The NOD2-Smoking Interaction in Crohn's Disease is likely Specific to the 1007 fs Mutation and may be Explained by Age at Diagnosis: A Meta-Analysis and Case-Only Study
M. Ellen Kuenzig,
Jeff Yim,
Stephanie Coward,
Bertus Eksteen,
Cynthia H. Seow,
Cheryl Barnabe,
Herman W. Barkema,
Mark S. Silverberg,
Peter L. Lakatos,
Paul L. Beck,
Richard Fedorak,
Levinus A. Dieleman,
Karen Madsen,
Remo Panaccione,
Subrata Ghosh,
Gilaad G. Kaplan
Affiliations
M. Ellen Kuenzig
Department of Medicine, University of Calgary, Calgary, Alberta, Canada
Jeff Yim
Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
Stephanie Coward
Department of Medicine, University of Calgary, Calgary, Alberta, Canada
Bertus Eksteen
Department of Medicine, University of Calgary, Calgary, Alberta, Canada
Cynthia H. Seow
Department of Medicine, University of Calgary, Calgary, Alberta, Canada
Cheryl Barnabe
Department of Medicine, University of Calgary, Calgary, Alberta, Canada
Herman W. Barkema
Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada
Mark S. Silverberg
Zane Cohen Centre for Digestive Diseases, Division of Gastroenterology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
Peter L. Lakatos
McGill University, Montreal General Hospital, Montreal, Quebec, Canada
Paul L. Beck
Department of Medicine, University of Calgary, Calgary, Alberta, Canada
Richard Fedorak
Department of Medicine, Division of Gastroenterology and CEGIIR, University of Alberta, Edmonton, Canada
Levinus A. Dieleman
Department of Medicine, Division of Gastroenterology and CEGIIR, University of Alberta, Edmonton, Canada
Karen Madsen
Department of Medicine, Division of Gastroenterology and CEGIIR, University of Alberta, Edmonton, Canada
Remo Panaccione
Department of Medicine, University of Calgary, Calgary, Alberta, Canada
Subrata Ghosh
Department of Medicine, University of Calgary, Calgary, Alberta, Canada
Gilaad G. Kaplan
Department of Medicine, University of Calgary, Calgary, Alberta, Canada
Background: NOD2 and smoking are risk factors for Crohn's disease. We meta-analyzed NOD2-smoking interactions in Crohn's disease (Phase 1), then explored the effect of age at diagnosis on NOD2-smoking interactions (Phase 2). Methods: Phase 1: MEDLINE and EMBASE were searched for studies (n = 18) providing data on NOD2 and smoking in Crohn's disease. NOD2-smoking interactions were estimated using odds ratios (ORs) and 95% confidence intervals (CIs) calculated using random effects models. Phase 2: A case-only study compared the proportion of smokers and carriers of the 1007 fs variant across ages at diagnosis (≤16, 17–40, >40 years). Findings: Phase 1: Having ever smoked was less common among carriers of the 1007 fs variant of NOD2 (OR 0.74, 95%CI:0.66–0.83). There was no interaction between smoking and the G908R (OR 0.96, 95%CI:0.82–1.13) or the R702W variant (OR 0.89, 95%CI:0.76–1.05). Phase 2: The proportion of patients (n = 627) carrying the 1007 fs variant decreased with age at diagnosis (≤16 years: 15%; 17–40: 12%; >40: 3%; p = 0.003). Smoking was more common in older patients (≤16 years: 4%; 17–40: 48%; >40: 71%; p < 0.001). Interpretation: The negative NOD2-smoking interaction in Crohn's disease is specific to the 1007 fs variant. However, opposing rates of this variant and smoking across age at diagnosis may explain this negative interaction.
