Genetic variants in TNF-a but not DLG5 are associated with inflammatory bowel disease in a large United Kingdom cohort

• Published in: Inflammatory bowel diseases Vol. 12; no. 3; pp. 178 - 184
• Main Authors: Tremellingcp, Mark, Waller, Sarah, Bredin, Francesca, Parkes, Simon Greenfield Miles, Dm
• Format: Journal Article
• Language: English
• Published: 01.03.2006
• Subjects: chromosome 10; chromosome 6; Crohn's disease; Cytokines; Epistasis; Gene frequency; Gene mapping; Gene polymorphism; Inflammatory bowel diseases; Mapping; NOD2 protein; Promoters; Tumor necrosis factor; Tumor necrosis factor- alpha; Ulcerative colitis
• ISSN: 1078-0998
• DOI: 10.1097/01.MIB.0000217766.90766.37

Background: Genetic variants in DLG5, which encodes a scaffolding protein on chromosome 10q23, and tumor necrosis factor (TNF)-, encoding a proinflammatory cytokine on chromosome 6p, have recently been reported to be associated with inflammatory bowel disease (IBD). We studied these variants to seek evidence of association with IBD in a large independent dataset. Methods: We genotyped 1104 unrelated white IBD subjects-496 with Crohn's disease, 512 with ulcerative colitis, and 96 with indeterminate colitis from the Cambridge/Eastern (UK) panel-and 760 healthy control subjects for DLG5_113G/A, DLG5_4136C/A, TNF-857C/T, and TNF-1031T/C polymorphisms. Known Crohn's disease-predisposing variants in CARD15/NOD2 were also genotyped to permit analysis for reported epistatic interactions. Results: TNF-857 was shown to be associated with IBD overall (P = 0.0079). A formal interaction test showed that TNF-857 is associated equally with ulcerative colitis and Crohn's disease. Neither of the DLG5 alleles, however, was associated with IBD (P = 0.32 and 0.35). Subgroup analysis also failed to show evidence of association between either DLG5 allele or genotype frequencies and ulcerative colitis or Crohn's disease. Stratification of TNF- and DLG5 cases by CARD15 genotype made no significant difference in the strength of associations. Conclusions: We have confirmed an association between the TNF-857 promoter polymorphism and IBD in a large independent UK dataset but were unable to replicate an association at the previously reported loci within DLG5. This may reflect heterogeneity between the populations, a smaller effect size than originally predicted, or possibly a false-positive result in the original study. Further fine mapping studies of the TNF promoter region and studies assessing functional consequences of TNF promoter polymorphisms are now required in IBD.