Kaplan, GilKuenzig, Mary Ellen2016-09-292016-09-2920162016Kuenzig, M. E. (2016). The Impact of Study Methodology on Studying Genetic and Environmental Risk Factors for the Inflammatory Bowel Diseases (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/28191http://hdl.handle.net/11023/3359Inflammatory bowel disease (IBD), comprised of Crohn’s disease and ulcerative colitis, results from a complex interaction between genetic and environmental factors. NOD2 and cigarette smoking are two of the most commonly replicated genetic and environmental risk factors, respectively, for Crohn’s disease. Studies examining the interaction between NOD2 and smoking in patients with Crohn’s disease have reached heterogeneous conclusions. Study methodology may explain these differences. Chapters Three and Four evaluate NOD2-smoking interactions in Crohn’s disease with a focus on study methodology. Chapter Three is a systematic review and meta-analysis that found a negative interaction between NOD2 and smoking. However, this interaction is SNP-specific and influenced by the definition of smoking used (i.e., dichotomizing smoking status vs. separately analyzing current, former, and never smoking). Using a case-only study design (Chapter Four), the impact of age at diagnosis was explored as a potential mechanism for the negative interaction between NOD2 and smoking. Age at diagnosis exhibits opposing trends in the proportion of individuals that carry a NOD2 mutation and smoke, with NOD2 being significantly more common among young individuals while smoking is more common among those older at diagnosis. Combining individuals of all ages artificially results in a negative interaction between these two factors. Chapter Five assesses the association between smoking and the need for surgery in patients with Crohn’s disease or ulcerative colitis in a systematic review and meta-analysis only including studies that separately analyzed current, former, and never smokers. Included studies also incorporated disease duration in the analysis. In the final manuscript, a case-control study using administrative data from Alberta Health was used to examine the association between asthma and Crohn’s disease or ulcerative colitis. Age at diagnosis modified the association between ulcerative colitis and asthma and these two diseases were only associated for individuals under the age of 17 or over the age of 40. The association between asthma and Crohn’s disease was consistently observed across all ages. The conclusions of all four manuscripts emphasize that study methodology may influence study results; this includes how exposure (genetic or environmental) and how sub-phenotypes (i.e., early- or late-onset) of disease are analyzed.engUniversity of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.EpidemiologyInflammatory Bowel DiseaseCrohn's diseaseUlcerative ColitissmokingNOD2Asthmagene-environment interactionsdoctoral thesis10.11575/PRISM/28191