CYP24A1 variant modifies the association between use of oestrogen plus progestogen therapy and colorectal cancer risk

Br J Cancer. 2016 Jan 19;114(2):221-9. doi: 10.1038/bjc.2015.443. Epub 2016 Jan 14.

Abstract

Background: Menopausal hormone therapy (MHT) use has been consistently associated with a decreased risk of colorectal cancer (CRC) in women. Our aim was to use a genome-wide gene-environment interaction analysis to identify genetic modifiers of CRC risk associated with use of MHT.

Methods: We included 10 835 postmenopausal women (5419 cases and 5416 controls) from 10 studies. We evaluated use of any MHT, oestrogen-only (E-only) and combined oestrogen-progestogen (E+P) hormone preparations. To test for multiplicative interactions, we applied the empirical Bayes (EB) test as well as the Wald test in conventional case-control logistic regression as primary tests. The Cocktail test was used as secondary test.

Results: The EB test identified a significant interaction between rs964293 at 20q13.2/CYP24A1 and E+P (interaction OR (95% CIs)=0.61 (0.52-0.72), P=4.8 × 10(-9)). The secondary analysis also identified this interaction (Cocktail test OR=0.64 (0.52-0.78), P=1.2 × 10(-5) (alpha threshold=3.1 × 10(-4)). The ORs for association between E+P and CRC risk by rs964293 genotype were as follows: C/C, 0.96 (0.61-1.50); A/C, 0.61 (0.39-0.95) and A/A, 0.40 (0.22-0.73), respectively.

Conclusions: Our results indicate that rs964293 modifies the association between E+P and CRC risk. The variant is located near CYP24A1, which encodes an enzyme involved in vitamin D metabolism. This novel finding offers additional insight into downstream pathways of CRC etiopathogenesis.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / epidemiology
  • Adenocarcinoma / genetics*
  • Aged
  • Bayes Theorem
  • Case-Control Studies
  • Colorectal Neoplasms / epidemiology
  • Colorectal Neoplasms / genetics*
  • Drug Therapy, Combination
  • Estrogen Replacement Therapy / methods*
  • Estrogens / therapeutic use*
  • Female
  • Gene-Environment Interaction
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Genotype
  • Humans
  • Logistic Models
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • Progestins / therapeutic use*
  • Risk Factors
  • Vitamin D3 24-Hydroxylase / genetics*

Substances

  • Estrogens
  • Progestins
  • CYP24A1 protein, human
  • Vitamin D3 24-Hydroxylase

Grant support