Genetic Risk Factors Modulate the Association Between Physical Activity and Colorectal Cancer
Background Physical activity (PA) is an established protective factor for colorectal cancer (CRC), but it is unclear if genetic variants modify this effect. To investigate this possibility, we conducted a genome-wide gene–PA interaction analysis. Methods Using logistic regression and two-step and joint tests, we analyzed interactions between common genetic variants across the genome and PA in relation to CRC risk. Self-reported PA levels were categorized as active (≥ 8.75 MET-h/wk) vs. inactive (< 8.75 MET-h/wk) and as study- and sex-specific quartiles of activity. Results PA had an overall protective effect on CRC (OR [active vs. inactive] = 0.85; 95%CI = 0.81–0.90). The two-step GxE method identified an interaction between rs4779584, an intergenic variant near the GREM1 and SCG5 genes, and PA for CRC risk (p-interaction = 2.6×10 − 8 ). Stratification by genotype at this locus showed a significant reduction in CRC risk by 20% in active vs. inactive participants with the CC genotype (OR = 0.80; 95%CI = 0.75–0.85), but no significant PA–CRC association among CT or TT carriers. When PA was modeled as quartiles, the 1-d.f. GxE test identified that rs56906466, an intergenic variant near the KCNG1 gene, modified the association between PA and CRC (p-interaction = 3.5×10 − 8 ). Stratification at this locus showed that increase in PA (highest vs. lowest quartile) was associated with a lower CRC risk solely among TT carriers (OR = 0.77; 95%CI = 0.72–0.82). Conclusions In summary, we identified two genetic variants that modified the association between PA and CRC risk. One of them, related to GREM1 and SCG5 , suggests that the bone morphogenetic protein (BMP)-related, inflammatory, and/or insulin signaling pathways may be associated with the protective influence of PA on colorectal carcinogenesis.
Authors:
Anita Peoples, Mireia Obón-Santacana, Andre Kim, Eric S. Kawaguchi, Yubo Fu, Conghui Qu, Ferran Moratalla-Navarro, John Morrison, Yi Lin, Volker Arndt, Sonja I. Berndt, Stephanie Bien (Rosse), David Timothy Bishop, Emmanouil Bouras, Hermann Brenner, Daniel D Buchanan, Peter T. Campbell, Andrew T. Chan, Jenny Cheng, David V. Conti, Douglas AC. Corley, Matthew A. Devall, Niki Dimou, David A. Drew, Stephen B. Gruber, Marc J. Gunter, Sophia Harlid, Tabitha A Harrison, Michael Hoffmeister, Li Hsu, Jeroen R. Huyghe, Temitope O. Keku, Anshul Kundaje, Juan Pablo Lewinger, Li Li, Brigid Lynch, Loic Le Marchand, Vicente Martín, Neil Murphy, Christina C Newton, Shuji Ogino, Sheetal Hardikar, Jennifer Ose, Rish K. Pai, Julie R. Palmer, Nikos Papadimitriou, Bens Pardamean, Andrew J. Pellatt, Mila Pinchev, Elizabeth A. Platz, John D. Potter, Gad Rennert, Edward Ruiz-Narváez, Lori Sakoda, Robert E. Schoen, Anna Shcherbina, Mariana C. Stern, Yu-Ru Su, Claire E Thomas, Yu Tian, Kostas Tsilidis, Caroline Um, Franzel J. B. van Duijnhoven, Bethany Van Guelpen, Kala Visvanathan, Jun Wang, Emily White, Alicja Wolk, Michael O Woods, Anna H. Wu, Cornelia M Ulrich, Ulrike Peters, W. James Gauderman, Victor Moreno.
BMC Medicine