Genetic variants in TNF-alpha but not DLG5 are associated with inflammatory bowel disease in a large United Kingdom cohort.
BACKGROUND
Genetic variants in DLG5, which encodes a scaffolding protein on chromosome 10q23, and tumor necrosis factor (TNF)-alpha, 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-alpha 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.
Department of Gastroenterology, Addenbrookes Hospital, Cambridge, UK.
Mark
M
Tremelling
Sarah
S
Waller
Francesca
F
Bredin
Simon
S
Greenfield
Miles
M
Parkes
D000328:Adult; D016022:Case-Control Studies; D015331:Cohort Studies; D003093:Colitis, Ulcerative / Q000453:epidemiology / Q000235:genetics / Q000473:pathology; D003424:Crohn Disease / Q000453:epidemiology / Q000235:genetics / Q000473:pathology; D005260:Female; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease / Q000453:epidemiology*; D014644:Genetic Variation; D006801:Humans; D015994:Incidence; D015212:Inflammatory Bowel Diseases / Q000453:epidemiology* / Q000235:genetics* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D012016:Reference Values; D012680:Sensitivity and Specificity; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D006113:United Kingdom / Q000453:epidemiology
C114461:DLG5 protein, human; D005819:Genetic Markers; D008565:Membrane Proteins; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins