Characterization of Additive Gene–environment Interactions For Colorectal Cancer Risk
Authors: Thomas Claire E. , Lin Yi , Kim Michelle , Kawaguchi Eric S. , Qu Conghui , Um Caroline Y. , Lynch Brigid M. , Van Guelpen Bethany , Tsilidis Kostas , Carreras-Torres Robert , van Duijnhoven Franzel J.B. , Sakoda Lori C. , Campbell Peter T. , Tian Yu , Chang-Claude Jenny , Bézieau Stéphane , Budiarto Arif , Palmer Julie R. , Newcomb Polly A. , Casey Graham , Le Marchandz Loic , Giannakis Marios , Li Christopher I. , Gsur Andrea , Newton Christina , Obón-Santacana Mireia , Moreno Victor , Vodicka Pavel , Brenner Hermann , Hoffmeister Michael , Pellatt Andrew J. , Schoen Robert E. , Dimou Niki , Murphy Neil , Gunter Marc J. , Castellví-Bel Sergi , Figueiredo Jane C. , Chan Andrew T. , Song Mingyang , Li Li , Bishop D. Timothy , Gruber Stephen B. , Baurley James W. , Bien Stephanie A. , Conti David V. , Huyghe Jeroen R. , Kundaje Anshul , Su Yu-Ru , Wang Jun , Keku Temitope O. , Woods Michael O. , Berndt Sonja I. , Chanock Stephen J. , Tangen Catherine M. , Wolk Alicja , Burnett-Hartman Andrea , Wu Anna H. , White Emily , Devall Matthew A. , Díez-Obrero Virginia , Drew David A , Giovannucci Edward , Hidaka Akihisa , Kim Andre E. , Lewinger Juan Pablo , Morrison John , Ose Jennifer , Papadimitriou Nikos , Pardamean Bens , Peoples Anita R. , Ruiz-Narvaez Edward A. , Shcherbina Anna , Stern Mariana C. , Chen Xuechen , Thomas Duncan C. , Platz Elizabeth A. , Gauderman W. James , Peters Ulrike , Hsu Li 
Published: September 2024

Background:
Colorectal cancer (CRC) is a common, fatal cancer. Identifying subgroups who may benefit more from intervention is of critical public health importance. Previous studies have assessed multiplicative interaction between genetic risk scores and environmental factors, but few have assessed additive interaction, the relevant public health measure.

Methods:
Using resources from CRC consortia, including 45,247 CRC cases and 52,671 controls, we assessed multiplicative and additive interaction (relative excess risk due to interaction, RERI) using logistic regression between 13 harmonized environmental factors and genetic risk score, including 141 variants associated with CRC risk.

Results:
There was no evidence of multiplicative interaction between environmental factors and genetic risk score. There was additive interaction where, for individuals with high genetic susceptibility, either heavy drinking (RERI = 0.24, 95% confidence interval [CI] = 0.13, 0.36), ever smoking (0.11 [0.05, 0.16]), high body mass index (female 0.09 [0.05, 0.13], male 0.10 [0.05, 0.14]), or high red meat intake (highest versus lowest quartile 0.18 [0.09, 0.27]) was associated with excess CRC risk greater than that for individuals with average genetic susceptibility. Conversely, we estimate those with high genetic susceptibility may benefit more from reducing CRC risk with aspirin/nonsteroidal anti-inflammatory drugs use (−0.16 [−0.20, −0.11]) or higher intake of fruit, fiber, or calcium (highest quartile versus lowest quartile −0.12 [−0.18, −0.050]; −0.16 [−0.23, −0.09]; −0.11 [−0.18, −0.05], respectively) than those with average genetic susceptibility.

Conclusions:
Additive interaction is important to assess for identifying subgroups who may benefit from intervention. The subgroups identified in this study may help inform precision CRC prevention.