Carriage of CARD15 variants and smoking as risk factors for resective surgery in patients with Crohn's ileal disease

Abstract

Summary Background: It is controversial whether CARD15 variants are truly associated with a more severe form of Crohn's disease. The relative role of CARD15 genotype and smoking in Crohn's disease progression is also debated. Aim: To investigate the association between CARD15 variants and history of resective surgery in patients with Crohn's ileal disease, taking into account smoking as a possible confounding factor. Methods: We originally assessed CARD15 genotype in 239 north Italian Crohn's disease patients (mean follow‐up: 10.1 ± 8.1 years). We then focused on 193 patients with proven ileal involvement, 70 of whom (36.3%) carried CARD15‐mutated alleles (G908R, R702W, L1007fs). Results: Carriage of CARD15 variants was positively associated with family history and ileal‐only disease and negatively associated with uncomplicated behaviour at maximal follow‐up (P < 0.05). Ileal resection was the only variable independently associated with CARD15 variants at multivariate analysis (OR 3.8; 95% CI 1.6–9.2; P = 0.003). Kaplan–Meier analysis showed that ileal resection was favoured both by CARD15 variant‐carriage (P = 0.01) and by smoking (P = 0.05), but smoking did not affect progression to surgery in variant carriers (P = 0.31). Thirteen of 14 (93%) patients being resection‐free at 15‐year follow‐up, had CARD15 wild‐type genotype (P = 0.01), whereas only seven (50%) had never smoked (P = 1.0). Conclusions: In summary, CARD15 variant‐associated Crohn's ileitis is virtually committed to stricturing and/or penetrating disease and, eventually, to resective surgery. Smoking accelerates progression to surgery in patients with wild‐type CARD15 genotype, but it seems to exert no additional effect in CARD15‐variant carriers.

CARD15 mutations in Dutch familial and sporadic inflammatory bowel disease and an overview of European studies

“…Reports regarding an association between CARD15 mutations and a positive family history for IBD are, however, not consistent. While some studies reported a significant association [20,40,42,55,77], most did not [15,25,33,38,41,43,53,[78][79][80][81][82]. In this study, we also found no association between CARD15 carriage and a positive familial history, although the number of patients without a familial history was relatively low compared with the group of familial patients.…”

Role of ASCA and the NOD2/CARD15 mutation Gly908Arg in predicting increased surgical costs in Crohnʼs disease patients: A project of the European Collaborative Study Group on Inflammatory Bowel Disease

“…3,9,[12][13][14] Given that cigarette smoking can accelerate the risk of surgery, 23 the rates of current and/or past smokers were compared with nonsmokers in patients positive or negative for ASCA or Gly908Arg. In view of the fact that young age at diagnosis of CD is associated with more severe disease, 24,25 the age at disease diagnosis in patients with and without ASCA or NOD2/ CARD15 mutations were compared.…”

The NOD2 -Smoking Interaction in Crohn's Disease is likely Specific to the 1007 fs Mutation and may be Explained by Age at Diagnosis: A Meta-Analysis and Case-Only Study

“…1) (de Diego et al, 2006, Helbig et al, 2012, Mendoza et al, 2003, Mardini et al, 2005). An additional 14 studies were included after obtaining SNP-specific data from study authors (Ananthakrishnan et al, 2014, Cleynen et al, 2013, Doecke et al, 2015, Giachino et al, 2004, Henckaerts et al, 2009, Karban et al, 2011, Laghi et al, 2005, Lakatos et al, 2005, Latiano, 2008, Nagy et al, 2005, Protic et al, 2008, Renda et al, 2008, Sabate et al, 2008, Walker et al, 2004). One study providing SNP-specific data was excluded from the analysis due to small cell sizes (Lauriola et al, 2011).…”

“…Our systematic review demonstrated that the majority of NOD2 -smoking studies were underpowered to detect an interaction; for example, 10 identified studies included fewer than 300 participants (de Diego et al, 2006, Giachino et al, 2004, Laghi et al, 2005, Mardini et al, 2005, Mendoza et al, 2003, Protic et al, 2008, Renda et al, 2008, Sabate et al, 2008, Walker et al, 2004, Nagy et al, 2005). Because of these small samples, the three most common NOD2 variants (1007fs, G908R, and R702W) were often combined.…”