title: Genotype-phenotype analysis of the Crohn's disease susceptibility haplotype on chromosome 5q31.
abstract: OBJECTIVE
  Recent molecular data suggest that genetic factors may underlie the disease heterogeneity observed in both ulcerative colitis (UC) and Crohn's disease (CD). A locus on chromosome 5q has been implicated in susceptibility to CD, and recently refined by linkage disequilibrium mapping to a conserved 250 kb haplotype (5q31). No data regarding the contribution of this locus to clinical phenotype exist. In this case control study, we investigated the contribution of this haplotype to both susceptibility and phenotype of CD and UC.
  
  
  METHODS
  We studied 330 Caucasian CD and 457 UC patients recruited from a single UK centre. Association with disease susceptibility and phenotype was analysed with haplotypes reconstructed from three single nucleotide polymorphisms chosen to span this susceptibility region. Evidence for possible genetic epistasis between IBD5 and NOD2/CARD15 was sought.
  
  
  RESULTS
  Linkage disequilibrium across this region was confirmed, with two haplotypes comprising 88% of all chromosomes. Susceptibility to CD, but not to UC, was associated with homozygosity for a common haplotype, H2 (p(c)=0.002; relative risk (RR) 2.0). Genotype-phenotype analyses demonstrated that this association was particularly strong in patients with perianal disease (p(c)=0.0005; RR 1.7), especially in individuals homozygous for this haplotype (p(c)=0.0005; RR 3.0). Importantly, no association with H2 was found in 186 patients without perianal disease. No evidence of epistasis between IBD5 and NOD2/CARD15 was demonstrated.
  
  
  CONCLUSIONS
  The IBD5 risk haplotype is associated with CD only. Genotype-phenotype analysis reveals that the strongest association is observed in patients with perianal CD. While the precise gene involved is unclear, these data provide further molecular evidence for a genetic basis of the clinical heterogeneity of CD.
authors.affiliation: Gastroenterology Unit, University of Oxford, Gibson Laboratories, Radcliffe Infirmary, Oxford, UK. alearmuzzi@yahoo.com
authors.forename: A
authors.initials: A
authors.lastname: Armuzzi
authors.forename: T
authors.initials: T
authors.lastname: Ahmad
authors.forename: K-L
authors.initials: KL
authors.lastname: Ling
authors.forename: A
authors.initials: A
authors.lastname: de Silva
authors.forename: S
authors.initials: S
authors.lastname: Cullen
authors.forename: D
authors.initials: D
authors.lastname: van Heel
authors.forename: T R
authors.initials: TR
authors.lastname: Orchard
authors.forename: K I
authors.initials: KI
authors.lastname: Welsh
authors.forename: S E
authors.initials: SE
authors.lastname: Marshall
authors.forename: D P
authors.initials: DP
authors.lastname: Jewell
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics*; D003424:Crohn Disease / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D012307:Risk Factors