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    • Our study provides the most comprehensive

    2018-11-03

    Our study provides the most comprehensive review of NOD2-smoking interactions in Crohn\'s disease, includes previously unpublished data, and evaluates the impact of age at diagnosis on this cathepsin inhibitor interaction. Nonetheless, limitations should be considered. Firstly, the association between NOD2 and smoking was not adjusted for potential confounders (e.g., age, family history). Also, the quality of the meta-analysis was dependent on the quality of the individual studies that were included. With regard to the case-only study we were limited by sample size, which impeded our ability to calculate age-specific ORs for the interaction between NOD2 and smoking and to investigate the role of sub-phenotypes of Crohn\'s disease (i.e., disease location and behavior). Gene-environment interactions for Crohn\'s disease are difficult to identify. Our meta-analysis demonstrated that gene-environment interaction studies need to be designed to assess SNP-specific effects, such that only 100fs variant of NOD2 interacted with smoking. Moreover, our case-only study showed that the negative interaction between the 1007fs variant of NOD2 and smoking may be influenced by the contrasting prevalence of NOD2 and smoking across ages at diagnosis with Crohn\'s disease. This is one example of how gene-environment interactions may depend on sub-phenotypes of Crohn\'s disease. Thus, we suggest that future gene-environment studies should be powered to assess SNP-specific interactions and be designed to evaluate interactions in specific phenotypes of patients with Crohn\'s disease.
    Funding Sources This project was funded by Alberta Innovates - Health Solutions and a CIHR Team Grant (Health Challenges in Chronic Inflammation). Funders had no role in the study design, data analysis, and interpretation of the study results.
    Conflict of Interest
    Author Contributions Guarantor of the Article: Gilaad G. Kaplan, MD MPH. Specific Author Contributions: Study concept and design: MEK, BE, CHS, CB, GGK. Data acquisition: MEK, JY, SC, PLL, GGK. Interpretation of the data: MEK, HWB, BE, CHS, CB, RP, SG, MSS, PLL, GGK. Statistical analysis: MEK, GGK. Drafting of the manuscript: MEK, BE, CHS, CB, GGK. Critical revision of the manuscript for important intellectual content: HWB, RP, SG, MSS, PLL, JY, SC, PLB, RF, LAD, KM. Final approval of the manuscript: MEK, JY, SC, BE, CHS, CB, HWB, MSS, PLL, PLB, RF, LAD, KM, RP, SG, GGK.
    Acknowledgements The study authors would like to thank the authors of the following studies for providing additional data: Ananthakrishnan et al. (2014) (Ashwin Ananthakrishnan); Cleynen et al. (2013) (Isabelle Cleynen); Cucchiara et al. (2007) (Anna Latiano, Vito Annese); Doecke et al. (2015) (James Doecke, Graham Radford-Smith); Fowler et al. (2014) (Sharyle Fowler, Vijay Yajnik); Giachino et al. (2004) (Mario De Marchi); Henckaerts et al. (2009) (Isabelle Cleynen, Liesbet Henckaerts); Karban et al. (2011) (Amir Karban); Laghi et al. (2005) (Alberto Malesci); Lakatos et al. (2005) (Peter Lakatos); Latiano (2008) (Anna Latiano, Vito Annese); Lauriola et al. (2011) (Mattia Lauriola); Maconi et al. (2009) (Giovanni Maconi); Protic et al. (2008) (Marijana Protic); Nagy et al. (2005) (Zsuzsanna Nagy); Renda et al. (2008) (Mario Cottone); Walker et al. (2004) (Marian Aldhous, Hazel E. Drummond, Jack Satsangi). We acknowledge the support of the Alberta IBD Consortium with data derived from patient registries from the Intestinal Inflammation Tissue Bank (IITB) at the University of Calgary and the Center of Excellence for Gastrointestinal Inflammation and Immunity Research (CEGIIR) at the University of Alberta. Gil Kaplan holds a CIHR Embedded Clinician Research Award and an Alberta Innovates Population Health Award.
    Introduction Aortic aneurysms and dissections are associated with high morbidity and mortality, accounting for over 152,000 deaths in the United States per annum (Benjamin et al., 2017). These are life-threatening diseases due to the predisposition for rupture. About 40% of patients with aortic dissection die immediately and have no enough time to reach a hospital. Aortic medial degeneration (AMD) is considered proceed thoracic aortic aneurysms and dissections (TAAD). AMD is histopathologically characterized by loss of smooth muscle cells (SMCs), and increased proteoglycans degradation.