Genotype-phenotype analysis of the Crohn’s disease susceptibility haplotype on chromosome 5q31

• Published in: Gut Vol. 52; no. 8; pp. 1133 - 1139
• Main Authors: Armuzzi, A, Ahmad, T, Ling, K-L, de Silva, A, Cullen, S, van Heel, D, Orchard, T R, Welsh, K I, Marshall, S E, Jewell, D P
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd and British Society of Gastroenterology 01-08-2003; BMJ; BMJ Publishing Group Ltd; BMJ Publishing Group LTD; Copyright 2003 by Gut
• Subjects: Adolescent; Adult; Age; Age of Onset; Aged; Aged, 80 and over; Biological and medical sciences; CARD15; caspase recruitment domain containing protein 15; Child; Child, Preschool; Chromosomes; Chromosomes, Human, Pair 5 - genetics; Crohn Disease - genetics; Crohn's disease; Crohns disease; Ethnicity; Evaluation; Family medical history; Female; Gastroenterology. Liver. Pancreas. Abdomen; Gene Frequency; Genes; Genetic aspects; Genetic Predisposition to Disease; genetics; Genomes; Genotype; genotype-phenotype analysis; Haplotypes; Humans; IBD; IBD5; Infant; Inflammatory Bowel Disease; interleukin; Male; Medical sciences; Middle Aged; Molecular genetics; Other diseases. Semiology; PAR; Phenotype; population attributable risk; relative risk; Risk Factors; single nucleotide polymorphism; SNP; Statistics; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Studies; ulcerative colitis; United Kingdom; Human; Crohn disease; Phenotype; Digestive diseases; Intestinal disease; Genotype; Genetics; Chromosome B5; Haplotype; Inflammatory disease
• ISSN: 0017-5749; 1468-3288; 1458-3288
• DOI: 10.1136/gut.52.8.1133

Background and aims: 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. Patients and 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 (pc=0.002; relative risk (RR) 2.0). Genotype-phenotype analyses demonstrated that this association was particularly strong in patients with perianal disease (pc=0.0005; RR 1.7), especially in individuals homozygous for this haplotype (pc=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.