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

Xabier Garcia-Albeniz, Anja Rudolph, Carolyn Hutter, Emily White, Yi Lin, Stephanie A Rosse, Jane C Figueiredo, Tabitha A Harrison, Shuo Jiao, Hermann Brenner, Graham Casey, Thomas J Hudson, Mark Thornquist, Loic Le Marchand, John Potter, Martha L Slattery, Brent Zanke, John A Baron, Bette J Caan, Stephen J Chanock, Sonja I Berndt, Deanna Stelling, Charles S Fuchs, Michael Hoffmeister, Katja Butterbach, Mengmeng Du, W James Gauderman, Marc J Gunter, Mathieu Lemire, Shuji Ogino, Jennifer Lin, Richard B Hayes, Robert W Haile, Robert E Schoen, Greg S Warnick, Mark A Jenkins, Stephen N Thibodeau, Fredrick R Schumacher, Noralane M Lindor, Laurence N Kolonel, John L Hopper, Jian Gong, Daniela Seminara, Bethann M Pflugeisen, Cornelia M Ulrich, Conghui Qu, David Duggan, Michelle Cotterchio, Peter T Campbell, Christopher S Carlson, Polly A Newcomb, Edward Giovannucci, Li Hsu, Andrew T Chan, Ulrike Peters, Jenny Chang-Claude, Xabier Garcia-Albeniz, Anja Rudolph, Carolyn Hutter, Emily White, Yi Lin, Stephanie A Rosse, Jane C Figueiredo, Tabitha A Harrison, Shuo Jiao, Hermann Brenner, Graham Casey, Thomas J Hudson, Mark Thornquist, Loic Le Marchand, John Potter, Martha L Slattery, Brent Zanke, John A Baron, Bette J Caan, Stephen J Chanock, Sonja I Berndt, Deanna Stelling, Charles S Fuchs, Michael Hoffmeister, Katja Butterbach, Mengmeng Du, W James Gauderman, Marc J Gunter, Mathieu Lemire, Shuji Ogino, Jennifer Lin, Richard B Hayes, Robert W Haile, Robert E Schoen, Greg S Warnick, Mark A Jenkins, Stephen N Thibodeau, Fredrick R Schumacher, Noralane M Lindor, Laurence N Kolonel, John L Hopper, Jian Gong, Daniela Seminara, Bethann M Pflugeisen, Cornelia M Ulrich, Conghui Qu, David Duggan, Michelle Cotterchio, Peter T Campbell, Christopher S Carlson, Polly A Newcomb, Edward Giovannucci, Li Hsu, Andrew T Chan, Ulrike Peters, Jenny Chang-Claude

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.

Figures

Figure 1
Figure 1
Forest plot for meta-analysis of the interaction between SNP and oestrogen plus progestogen use, using the empirical Bayes (A and C) and case–control logistic regression method (B and D) for rs964293 (A and B) and rs6023015 (C and D). DALS and PLCO studies are not plotted because they do not have information on the type of hormone compound.
Figure 2
Figure 2
Forest plot for meta-analysis of the marginal association of oestrogen plus progestogen with colorectal cancer risk in strata defined by zero, one or two minor alleles of rs964293 (A, B and C, respectively) and rs6023015 (D, E and F, respectively).

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