Defining Complex Contributions of NOD2/CARD15 Gene Mutations, Age at Onset, and Tobacco Use On Crohn's Disease Phenotypes

BackgroundMultiple factors, particularly IBD family history, tobacco use, age at diagnosis and recently, NOD2 mutant genotypes may influence Crohn's disease (CD) heterogeneity. MethodsWe performed a multicenter retrospective record analysis of 275 unrelated patients with CD. Age at diagnosis, IBD family history, Jewish ethnicity, tobacco use at diagnosis, surgical history, disease site and clinical behavior were correlated with genotypes for NOD2 mutations, and all risk factors were assessed for independent influence on outcomes of disease site, behavior and surgery free survival. ResultsRisk of ileal disease was increased for CD patients with two NOD2 mutations (Odds Ratio, O.R. 10.1), a smoking history (O.R. 2.25 per pack per day at diagnosis) or a younger age at diagnosis (O.R. 0.97 per each increased year). Presence of ileal disease (O.R. 4.8) and carrying one or two NOD2 mutations (O.R. 1.9 and 3.5, respectively) were independent risk factors for stricturing or non-perianal fistulizing behavior. Ileal disease, youthful onset and smoking at diagnosis (but not NOD2 mutations) were risk factors for early surgery. ConclusionsCarrying two NOD2 mutations predicts youthful onset, ileal disease involvement, and development of stricturing or non-perianal fistulizing complications. Smoking and early onset independently influence ileal site and time to surgery.

[1]  T. Bayless,et al.  Tobacco Consumption and Disease Duration Are Associated With Fistulizing and Stricturing Behaviors in the First 8 Years of Crohn's Disease , 2003, American Journal of Gastroenterology.

[2]  M. Daly,et al.  CARD15 genetic variation in a Quebec population: prevalence, genotype-phenotype relationship, and haplotype structure. , 2002, American journal of human genetics.

[3]  C. Folwaczny,et al.  The c-insertion mutation of the NOD2 gene is associated with fistulizing and fibrostenotic phenotypes in Crohn's disease. , 2002, Gastroenterology.

[4]  M. Vatn,et al.  Association of NOD2 (CARD 15) genotype with clinical course of Crohn's disease: a cohort study , 2002, The Lancet.

[5]  C. O'Morain,et al.  CARD15/NOD2 mutational analysis and genotype-phenotype correlation in 612 patients with inflammatory bowel disease. , 2002, American journal of human genetics.

[6]  Alastair Forbes,et al.  The contribution of NOD2 gene mutations to the risk and site of disease in inflammatory bowel disease. , 2002, Gastroenterology.

[7]  T. Ahmad,et al.  The molecular classification of the clinical manifestations of Crohn's disease. , 2002, Gastroenterology.

[8]  J. Belaiche,et al.  Behaviour of Crohn's disease according to the Vienna classification: changing pattern over the course of the disease , 2001, Gut.

[9]  W. Sandborn,et al.  Diagnosis and Treatment of Perianal Fistulas in Crohn Disease , 2001, Annals of Internal Medicine.

[10]  F. T. Veloso,et al.  Clinical Outcome of Crohn's Disease: Analysis According to the Vienna Classification and Clinical Activity , 2001, Inflammatory bowel diseases.

[11]  T. Bayless,et al.  Methodologic Pitfalls in the Determination of Genetic Anticipation: The Case of Crohn Disease , 2001, Annals of Internal Medicine.

[12]  S. Fisher,et al.  Association between insertion mutation in NOD2 gene and Crohn's disease in German and British populations , 2001, The Lancet.

[13]  Mourad Sahbatou,et al.  Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease , 2001, Nature.

[14]  Judy H. Cho,et al.  A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease , 2001, Nature.

[15]  J. Cavanaugh,et al.  International collaboration provides convincing linkage replication in complex disease through analysis of a large pooled data set: Crohn disease and chromosome 16. , 2001, American journal of human genetics.

[16]  M. Daly,et al.  The IBD1 locus for susceptibility to Crohn's disease has a greater impact in Ashkenazi Jews with early onset disease , 2001, American Journal of Gastroenterology.

[17]  C. Panhuysen,et al.  Linkage heterogeneity for the IBD1 locus in Crohn's disease pedigrees by disease onset and severity. , 2000, Gastroenterology.

[18]  S. Vermeire,et al.  Familial and Sporadic Inflammatory Bowel Disease: Different Entities? , 2000, Inflammatory bowel diseases.

[19]  D. Jewell,et al.  A Simple Classification of Crohn's Disease: Report of the Working Party for the World Congresses of Gastroenterology, Vienna 1998 , 2000, Inflammatory bowel diseases.

[20]  E. Jabs,et al.  American families with Crohn's disease have strong evidence for linkage to chromosome 16 but not chromosome 12. , 1998, Gastroenterology.

[21]  E. J. Schoon,et al.  Inflammatory Bowel Disease: Is There Any Relation Between Smoking Status and Disease Presentation? , 1998 .

[22]  B. Childs,et al.  Crohn's disease: influence of age at diagnosis on site and clinical type of disease. , 1996, Gastroenterology.

[23]  E. Mellits,et al.  Crohn's disease: concordance for site and clinical type in affected family members--potential hereditary influences. , 1996, Gastroenterology.

[24]  P. Rutgeerts,et al.  Familial aggregation in Crohn's disease: increased age-adjusted risk and concordance in clinical characteristics. , 1996, Gastroenterology.

[25]  J. Belaiche,et al.  Clinical characteristics of Crohn's disease in 72 families. , 1996, Gastroenterology.

[26]  F. Carbonnel,et al.  Effects of cigarette smoking on the long-term course of Crohn's disease. , 1996, Gastroenterology.

[27]  P. Aeberhard,et al.  Surgical recurrence of perforating and nonperforating Crohn's disease , 1996, Diseases of the colon and rectum.

[28]  E. Baráth,et al.  Fundamentals of Biostatistics. , 1992 .

[29]  B. Huitfeldt,et al.  Smoking in Crohn's disease: effect on localisation and clinical course. , 1992, Gut.

[30]  D. Podolsky,et al.  Inflammatory bowel disease (1) , 1991, The New England journal of medicine.

[31]  D. Sachar,et al.  Perforating and non-perforating indications for repeated operations in Crohn's disease: evidence for two clinical forms. , 1988, Gut.

[32]  A. Berger.  FUNDAMENTALS OF BIOSTATISTICS , 1969 .

[33]  Judy H. Cho,et al.  Crohn's disease-associated NOD2 variants share a signaling defect in response to lipopolysaccharide and peptidoglycan. , 2003, Gastroenterology.

[34]  S. Targan,et al.  Mutations in NOD2 are associated with fibrostenosing disease in patients with Crohn's disease. , 2002, Gastroenterology.

[35]  E. J. Schoon,et al.  Inflammatory bowel disease: is there any relation between smoking status and disease presentation? European Collaborative IBD Study Group. , 1998, Inflammatory bowel diseases.

[36]  J. Lennard-jones,et al.  Classification of inflammatory bowel disease. , 1989, Scandinavian journal of gastroenterology. Supplement.