Genotype-phenotype analysis in childhood-onset Crohn's disease: NOD2/CARD15 variants consistently predict phenotypic characteristics of severe disease
Article first published online: 14 DEC 2006
Copyright © 2005 Crohn's & Colitis Foundation of America, Inc.
Inflammatory Bowel Diseases
Volume 11, Issue 11, pages 955–964, November 2005
How to Cite
Russell, R. K., Drummond, H. E., Nimmo, E. E., Anderson, N., Smith, L., Wilson, D. C., Gillett, P. M., McGrogan, P., Hassan, K., Weaver, L. T., Bisset, M., Mahdi, G. and Satsangi, J. (2005), Genotype-phenotype analysis in childhood-onset Crohn's disease: NOD2/CARD15 variants consistently predict phenotypic characteristics of severe disease. Inflamm Bowel Dis, 11: 955–964. doi: 10.1097/01.MIB.0000183423.38037.f3
- Issue published online: 14 DEC 2006
- Article first published online: 14 DEC 2006
- Manuscript Accepted: 10 AUG 2005
- Manuscript Received: 9 AUG 2005
- Crohn's disease;
The incidence of early-onset CD in Scotland is among the highest worldwide. Three single nucleotide polymorphisms (SNPs) R702W, G908R and Leu1007finsC in the NOD2/CARD15 gene predispose to adult CD. We investigated the contribution of these variants to disease susceptibility and phenotype in the Scottish early-onset IBD population.
Patients and Methods:
906 individuals including 247 Scottish IBD patients aged <16 years at diagnosis, 414 parents and 245 controls were genotyped. Transmission disequilibrium testing (TDT), case-control analysis and detailed genotype-phenotype analysis were performed.
The Leu1007finsC variant was associated with susceptibility to CD by case-control (4.2% versus. 1.4%, P = 0.01) and TDT analysis (P = 0.006). The Population Attributable Risk (PAR) for the 3 NOD2/CARD15 mutations was 7.9%. Carriage of NOD2/CARD15 variants was associated with, at diagnosis: decreased albumin (31.0% versus. 9.0%, P = 0.001) and raised CRP (25% versus. 9.5%, P = 0.04) and at follow up: need for surgery (39.5% versus. 12.8%, P = 0.0002) jejunal involvement (50% versus. 18.4%, P = 0.01) jejunal and ileal involvement (50% versus. 10.7%, P = 0.009), raised CRP (57.1% and 12.8%, P = 0.0009), lower weight/height centile (75.0% versus. 20.2%, P = 0.03, 50.0% versus. 16.0%, P = 0.001 respectively) and stricturing disease (45.5% versus. 19.4%, P < 0.05). Multifactorial analysis demonstrated carriage was associated with need for surgery (P = 0.004, OR 4.9 [1.5-14.7]).
These NOD2/CARD 15 variants in the Scottish early onset CD population have a definite, albeit relatively small contribution to CD susceptibility (PAR 7.9%) but a major impact on phenotype. In particular NOD2/CARD15 variants are strongly associated with several markers of disease severity in pediatric CD, notably need for surgery.