Genome-Wide Interaction Analysis of Genetic Variants With Menopausal Hormone Therapy for Colorectal Cancer Risk
Authors: Tian Yu , Kim Andre E , Bien Stephanie A , Lin Yi , Qu Conghui , Harrison Tabitha A , Carreras-Torres Robert , Díez-Obrero Virginia , Dimou Niki , Drew David A , Hidaka Akihisa , Huyghe Jeroen R , Jordahl Kristina M , Morrison John , Murphy Neil , Obón-Santacana Mireia , Ulrich Cornelia M , Ose Jennifer , Peoples Anita R , Ruiz-Narvaez Edward A , Shcherbina Anna , Stern Mariana C , Su Yu-Ru , van Duijnhoven Franzel J B , Arndt Volker , Baurley James W , Berndt Sonja I , Bishop D Timothy , Brenner Hermann , Buchanan Daniel D , Chan Andrew T , Figueiredo Jane C , Gallinger Steven , Gruber Stephen B , Harlid Sophia , Hoffmeister Michael , Jenkins Mark A , Joshi Amit D , Keku Temitope O , Larsson Susanna C , Le Marchand Loic , Li Li , Giles Graham G , Milne Roger L , Nan Hongmei , Nassir Rami , Ogino Shuji , Budiarto Arif , Platz Elizabeth A , Potter John D , Prentice Ross L , Rennert Gad , Sakoda Lori C , Schoen Robert E , Slattery Martha L , Thibodeau Stephen N , Van Guelpen Bethany , Visvanathan Kala , White Emily , Wolk Alicja , Woods Michael O , Wu Anna H , Campbell Peter T , Casey Graham , Conti David V , Gunter Marc J , Kundaje Anshul , Lewinger Juan Pablo , Moreno Victor , Newcomb Polly A , Pardamean Bens , Thomas Duncan C , Tsilidis Konstantinos K , Peters Ulrike , Gauderman W James , Hsu Li , Chang-Claude Jenny 
Published: April 2022

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 &lt; 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.