title: Prediction of Crohn's disease aggression through NOD2/CARD15 gene sequencing in an Australian cohort.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Maneesha Bhullar, Finlay Macrae, Gregor Brown, Department of Colorectal Medicine and Genetics, 3 Centre, The Royal Melbourne Hospital, Parkville 3052, Australia.
authors.forename: Maneesha
authors.initials: M
authors.lastname: Bhullar
authors.affiliation: Maneesha Bhullar, Finlay Macrae, Gregor Brown, Department of Colorectal Medicine and Genetics, 3 Centre, The Royal Melbourne Hospital, Parkville 3052, Australia.
authors.forename: Finlay
authors.initials: F
authors.lastname: Macrae
authors.affiliation: Maneesha Bhullar, Finlay Macrae, Gregor Brown, Department of Colorectal Medicine and Genetics, 3 Centre, The Royal Melbourne Hospital, Parkville 3052, Australia.
authors.forename: Gregor
authors.initials: G
authors.lastname: Brown
authors.affiliation: Maneesha Bhullar, Finlay Macrae, Gregor Brown, Department of Colorectal Medicine and Genetics, 3 Centre, The Royal Melbourne Hospital, Parkville 3052, Australia.
authors.forename: Margie
authors.initials: M
authors.lastname: Smith
authors.affiliation: Maneesha Bhullar, Finlay Macrae, Gregor Brown, Department of Colorectal Medicine and Genetics, 3 Centre, The Royal Melbourne Hospital, Parkville 3052, Australia.
authors.forename: Ken
authors.initials: K
authors.lastname: Sharpe
mesh_terms: D000328:Adult; D000368:Aged; D003424:Crohn Disease / Q000175:diagnosis* / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005091:Exons; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics*; D010641:Phenotype; D011237:Predictive Value of Tests; D012307:Risk Factors; D012720:Severity of Illness Index; D014739:Victoria
chemical_list: C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein
keywords: Crohn’s disease; Genotyping; Inflammatory bowel disease; Natural history; Oligomerisation domain 2/caspase recruitment domains 15