Polymorphisms in NFKB1 and TLR4 and interaction with dietary and life style factors in relation to colorectal cancer in a Danish prospective case-cohort study

PLoS One. 2015 Feb 23;10(2):e0116394. doi: 10.1371/journal.pone.0116394. eCollection 2015.

Abstract

Maintenance of a balance between commensal bacteria and the mucosal immune system is crucial and intestinal dysbiosis may be a key event in the pathogenesis of colorectal cancer (CRC). The toll-like receptor 4 (TLR4) is an important pattern-recognition receptor that regulates inflammation and barrier function in the gut by a mechanism that involves activation of the nuclear factor-κB (NF-κB) transcription factor. Dietary and life style factors may impact these functions. We therefore used a Danish prospective case-cohort study of 1010 CRC cases and 1829 randomly selected participants from the Danish Diet, Cancer and Health cohort to investigate three polymorphisms in NFKB1 and TLR4 and their possible interactions with diet and life style factors in relation to risk of CRC. Homozygous carriage of the variant allele of the TLR4/rs5030728 polymorphism was associated with increased risk of CRC (incidence rate ratio (IRR) = 1.30; 95% confidence interval (CI): 1.05-1.60; P = 0.02 (gene-dose model); IRR = 1.24; 95%CI: 1.01-1.51; P = 0.04 (recessive model)). Del-carriers of the NFKB1/rs28362491 polymorphism had a 17% (95%CI: 1.03-1.34; P = 0.02) increased risk of CRC compared to homozygous carriers of the ins-allele. However, none of these risk estimates withstood adjustment for multiple comparisons. We found no strong gene-environment interactions between the examined polymorphism and diet and life style factors in relation to CRC risk.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Case-Control Studies
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / pathology
  • Denmark
  • Diet*
  • Female
  • Gene-Environment Interaction
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Genotype
  • Humans
  • Life Style*
  • Male
  • Middle Aged
  • NF-kappa B p50 Subunit / genetics*
  • Polymorphism, Single Nucleotide*
  • Prospective Studies
  • Toll-Like Receptor 4 / genetics*

Substances

  • NF-kappa B p50 Subunit
  • NFKB1 protein, human
  • Toll-Like Receptor 4

Grants and funding

The project was supported by a PhD stipend from the Danish Research Councils in the programme ‘An integrated approach to risk-benefit assessment of human health effects of food and food contaminants’ (Forskeruddannelse 2009-10), and by a Mobility PhD grant (09-06 7572) from the Danish Council for Independent Research (www.ufm.dk) and as part of the project: “Beef versus pork consumption in the etiology of cancers in the colon and rectum: investigations performed within the Diet, Cancer and Health cohort” also from the Danish Council for Independent Research; Medical Sciences (grant no. 09-073597) (www.ufm.dk). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.