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Open Access Research article

A case-only study of gene-environment interaction between genetic susceptibility variants in NOD2 and cigarette smoking in Crohn's disease aetiology

Katherine L Helbig1*, Michael Nothnagel2, Jochen Hampe3, Tobias Balschun4, Susanna Nikolaus3, Stefan Schreiber34, Andre Franke4 and Ute Nöthlings15

Author Affiliations

1 Institute for Experimental Medicine, Section of Epidemiology, Christian-Albrechts-University of Kiel, Arnold-Heller-Straβe 3, Haus 3, 24105 Kiel, Germany

2 Institute of Medical Informatics and Statistics, Christian-Albrechts-University of Kiel, Kiel, Germany

3 Department of General Internal Medicine, University Hospital Schleswig-Holstein, Christian-Albrechts-University of Kiel, Kiel, Germany

4 Institute for Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany

5 Biobank popgen, University Hospital Schleswig-Holstein, Christian-Albrechts-University of Kiel, Kiel, Germany

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BMC Medical Genetics 2012, 13:14  doi:10.1186/1471-2350-13-14

Published: 14 March 2012

Abstract

Background

Genetic 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.

Methods

Three 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.

Results

We 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).

Conclusions

The 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.

Keywords:
Gene-environment interaction; Case-only; Crohn's disease; NOD2/CARD15; Cigarette smoking