The use of menopausal hormone therapy (MHT) may interact with genetic variants to influence colorectal cancer (CRC) risk. Methods: We conducted a genome-wide gene-environment interaction between single nucleotide polymorphisms and the use of any MHT, estrogen-only, and combined estrogen-progestogen therapy with CRC risk, among 28,486 postmenopausal women (11,519 cases and 16,967 controls) from 38 studies, using logistic regression, two-step method, and 2- or 3-degree-of-freedom (d.f.) joint test. A set-based score test was applied for rare genetic variants. Results: The use of any MHT, estrogen-only and estrogen-progestogen were associated with a reduced CRC risk [odds ratio (OR) with 95% confidence interval (95% CI) of 0.71 (0.64-0.78), 0.65 (0.53-0.79), and 0.73 (0.59-0.90), respectively]. The two-step method identified a statistically significant interaction between a GRIN2B variant rs117868593 and MHT use, whereby MHT-associated CRC risk was significantly reduced in women with the GG genotype [0.68 (0.64-0.72)] but not within strata of GC or CC genotypes. A statistically significant interaction between a DCBLD1 intronic variant at 6q22.1 (rs10782186) and MHT use was identified by the 2-d.f. joint test. The MHT-associated CRC risk was reduced with increasing number of rs10782186-C alleles, showing ORs of 0.78 (0.70-0.87) for TT, 0.68 (0.63-0.73) for TC, and 0.66 (0.60-0.74) for CC genotypes. In addition, five genes in rare variant analysis showed suggestive interactions with MHT (two-sided P < 1.2×10-4). Conclusion: Genetic variants that modify the association between MHT and CRC risk were identified, offering new insights into pathways of CRC carcinogenesis and potential mechanisms involved.<\/p>\n
Journal of the National Cancer Institute<\/p>\n
Yu Tian, Andre E Kim, Stephanie Bien (Rosse), Yi Lin, Conghui Qu, Tabitha A Harrison, Robert Carreras-Torres, Virginia D\u00edez-Obrero, Niki Dimou, David A Drew, Akihisa Hidaka, Jeroen Huyghe, Kristina M Jordahl, John Morrison, Neil Murphy, Mireia Ob\u00f3n-Santacana, Cornelia M Ulrich, Jennifer Ose, Anita Peoples, Edward Ruiz-Narv\u00e1ez, Anna Shcherbina, Mariana C Stern, Yu-Ru Su, Franzel J B van Duijnhoven, Volker Arndt, James W Baurley, Sonja I Berndt, D Timothy Bishop, Hermann Brenner, Daniel D Buchanan, Andrew T Chan, Jane C Figueiredo, Steven Gallinger, Stephen B Gruber, Sophia Harlid, Michael Hoffmeister, Mark Jenkins, Amit D Joshi, Temitope O Keku, Susanna C Larsson, Loic Le Marchand, Li Li, Graham G Giles, Roger L Milne, Hongmei Nan, Rami Nassir, Shuji Ogino, Arif Budiarto, Elizabeth A Platz, John D Potter, Ross L Prentice, Gad Rennert, Lori C Sakoda, Robert E Schoen, Martha Slattery, Stephen N Thibodeau, Bethany Van Guelpen, Kala Visvanathan, Emily White, Alicja Wolk, Michael O Woods, Anna H Wu, Peter T Campbell, Graham Casey, David V Conti, Marc J Gunter, Anshul Kundaje, Juan Pablo Lewinger, Victor Moreno, Polly A Newcomb, Bens Pardamean, Duncan C Thomas, Kostas Tsilidis, Ulrike Peters, W James Gauderman, Li Hsu, Jenny Chang-Claude<\/p>\n