The NOD2-Smoking Interaction in Crohn's Disease is likely Specific to the 1007fs 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

doi:10.1016/j.ebiom.2017.06.012

The NOD2-Smoking Interaction in Crohn's Disease is likely Specific to the 1007fs Mutation and may be Explained by Age at Diagnosis: A Meta-Analysis and Case-Only Study

EBioMedicine. 2017 Jul:21:188-196. doi: 10.1016/j.ebiom.2017.06.012. Epub 2017 Jun 16.

Authors

M Ellen Kuenzig¹, Jeff Yim², Stephanie Coward¹, Bertus Eksteen³, Cynthia H Seow⁴, Cheryl Barnabe¹, Herman W Barkema⁵, Mark S Silverberg⁶, Peter L Lakatos⁷, Paul L Beck³, Richard Fedorak⁸, Levinus A Dieleman⁸, Karen Madsen⁸, Remo Panaccione³, Subrata Ghosh⁹, Gilaad G Kaplan¹⁰

Affiliations

¹ Department of Medicine, University of Calgary, Calgary, Alberta, Canada; Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada; O'Brien Institute for Public Health, University of Calgary, Calgary, Alberta, Canada; (i)Alberta Inflammatory Bowel Disease Consortium, University of Calgary, Calgary, Alberta, Canada.
² Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada; (i)Alberta Inflammatory Bowel Disease Consortium, University of Calgary, Calgary, Alberta, Canada.
³ Department of Medicine, University of Calgary, Calgary, Alberta, Canada; (i)Alberta Inflammatory Bowel Disease Consortium, University of Calgary, Calgary, Alberta, Canada.
⁴ Department of Medicine, University of Calgary, Calgary, Alberta, Canada; Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada; (i)Alberta Inflammatory Bowel Disease Consortium, University of Calgary, Calgary, Alberta, Canada.
⁵ Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada; O'Brien Institute for Public Health, University of Calgary, Calgary, Alberta, Canada; Faculty of Veterinary Medicine, University of Calgary, Calgary, Alberta, Canada; (i)Alberta Inflammatory Bowel Disease Consortium, University of Calgary, Calgary, Alberta, Canada.
⁶ Zane Cohen Centre for Digestive Diseases, Division of Gastroenterology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada; (i)Alberta Inflammatory Bowel Disease Consortium, University of Calgary, Calgary, Alberta, Canada.
⁷ McGill University, Montreal General Hospital, Montreal, Quebec, Canada; (i)Alberta Inflammatory Bowel Disease Consortium, University of Calgary, Calgary, Alberta, Canada.
⁸ Department of Medicine, Division of Gastroenterology and CEGIIR, University of Alberta, Edmonton, Canada; (i)Alberta Inflammatory Bowel Disease Consortium, University of Calgary, Calgary, Alberta, Canada.
⁹ Department of Medicine, University of Calgary, Calgary, Alberta, Canada; Faculty of Veterinary Medicine, University of Calgary, Calgary, Alberta, Canada; (i)Alberta Inflammatory Bowel Disease Consortium, University of Calgary, Calgary, Alberta, Canada.
¹⁰ Department of Medicine, University of Calgary, Calgary, Alberta, Canada; Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada; O'Brien Institute for Public Health, University of Calgary, Calgary, Alberta, Canada; Faculty of Veterinary Medicine, University of Calgary, Calgary, Alberta, Canada; (i)Alberta Inflammatory Bowel Disease Consortium, University of Calgary, Calgary, Alberta, Canada. Electronic address: [email protected].

Abstract

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 1007fs variant across ages at diagnosis (≤16, 17-40, >40years).

Findings: Phase 1: Having ever smoked was less common among carriers of the 1007fs 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 1007fs variant decreased with age at diagnosis (≤16years: 15%; 17-40: 12%; >40: 3%; p=0.003). Smoking was more common in older patients (≤16years: 4%; 17-40: 48%; >40: 71%; p<0.001).

Interpretation: The negative NOD2-smoking interaction in Crohn's disease is specific to the 1007fs variant. However, opposing rates of this variant and smoking across age at diagnosis may explain this negative interaction.

Keywords: Age; Cigarette smoking; Crohn's disease; Gene-environment interactions; NOD2.

Publication types

Meta-Analysis
Review

MeSH terms

Age Factors
Alleles
Case-Control Studies
Crohn Disease / etiology*
Disease Susceptibility
Female
Gene-Environment Interaction*
Genotype
Humans
Male
Mutation*
Nod2 Signaling Adaptor Protein / genetics*
Nod2 Signaling Adaptor Protein / metabolism
Odds Ratio
Polymorphism, Single Nucleotide
Publication Bias
Smoking / adverse effects*

Substances

NOD2 protein, human
Nod2 Signaling Adaptor Protein