Polymorphisms in NFkB, PXR, LXR and risk of colorectal cancer in a prospective study of Danes.
BACKGROUND
Transcription factors and nuclear receptors constitute a link between exposure to heterocyclic amines and polycyclic aromatic hydrocarbons from meat and tobacco smoke and colorectal cancer (CRC) risk. The aim of this study was to investigate if polymorphisms in nuclear factor kappa-B, pregnane X receptor, and liver X receptor were associated with risk of CRC, and to investigate possible interactions with lifestyle factors such as smoking, meat consumption, and NSAID use.


METHODS
The polymorphisms nuclear factor kappa-B (NFkB, NFKB1) -94 insertion/deletion ATTG (rs28362491), pregnane X receptor (PXR, NR1I2) A-24381C (rs1523127), C8055T (rs2276707), A7635G (rs6785049), liver X receptor (LXR-β, NR1H3) C-rs1405655T, T-rs2695121C were assessed together with lifestyle factors in a nested case-cohort study of 378 CRC cases and 756 random participants from the Danish prospective Diet, Cancer and Health study of 57,053 persons.


RESULTS
Carriers of NFkB -94deletion were at 1.45-fold higher risk of CRC than homozygous carriers of the insertion allele (incidence rate ratio (IRR) = 1.45, 95% confidence interval (95% CI): 1.10-1.92). There was interaction between this polymorphism and intake of red and processed meat in relation to CRC risk. Carriers of NFkB -94deletion were at 3% increased risk pr 25 gram meat per day (95% CI: 0.98-1.09) whereas homozygous carriers of the insertion were not at increased risk (p for interaction = 0.03). PXR and LXR polymorphisms were not associated with CRC risk. There was no interaction between use of nonsteroid antiinflammatory drugs (NSAID) or smoking status and NFkB, PXR or LXR polymorphisms.


CONCLUSIONS
A polymorphism in NFkB was associated with CRC risk and there was interaction between this polymorphism and meat intake in relation to CRC risk. This study suggests a role for NFkB in CRC aetiology.
Andersen
Vibeke
V
Medical Department, Viborg Regional Hospital, Heibergs Allé 4, DK-8800 Viborg, Denmark. vibeke.andersen@viborg.rm.dk
Christensen
Jane
J
Overvad
Kim
K
Tjønneland
Anne
A
Vogel
Ulla
U
D016022:Case-Control Studies; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000097:blood / Q000235:genetics* / Q000473:pathology; D004273:DNA, Neoplasm / Q000235:genetics; D004032:Diet; D005260:Female; D005838:Genotype; D006801:Humans; D000071518:Liver X Receptors; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000235:genetics*; D057093:Orphan Nuclear Receptors / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic / Q000235:genetics*; D000077297:Pregnane X Receptor; D011379:Prognosis; D011446:Prospective Studies; D011987:Receptors, Steroid / Q000235:genetics*
D004273:DNA, Neoplasm; D000071518:Liver X Receptors; D016328:NF-kappa B; C000605213:NR1H3 protein, human; C000625852:NR1I2 protein, human; D057093:Orphan Nuclear Receptors; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid