Genome-Wide Interaction Analysis of Genetic Variants with Menopausal Hormone Therapy for Colorectal Cancer Risk

Yu Tian, Andre E. Kim, Stephanie A. Bien, Yi Lin, Conghui Qu, Tabitha A. Harrison, Robert Carreras-Torres, Virginia Díez-Obrero, Niki Dimou, David A. Drew, Akihisa Hidaka, Jeroen R. Huyghe, Kristina M. Jordahl, John Morrison, Neil Murphy, Mireia Obón-Santacana, Cornelia M. Ulrich, Jennifer Ose, Anita R. Peoples, Edward A. Ruiz-NarvaezAnna 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 A. 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 L. 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, Konstantinos K. Tsilidis, Ulrike Peters, W. James Gauderman, Li Hsu, Jenny Chang-Claude

Research output: Contribution to journalArticlepeer-review


Background: 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 CRC patients and 16 967 participants without CRC) from 38 studies, using logistic regression, 2-step method, and 2-or 3-degree-of-freedom 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] = 0.71, 95% confidence interval [CI] = 0.64 to 0.78; OR = 0.65, 95% CI = 0.53 to 0.79; and OR = 0.73, 95% CI = 0.59 to 0.90, respectively). The 2-step method identified a statistically significant interaction between a GRIN2B variant rs117868593 and MHT use, whereby MHT-Associated CRC risk was statistically significantly reduced in women with the GG genotype (OR = 0.68, 95% CI = 0.64 to 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-degree-of-freedom joint test. The MHT-Associated CRC risk was reduced with increasing number of rs10782186-C alleles, showing odds ratios of 0.78 (95% CI = 0.70 to 0.87) for TT, 0.68 (95% CI = 0.63 to 0.73) for TC, and 0.66 (95% CI = 0.60 to 0.74) for CC genotypes. In addition, 5 genes in rare variant analysis showed suggestive interactions with MHT (2-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.

Original languageEnglish (US)
Pages (from-to)1135-1148
Number of pages14
JournalJournal of the National Cancer Institute
Issue number8
StatePublished - Aug 1 2022

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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