SMAD3 gene variant is a risk factor for recurrent surgery in patients with Crohn's disease

Background and aims: More than 80% of Crohn's disease (CD) patients will require surgery. Surgery is not curative and rates of re-operation are high. Identification of genetic variants associated with repeat surgery would allow risk stratification of patients who may benefit from early aggressive therapy and/or post-operative prophylactic treatment. Methods: CD patients who had at least one CD-related bowel resection were identified from the Prospective Registry in IBD Study at Massachusetts General Hospital (PRISM). The primary outcome was surgical recurrence. Covariates and potential interactions were assessed using the Cox proportional hazard model. Kaplan-Meier curves for time to surgical recurrence were developed for each genetic variant and analyzed with the log-rank test. Results: 194 patients were identified who had at least 1 resection. Of these, 69 had two or more resections. Clinical predictors for repeat surgery were stricturing (HR 4.18, p = 0.022) and penetrating behavior (HR 3.97, p = 0.024). Smoking cessation was protective for repeat surgery (HR 0.45, p = 0.018). SMAD3 homozygosity for the risk allele was also independently associated with increased risk of repeat surgery (HR 4.04, p = 0.001). NOD2 was not associated with increased risk of surgical recurrence. Conclusion: Stricturing and penetrating behavior were associated with increased risk of surgical recurrence, while smoking cessation was associated with a decreased risk. A novel association between SMAD3 and increased risk of repeat operation and shorter time to repeat surgery was observed. This finding is of particular interest as SMAD3 may represent a new therapeutic target specifically for prevention of post-surgical disease recurrence.