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

Highlights

• There is a negative interaction between NOD2 smoking in Crohn's disease and it is specific to the 1007fs variant.

• With increasing age, the prevalence of the 1007fs variant decreases and exposure to cigarette smoke increases.

• Contrasting trends in the 1007fs variant and cigarette smoking may explain the negative NOD2-smoking interaction.

We reviewed 18 studies evaluating NOD2-smoking interactions in Crohn's disease. Only the 1007fs variant interacted with smoking. Smokers with this mutation were less likely to develop Crohn's disease. We then conducted a study of 627 patients with Crohn's disease, which showed that the 1007fs variant was common in young patients and rare in older patients, whereas smoking was more common among older patients. The decreasing prevalence of 1007fs mutation and increasing exposure to smoking as age of diagnosis advances may explain the negative interaction between NOD2 and smoking observed in our meta-analysis. Our study highlights the challenges of identifying gene-environment interactions.

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 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.