Two Genome-wide Interaction Loci Modify the Association of Nonsteroidal Anti-inflammatory Drugs With Colorectal Cancer
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.
Authors:
David A. Drew, Andre E. Kim, Yi Lin, Conghui Qu, John Morrison, Juan Pablo Lewinger, Eric Kawaguchi, Jun Wang, Yubo Fu, Natalia Zemlianskaia, Virginia Díez-Obrero, Stephanie A. Bien, Niki Dimou, Demetrius Albanes, James W. Baurley, Anna H. Wu, Daniel D. Buchanan, John D. Potter, Ross L. Prentice, Sophia Harlid, Volker Arndt, Elizabeth L. Barry, Sonja I. Berndt, Emmanouil Bouras, Hermann Brenner, Arif Budiarto, Andrea Burnett-Hartman, Peter T. Campbell, Robert Carreras-Torres, Graham Casey, Jenny Chang-Claude, David V. Conti, Matthew A.M. Devall, Jane C. Figueiredo, Stephen B. Gruber, Andrea Gsur, Marc J. Gunter, Tabitha A. Harrison, Akihisa Hidaka, Michael Hoffmeister, Jeroen R. Huyghe, Mark A. Jenkins, Kristina M. Jordahl, Anshul Kundaje, Loic Le Marchand, Li Li, Brigid M. Lynch, Neil Murphy, Rami Nassir, Polly A. Newcomb, Christina C. Newton, Mireia Obón-Santacana, Shuji Ogino, Jennifer Ose, Rish K. Pai, Julie R. Palmer, Nikos Papadimitriou, Bens Pardamean, Andrew J. Pellatt, Anita R. Peoples, Elizabeth A. Platz, Gad Rennert, Edward Ruiz-Narvaez, Lori C. Sakoda, Peter C. Scacheri, Stephanie L. Schmit, Robert E. Schoen, Mariana C. Stern, Yu-Ru Su, Duncan C. Thomas, Yu Tian, Konstantinos K. Tsilidis, Cornelia M. Ulrich, Caroline Y. Um, Fränzel J.B. van Duijnhoven, Bethany Van Guelpen, Emily White, Li Hsu, Victor Moreno, Ulrike Peters, Andrew T. Chan, W. James Gauderman
Science Advances