Abstract
BackgroundGenetic variation in NOD2 and cigarette smoking are well-established risk factors for the development of Crohn's disease (CD). However, little is known about a potential interaction between these risk factors. We investigated gene-environment interactions between CD-associated NOD2 alleles and cigarette smoking in a large sample of patients with CD.MethodsThree previously reported CD-associated variants in NOD2 (R702W, G908R, 1007fs) were genotyped in 1636 patients with CD continuously recruited between 1995 and 2010 based on physician referral. Data on history of smoking behaviour was obtained for all participants through a written questionnaire. Using a case-only design, we performed logistic regression analyses to investigate statistical interactions between NOD2 risk alleles and smoking status.ResultsWe detected a significant negative interaction between carriership of at least one of the NOD2 risk alleles and history of ever having smoked (OR = 0.71; p = 0.005) as well as smoking at the time of CD diagnosis (OR = 0.68; p = 0.005). Subsequent separate analyses of the three variants revealed a significant negative interaction between the 1007fs variant and history of ever having smoked (OR = 0.64; p = 9 × 10-4) and smoking at the time of CD diagnosis (OR = 0.53; p = 7 × 10-5).ConclusionsThe observed significant negative gene-environment interaction suggests that the risk increase for CD conferred simultaneously by cigarette smoking and the 1007fs NOD2 polymorphism is smaller than expected and may point to a biological interaction. Our findings warrant further investigation in epidemiological and functional studies to elucidate pathophysiology as well as to aid in the development of recommendations for disease prevention.
Highlights
Genetic variation in NOD2 and cigarette smoking are well-established risk factors for the development of Crohn’s disease (CD)
Among the first and most consistently replicated genetic associations discovered in CD were three variants in NOD2 [6,7], which represent the strongest genetic risk factors for CD identified to date [8]
Using a control population from the popgen biobank as a comparison group, we confirmed smoking as a risk factor for Crohn’s disease in our study population (OR 1.24 (1.04-1.47), p = 0.016 for ever having smoked)
Summary
Genetic variation in NOD2 and cigarette smoking are well-established risk factors for the development of Crohn’s disease (CD). Among the first and most consistently replicated genetic associations discovered in CD were three variants in NOD2 (nucleotidebinding oligomerisation domain containing 2; previously known as CARD15) [6,7], which represent the strongest genetic risk factors for CD identified to date [8]. Associations between CD and the three main susceptibility variants are well-established [11,13,14] with a recent meta-analysis revealing disease odds ratios (OR) under a dominant genetic model of 2.2 (95% CI 2.0-2.5) for the R702W polymorphism, 2.6 (95% CI 2.2-2.9) for G908R, and 3.8 (95% CI 3.4-4.3) for 1007fs [15]. When data for all three variants are combined, the disease OR associated with simple heterozygotes is 2.4 (95% CI 2.02.8) and for compound heterozygotes is 9.0 (95% CI 6.013.5) [15]
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