Prediction of Crohn's disease aggression through NOD2 /CARD15 gene sequencing in an Australian cohort

Aim: To investigate the association between mutations in oligomerisation domain 2/caspase recruitment domains 15 (NOD2 /CARD15) and the natural history of Crohn's disease (CD) to identify patients who would benefit from early aggressive medical intervention. Methods: We recruited thirty consecutive unrelated CD patients with a history of ileo-caecal or small bowel resection during the period 1980-2000; Fifteen patients of these had post-operative relapse that required further surgery and fifteen did not. Full sequencing of the NOD2 /CARD15 gene using dHPLC for exons 3, 5, 7, 10 and 12 and direct sequencing for exons 2, 4, 6, 8, 9 and 11 was conducted. CD patients categorized as carrying variants were anyone with at least 1 variant of the NOD2 /CARD15 gene. Results: About 13.3% of the cohort (four patients) carried at least one mutant allele of 3020ins C of the NOD2 /CARD15 gene. There were 20 males and 10 females with a mean age of 43.3 years (range 25-69 years). The mean follow up was 199.6 mo and a median of 189.5 mo. Sixteen sequence variations within the NOD2 /CARD15 gene were identified, with 9 of them occurring with an allele frequency of greater than 10 %. In this study, there was a trend to suggest that patients with the 3020ins C mutation have a higher frequency of operations compared to those without the mutation. Patients with the 3020ins C mutation had a significantly shorter time between the diagnosis of CD and initial surgery. This study included Australian patients of ethnically heterogenous background unlike previous studies conducted in different countries. Conclusion: These findings suggest that patients carrying NOD2 /CARD15 mutations follow a rapid and more aggressive form of Crohn's disease showing a trend for multiple surgical interventions and significantly shorter time to early surgery.