Brief Article
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World J Gastroenterol. May 7, 2014; 20(17): 5008-5016
Published online May 7, 2014. doi: 10.3748/wjg.v20.i17.5008
Prediction of Crohn’s disease aggression through NOD2/CARD15 gene sequencing in an Australian cohort
Maneesha Bhullar, Finlay Macrae, Gregor Brown, Margie Smith, Ken Sharpe
Maneesha Bhullar, Finlay Macrae, Gregor Brown, Department of Colorectal Medicine and Genetics, 3 Centre, The Royal Melbourne Hospital, Parkville 3052, Australia
Margie Smith, Department of Molecular Genetics, CMR Room 204, Pathology, The Royal Melbourne Hospital, Parkville 3052, Australia
Ken Sharpe, Department of Statistics, University of Melbourne, Parkville 3050, Australia
Author contributions: Bhullar M and Macrae F recruited the patients and wrote the manuscript; Bhullar M, Macrae F and Brown G designed the study methodology; Smith M conducted the genetic sequencing and interpretation of the genetic material; Sharpe K performed the statistical analysis of the data.
Supported by Schering Plough
Correspondence to: Maneesha Bhullar, MBBS, MedSc, Department of Colorectal Medicine and Genetics, 3 Centre, The Royal Melbourne Hospital, Grattan St, Parkville 3052, Australia. maneesha.bhullar@mh.org.au
Telephone: +61-4-21205039 Fax: +61-4-67728130
Received: April 25, 2013
Revised: September 12, 2013
Accepted: September 16, 2013
Published online: May 7, 2014
Abstract

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 3020insC 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 3020insC mutation have a higher frequency of operations compared to those without the mutation. Patients with the 3020insC 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.

Keywords: Inflammatory bowel disease, Oligomerisation domain 2/caspase recruitment domains 15, Genotyping, Crohn’s disease, Natural history

Core tip: This study conducted a full gene sequencing of nNucleotide-binding oligomerisation domain 2/caspase recruitment domains 15 (NOD2/CARD15) within an Australian cohort of patient with Crohn’s disease (CD). In this study, there was a trend to suggest that patients with the 3020insC mutation have a higher frequency of operations compared to those without the mutation. Patients with the 3020insC mutation had a significantly shorter time between the diagnosis of CD and initial surgery. The clinical significance of understanding pathogenic NOD2/CARD15 mutations is to shift management to a top down approach whereby active medical therapy could be introduced at an early stage to impact on aggressive disease behaviour in mutation positive patients.