title: Genotype-phenotype analysis in childhood-onset Crohn's disease: NOD2/CARD15 variants consistently predict phenotypic characteristics of severe disease.
abstract: BACKGROUND
  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.
  
  
  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.
  
  
  RESULTS
  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]).
  
  
  CONCLUSIONS
  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.
authors.affiliation: MRCPCH, Gastrointestinal Unit, Western General Hospital, Crewe Road, Edinburgh, Scotland. rrussell@ed.ac.uk
authors.forename: Richard K
authors.initials: RK
authors.lastname: Russell
authors.forename: Hazel E
authors.initials: HE
authors.lastname: Drummond
authors.forename: Elaine E
authors.initials: EE
authors.lastname: Nimmo
authors.forename: Niall
authors.initials: N
authors.lastname: Anderson
authors.forename: Linda
authors.initials: L
authors.lastname: Smith
authors.forename: David C
authors.initials: DC
authors.lastname: Wilson
authors.forename: Peter M
authors.initials: PM
authors.lastname: Gillett
authors.forename: Paraic
authors.initials: P
authors.lastname: McGrogan
authors.forename: Kamal
authors.initials: K
authors.lastname: Hassan
authors.forename: Lawrence T
authors.initials: LT
authors.lastname: Weaver
authors.forename: Michael
authors.initials: M
authors.lastname: Bisset
authors.forename: Gamal
authors.initials: G
authors.lastname: Mahdi
authors.forename: Jack
authors.initials: J
authors.lastname: Satsangi
mesh_terms: D000293:Adolescent; D017668:Age of Onset; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D003424:Crohn Disease / Q000235:genetics* / Q000473:pathology*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D053473:Nod2 Signaling Adaptor Protein; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012606:Scotland; D012720:Severity of Illness Index
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein