Probing the diabetes and colorectal cancer relationship using gene – environment interaction analyses
Niki Dimou, Andre E. Kim, Orlagh Flanagan, Neil Murphy, Virginia Díez‐Obrero, Anna Shcherbina, Elom K. Aglago, Emmanouil Bouras, Peter T. Campbell, Graham Casey, Steven Gallinger, Stephen B. Gruber, Mark A. Jenkins, Yi Lin, Vı́ctor Moreno, Edward Ruiz-Narváez, Mariana C. Stern, Yu Tian, Kostas K. Tsilidis, Volker Arndt, Elizabeth L. Barry, James W. Baurley, Sonja I. Berndt, Stéphane Bezieau, Stephanie A. Bien, D. Timothy Bishop, Hermann Brenner, Arif Budiarto, Robert Carreras‐Torres, Tjeng Wawan Cenggoro, Andrew T. Chan, Jenny Chang‐Claude, Stephen J. Chanock, Xuechen Chen, David V. Conti, Christopher H. Dampier, Matthew A.M. Devall, David A. Drew, Jane C. Figueiredo, Graham G. Giles, Andrea Gsur, Tabitha A. Harrison, Akihisa Hidaka, Michael Hoffmeister, Jeroen R. Huyghe, Kristina M. Jordahl, Eric S. Kawaguchi, Temitope O. Keku, Susanna C. Larsson, Loı̈c Le Marchand, Juan Pablo Lewinger, Li Li, Bharuno Mahesworo, John L. Morrison, Polly A. Newcomb, Christina C. Newton, Mireia Obón‐Santacana, Jennifer Ose, Rish K. Pai, Julie R. Palmer, Nikos Papadimitriou, Bens Pardamean, Anita R. Peoples, Paul D.P. Pharoah, Elizabeth A. Platz, John D. Potter, Gad Rennert, Peter C. Scacheri, Robert E. Schoen, Yu‐Ru Su, Catherine M. Tangen, Stephen N. Thibodeau, Duncan C. Thomas, Cornelia M. Ulrich, Caroline Y. Um, Fränzel J.B. van Duijnhoven, Kala Visvanathan, Pavel Vodička, Ludmila Vodičková, Emily White, Alicja Wolk, Michael O. Woods, Conghui Qu, Anshul Kundaje, Li Hsu, W. James Gauderman, Marc J. Gunter, Ulrike Peters
Abstract
Abstract Background Diabetes is an established risk factor for colorectal cancer. However, the mechanisms underlying this relationship still require investigation and it is not known if the association is modified by genetic variants. To address these questions, we undertook a genome-wide gene-environment interaction analysis. Methods We used data from 3 genetic consortia (CCFR, CORECT, GECCO; 31,318 colorectal cancer cases/41,499 controls) and undertook genome-wide gene-environment interaction analyses with colorectal cancer risk, including interaction tests of genetics(G)xdiabetes (1-degree of freedom; d.f.) and joint testing of Gxdiabetes, G-colorectal cancer association (2-d.f. joint test) and G-diabetes correlation (3-d.f. joint test). Results Based on the joint tests, we found that the association of diabetes with colorectal cancer risk is modified by loci on chromosomes 8q24.11 (rs3802177, SLC30A8 – OR AA : 1.62, 95% CI: 1.34–1.96; OR AG : 1.41, 95% CI: 1.30–1.54; OR GG : 1.22, 95% CI: 1.13–1.31; p -value 3-d.f. : 5.46 × 10 −11 ) and 13q14.13 (rs9526201, LRCH1 – OR GG : 2.11, 95% CI: 1.56–2.83; OR GA : 1.52, 95% CI: 1.38–1.68; OR AA : 1.13, 95% CI: 1.06–1.21; p -value 2-d.f. : 7.84 × 10 −09 ). Discussion These results suggest that variation in genes related to insulin signaling ( SLC30A8 ) and immune function ( LRCH1 ) may modify the association of diabetes with colorectal cancer risk and provide novel insights into the biology underlying the diabetes and colorectal cancer relationship.