The Interaction Between NOD2 and Smoking Is Specific to the 1007fs SNP of the NOD2 Gene in Crohnʼs Disease: A Systematic Review and Meta-analysis

Abstract

Introduction: NOD2 variants and cigarette smoking are both commonly implicated risk factors for Crohn's disease (CD). The three most commonly studied single nucleotide polymorphisms (SNP) of the NOD2 gene are 1007fs, G908R, and R072W. However, only the 1007fs SNP has been confirmed as the susceptibility NOD2 gene for Crohn's disease in a genome-wide meta-analysis. Prior studies examining the interaction between NOD2 variants and cigarette smoking have reported heterogeneous findings. Because many of these studies were underpowered, the 1007fs, G908R, and R072W SNPs were often pooled together rather than evaluated individually. We hypothesize that some of the heterogeneity observed between studies is explained by SNP-specific NOD2-smoking interactions. Methods: We searched MEDLINE and EMBASE for studies that provided data on both NOD2 and cigarette smoking among patients with CD. Authors were contacted if the interaction was not reported or when the 1007fs, G908R, and R072W variants were combined. Pooled odds ratios (OR) and 95% confidence intervals (CIs) were calculated using random effects models to estimate the NOD2-smoking interaction. Smoking status was defined as ever or never. We compared the odds of smoking for carriers of a NOD2 mutation to those without a NOD2 mutation. All analyses were a priori conducted separately for the 1007fs, G908R, and R702W variants. Heterogeneity was assessed using the I2 and Cochran Q statistic. Publication bias was assessed using the Begg and Mazumdar adjusted rank correlation test. Results: Ten studies provided SNP-specific NOD2-smoking interaction data. A significant interaction between the 1007fs SNP and smoking (OR 0.66, 95% CI 0.50 to 0.88) was observed (Figure 1). Neither the G908R variant (OR 0.94, 95% CI 0.70 to 1.28) nor the R072W variant (OR 0.92, 95% CI 0.71 to 1.18) were found to have a significant interaction with smoking. Statistically significant heterogeneity and publication bias were not observed for the pooled analyses of 1007fs, G908R, or R702W.Figure 1Conclusion: Only the 1007fs NOD2 variant interacts with cigarette smoking in CD. Individuals with CD who have a 1007fs NOD2 mutation are less likely to smoke prior to their diagnosis. Future geneenvironment studies in CD should be designed and powered to evaluate SNP-specific mutations.