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

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.