Citations 2
Genetic risk factors modulate the association between physical activity and colorectal cancer
Kim, Andre E., Fu, Yubo, Morrison, John, Lin, Yi, Berndt, Sonja, Chang-Claude, Jenny, Conti, David V., Corley, Douglas A. , Gruber, Stephen B. , Harlid, Sophia , Huyghe, Jeroen R. , Kundaje, Anshul , Martín, Vicente , Newton, Christina C. , Hardikar, Sheetal , Pai, Rish K. , Papadimitriou, Nikos , Pinchev, Mila, Schoen, Robert , Tsilidis, Konstantinos K, Duijnhoven, Franzel J. B. van, Visvanathan, Kala , Wolk, Alicja, Woods, Michael O. , Wu, Anna H. , Ulrich, Cornelia M. , Peters, Ulrike, Gauderman, W. James, Moreno, Victor, Martín, Vicente , Drew, David A. , Martín, Vicente , Drew, David A , Visvanathan, Kala , Kundaje, Anshul , Papadimitriou, Nikos , Peoples, Anita R , Obón‐Santacana, Mireia , Kawaguchi, Eric , Qu, Conghui , Moratalla-Navarro, Ferrán , Morrison, John, Arndt, Volker , Bien, Stephanie A. , Bishop, D. Timothy , Bouras, Emmanouil , Brenner, Hermann , Buchanan, Daniel D. , Campbell, Peter T. , Chan, Andrew T. , Chang‐Claude, Jenny , Conti, David V. , Devall, Matthew A M , Dimou, Niki , Gunter, Marc J. , Harrison, Tabitha A. , Hoffmeister, Michael , Hsu, Li , Keku, Temitope O , Lewinger, Juan Pablo , Lynch, Brigid M , Marchand, Loı̈c Le , Murphy, Neil , Ogino, Shuji , Ose, Jennifer , Palmer, Julie R. , Pardamean, Bens , Pellatt, Andrew J. , Platz, Elizabeth A. , Potter, John D. , Rennert, Gad , Ruiz-Narvaez, Edward , Sakoda, Lori C. , Schoen, Robert E., Shcherbina, Anna, Stern, Mariana Carla , Su, Yu-Ru , Thomas, Claire E. , Tian, Yu , Tsilidis, Konstantinos K. , Um, Caroline Y. , Guelpen, Bethany Van , Wang, Jun, White, Emily , Wolk, Alicja , Peters, Ulrike, Gauderman, W. James
No container title available | September 2, 2025 | Volume: No volume available | Issue: No issue available | Pages: No page available
Abstract 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.
Two genome-wide interaction loci modify the association of nonsteroidal anti-inflammatory drugs with colorectal cancer
Drew, David A. , Kim, Andre E. , Lin, Yi , Morrison, John L. , Lewinger, Juan Pablo , Fu, Yubo, Zemlianskaia, Natalia , Díez‐Obrero, Virginia , Baurley, James W. , Wu, Anna H. , Prentice, Ross L. , Harlid, Sophia , Barry, Elizabeth L. , Berndt, Sonja I. , Bouras, Emmanouil , Burnett‐Hartman, Andrea N. , Casey, Graham , Chang‐Claude, Jenny , Figueiredo, Jane C. , Gruber, Stephen B. , Gsur, Andrea , Harrison, Tabitha A. , Huyghe, Jeroen R. , Jordahl, Kristina M. , Kundaje, Anshul , Li, Li , Newton, Christina C. , Obón‐Santacana, Mireia , Pai, Rish K. , Papadimitriou, Nikos , Scacheri, Peter C. , Schmit, Stephanie L. , Thomas, Duncan C. , Duijnhoven, Fränzel J.B. van , Guelpen, Bethany Van , Peters, Ulrike , Gauderman, W. James , Morrison, John L , Lewinger, Juan Pablo , Wang, Jun , Zemlianskaia, Natalia , Bien, Stephanie A , Dimou, Niki , Buchanan, Daniel D , Potter, John D , Prentice, Ross L , Harlid, Sophia , Arndt, Volker , Bouras, Emmanouil , Carreras-Torres, Robert , Casey, Graham , Devall, Matthew A M , Gruber, Stephen B , Gsur, Andrea , Gunter, Marc J , Harrison, Tabitha A , Hoffmeister, Michael , Huyghe, Jeroen R , Jenkins, Mark A , Jordahl, Kristina M , Kundaje, Anshul , Li, Li , Lynch, Brigid M , Nassir, Rami , Newton, Christina C , Ogino, Shuji , Ose, Jennifer , Pai, R K , Palmer, Julie R , Pardamean, Bens , Pellatt, Andrew J , Peoples, Anita R , Platz, Elizabeth A. , Rennert, Gad , Ruiz-Narvaez, Edward , Sakoda, Lori C , Schmit, Stephanie L , Schoen, Robert E , Su, Yu-Ru , Tian, Yu , Tsilidis, Konstantinos K , Ulrich, Cornelia M , Um, Caroline Y , van Duijnhoven, Fränzel J B , Van Guelpen, Bethany , Hsu, Li , Moreno, Victor , Peters, Ulrike , Chan, Andrew T , Gauderman, W James , Drew, David A , Obón-Santacana, Mireia , Papadimitriou, Nikos , Diez-Obrero, Virginia , Qu, Conghui , Kawaguchi, Eric , Bien, Stephanie A. , Dimou, Niki , Albanes, Demetrius , Buchanan, Daniel D. , Potter, John D. , Arndt, Volker , Brenner, Hermann , Budiarto, Arif , Campbell, Peter T. , Carreras‐Torres, Robert , Conti, David V. , Gunter, Marc J. , Hidaka, Akihisa , Hoffmeister, Michael , Jenkins, Mark A. , Marchand, Loı̈c Le , Murphy, Neil , Nassir, Rami , Newcomb, Polly A. , Ose, Jennifer , Palmer, Julie R. , Pardamean, Bens , Pellatt, Andrew J. , Rennert, Gad , Sakoda, Lori C. , Schoen, Robert E. , Stern, Mariana Carla , Tian, Yu , Tsilidis, Konstantinos K. , Ulrich, Cornelia M. , Um, Caroline Y. , White, Emily E. , Moreno, Vı́ctor , Chan, Andrew T.
Science Advances | May 29, 2024 | Volume: 10 | Issue: 22 | Pages: No page available
Regular, long-term aspirin use may act synergistically with genetic variants, particularly those in mechanistically relevant pathways, to confer a protective effect on colorectal cancer (CRC) risk. We leveraged pooled data from 52 clinical trial, cohort, and case-control studies that included 30,806 CRC cases and 41,861 controls of European ancestry to conduct a genome-wide interaction scan between regular aspirin/nonsteroidal anti-inflammatory drug (NSAID) use and imputed genetic variants. After adjusting for multiple comparisons, we identified statistically significant interactions between regular aspirin/NSAID use and variants in 6q24.1 (top hit rs72833769 ), which has evidence of influencing expression of TBC1D7 (a subunit of the TSC1-TSC2 complex, a key regulator of MTOR activity), and variants in 5p13.1 (top hit rs350047 ), which is associated with expression of PTGER4 (codes a cell surface receptor directly involved in the mode of action of aspirin). Genetic variants with functional impact may modulate the chemopreventive effect of regular aspirin use, and our study identifies putative previously unidentified targets for additional mechanistic interrogation.