title: CYP24A1 variant modifies the association between use of oestrogen plus progestogen therapy and colorectal cancer risk.
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.
authors.affiliation: Department of Epidemiology, Harvard T.H., Chan School of Public Health, Boston, MA 02115, USA.|Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
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authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA.|Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10017, USA.
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authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA.|Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10017, USA.
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authors.affiliation: Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.|Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.|German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.
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mesh_terms: D000230:Adenocarcinoma / Q000453:epidemiology / Q000235:genetics*; D000368:Aged; D001499:Bayes Theorem; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000235:genetics*; D004359:Drug Therapy, Combination; D015914:Estrogen Replacement Therapy / Q000379:methods*; D004967:Estrogens / Q000627:therapeutic use*; D005260:Female; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D016015:Logistic Models; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011372:Progestins / Q000627:therapeutic use*; D012307:Risk Factors; D065668:Vitamin D3 24-Hydroxylase / Q000235:genetics*
chemical_list: D004967:Estrogens; D011372:Progestins; C585549:CYP24A1 protein, human; D065668:Vitamin D3 24-Hydroxylase