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

Abstract

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.

• Authors: 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-Narvaez, 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 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
• Journal: Journal of the National Cancer Institute (J Natl Cancer Inst) Vol. 114 Issue 8 Pg. 1135-1148 (08 08 2022) ISSN: 1460-2105 [Electronic] United States
• PMID: 35512400 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: © The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please email: [email protected].

Chemical References

• Estrogens
• Progestins

Topics

• Case-Control Studies
• Colorectal Neoplasms (epidemiology, genetics)
• Estrogens
• Female
• Humans
• Menopause
• Polymorphism, Single Nucleotide
• Progestins
• Risk Factors