A Genetic Locus within the FMN1/GREM1 Gene Region Interacts with Body Mass Index in Colorectal Cancer Risk
Elom K. Aglago, Andre E. Kim, Yi Lin, Conghui Qu, Marina Evangelou, Ren Yu, John L. Morrison, Demetrius Albanes, Volker Arndt, Elizabeth L. Barry, James W. Baurley, Sonja I. Berndt, Stephanie A. Bien, D. Timothy Bishop, Emmanouil Bouras, Hermann Brenner, Daniel D. Buchanan, Arif Budiarto, Robert Carreras‐Torres, Graham Casey, Tjeng Wawan Cenggoro, Andrew T. Chan, Jenny Chang‐Claude, Xuechen Chen, David V. Conti, Matthew A.M. Devall, Virginia Díez‐Obrero, Niki Dimou, David A. Drew, Jane C. Figueiredo, Steven Gallinger, Graham G. Giles, Stephen B. Gruber, Andrea Gsur, Marc J. Gunter, Heather Hampel, Sophia Harlid, Akihisa Hidaka, Tabitha A. Harrison, Michael Hoffmeister, Jeroen R. Huyghe, Mark A. Jenkins, Kristina M. Jordahl, Amit D. Joshi, Eric S. Kawaguchi, Temitope O. Keku, Anshul Kundaje, Susanna C. Larsson, Loı̈c Le Marchand, Juan Pablo Lewinger, Li Li, Brigid M. Lynch, Bharuno Mahesworo, Marko Mandic, Mireia Obón‐Santacana, Vı́ctor Moreno, Neil Murphy, Hongmei Nan, Rami Nassir, Polly A. Newcomb, Shuji Ogino, Jennifer Ose, Rish K. Pai, Julie R. Palmer, Nikos Papadimitriou, Bens Pardamean, Anita R. Peoples, Elizabeth A. Platz, John D. Potter, Ross L. Prentice, Gad Rennert, Edward Ruiz-Narváez, Lori C. Sakoda, Peter C. Scacheri, Stephanie L. Schmit, Robert E. Schoen, Anna Shcherbina, Martha L. Slattery, Mariana C. Stern, Yu‐Ru Su, Catherine M. Tangen, Stephen N. Thibodeau, Duncan C. Thomas, Yu Tian, Cornelia M. Ulrich, Fränzel J.B. van Duijnhoven, Bethany Van Guelpen, Kala Visvanathan, Pavel Vodička, Jun Wang, Emily White, Alicja Wolk, Michael O. Woods, Anna H. Wu, Natalia Zemlianskaia, Li Hsu, W. James Gauderman, Ulrike Peters, Konstantinos K. Tsilidis, Peter T. Campbell
Abstract
Colorectal cancer risk can be impacted by genetic, environmental, and lifestyle factors, including diet and obesity. Gene-environment interactions (G × E) can provide biological insights into the effects of obesity on colorectal cancer risk. Here, we assessed potential genome-wide G × E interactions between body mass index (BMI) and common SNPs for colorectal cancer risk using data from 36,415 colorectal cancer cases and 48,451 controls from three international colorectal cancer consortia (CCFR, CORECT, and GECCO). The G × E tests included the conventional logistic regression using multiplicative terms (one degree of freedom, 1DF test), the two-step EDGE method, and the joint 3DF test, each of which is powerful for detecting G × E interactions under specific conditions. BMI was associated with higher colorectal cancer risk. The two-step approach revealed a statistically significant G×BMI interaction located within the Formin 1/Gremlin 1 (FMN1/GREM1) gene region (rs58349661). This SNP was also identified by the 3DF test, with a suggestive statistical significance in the 1DF test. Among participants with the CC genotype of rs58349661, overweight and obesity categories were associated with higher colorectal cancer risk, whereas null associations were observed across BMI categories in those with the TT genotype. Using data from three large international consortia, this study discovered a locus in the FMN1/GREM1 gene region that interacts with BMI on the association with colorectal cancer risk. Further studies should examine the potential mechanisms through which this locus modifies the etiologic link between obesity and colorectal cancer. SIGNIFICANCE: This gene-environment interaction analysis revealed a genetic locus in FMN1/GREM1 that interacts with body mass index in colorectal cancer risk, suggesting potential implications for precision prevention strategies.