Our results agree with the strategy of shortening the

Our results agree with the strategy of shortening the duration of dual NS5B/NS5A combined therapy to 8weeks, but based on an on-treatment response predictor rather than a baseline variable. This supports the findings of many other studies for the validity of early on-treatment response kinetics as a powerful positive predictor for the sustained virologic response to different combinations of DAAs therapy (Sulkowski et al., 2016; Maasoumy et al., 2016; D\'Offizi et al., 2017).
Role of the Funding Source Abbass Helmy Charity and Pharco shared in funding the study, they learning pathways contributed to study design, participated in the collection, analysis, and interpretation of data, and in preparation and approval of this report. All authors had access to all relevant study data, reviewed and approved the final report, and take full responsibility for the accuracy of the data and statistical analysis. The corresponding author had full access to all relevant study data and had final responsibility for the decision to submit for publication.
We thank Abbass Helmy Charity establishment and Pharco for their sincere help and support for the study.
Introduction Crohn\'s disease is a chronic inflammatory disease of the gastrointestinal tract believed to result from the interaction between genetic and environmental factors, leading to an inappropriate immune response to intestinal microbes (Knights et al., 2013). However, identifying reproducible gene-environment interactions in patients with Crohn\'s disease remains elusive. Previous studies examining the effects of NOD2 (nucleotide binding oligomerization domain containing 2) on Crohn\'s disease focus on three single nucleotide polymorphisms (SNPs): 1007fs, G908R, and R702W. Individuals with the 1007fs variant have a 4-fold increased odds of developing Crohn\'s disease, while the G908R variant triples and the R702W variant doubles the odds of Crohn\'s disease (Economou et al., 2004). Active and ex-smokers both have an approximately 2-fold increase in the odds of developing Crohn\'s disease (Mahid et al., 2006). Although NOD2 and smoking both independently increase the risk of Crohn\'s disease, an interactive effect is not consistently demonstrated. Some studies demonstrated a negative interaction between NOD2 and smoking (de Diego et al., 2006; Helbig et al., 2012) while others failed to demonstrate a significant interaction (Mardini et al., 2005; Mendoza et al., 2003). In part, this may be explained by age-specific effects of genetic and environmental factors. Genetic susceptibility may play a larger role in patients with early-onset Crohn\'s disease (i.e., diagnosis before age 16) compared to those diagnosed later in life (i.e., after age 40) (de Ridder et al., 2007). In contrast, patients with late-onset Crohn\'s disease may have a greater cumulative exposure to environmental factors (e.g., longer history of smoking) than those with early-onset Crohn\'s disease. The aim of this study was to systematically review and summarize the current knowledge of NOD2-smoking interactions in Crohn\'s disease, including SNP-specific NOD2-smoking interactions, and carry out a case-only study to explore the role of age at diagnosis on the association between NOD2 and smoking.
Materials and Methods
Results
Discussion We systematically reviewed the interaction between NOD2 and cigarette smoking in Crohn\'s disease by analyzing 18 studies with >9000 patients, including previously unpublished data from 14 studies. Our pooled analyses demonstrated that the negative association between NOD2 and cigarette smoking was specific to the 1007fs variant. Moreover, our case-only study showed that the prevalence of both the 1007fs mutation and cigarette smoking vary across ages at diagnosis such that with advancing age, the prevalence of the 1007fs variant decreases and exposure to cigarette smoke increases. These findings may explain inconsistencies between studies and the elusiveness of identifying reproducible gene-environment interactions.