomol Tech 16 (2005) 398-406
Ritchie M.D., Hahn L.W., Roodi N., et al. Multifactor-dimensionality reduction reveals high-order interactions among estrogen-metabolism genes in sporadic breast cancer. Am J Hum Genet 69 (2001) 138-147
Ritchie M.D., Hahn L.W., and Moore J.H. Power of multifactor dimensionality reduction for detecting gene-gene interactions in the presence of genotyping error, missing data, phenocopy, and genetic heterogeneity. Genet Epidemiol 24 (2003) 150-157
Lou X.Y., Chen G.B., Yan L., et al. A generalized combinatorial approach for detecting gene-by-gene and gene-by-environment interactions with application to nicotine dependence. Am J Hum Genet 80 (2007) 1125-1137
Vermeire S., Van Assche G., and Rutgeerts P. Review article: altering the natural history of Crohn's disease-evidence for and against current therapies. Aliment Pharmacol Ther 25 (2007) 3-12
D'Haens G., Baert F., Van Assche G., et al. Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn's disease: an open randomised trial. Lancet 371 (2008) 660-667
Pabst O., Zweigerdt R., and Arnold H.H. Targeted disruption of the homeobox transcription factor Nkx2-3 in mice results in postnatal lethality and abnormal development of small intestine and spleen. Development 126 (1999) 2215-2225
Pabst O., Förster R., Lipp M., et al. NKX2.3 is required for MAdCAM-1 expression and homing of lymphocytes in spleen and mucosa-associated lymphoid tissue. EMBO J 19 (2000) 2015-2023
Arihiro S., Ohtani H., Suzuki M., et al. Differential expression of mucosal addressin cell adhesion molecule-1 (MAdCAM-1) in ulcerative colitis and Crohn's disease. Pathol Int 52 (2002) 367-374
Peltekova V.D., Wintle R.F., Rubin L.A., et al. Functional variants of OCTN cation transporter genes are associated with Crohn disease. Nat Genet 36 (2004) 471-475
Kobayashi K.S., Chamaillard M., Ogura Y., et al. Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science 307 (2005) 731-734
Maeda S., Hsu L.C., Liu H.J., et al. Nod2 mutation in Crohn's disease potentiates NF-kappa B activity and IL-10 processing. Science 307 (2005) 734-738
Watanabe T., Kitani A., Murray P.J., et al. NOD2 is a negative regulator of Toll-like receptor 2-mediated T helper type 1 responses. Nat Immunol 5 (2004) 800-808
Cadwell K., Liu J.Y., Brown S.L., et al. A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells. Nature 456 (2008) 259-263
Calle M.L., Urrea V., Vellalta G., et al. MB-MDR: model-based multifactor dimensionality reduction for detecting interactions in high-dimensional genomic data (2008), Universitat de Vic, Vic, Spain Technical report ("Documents de Recerca")