• Hongmei Nan, Carolyn M Hutter, Yi Lin, Eric J Jacobs, Cornelia M Ulrich, Emily White, John A Baron, Sonja I Berndt, Hermann Brenner, Katja Butterbach, Bette J Caan, Peter T Campbell, Christopher S Carlson, Graham Casey, Jenny Chang-Claude, Stephen J Chanock, Michelle Cotterchio, David Duggan, Jane C Figueiredo, Charles S Fuchs, Edward L Giovannucci, Jian Gong, Robert W Haile, Tabitha A Harrison, Richard B Hayes, Michael Hoffmeister, John L Hopper, Thomas J Hudson, Mark A Jenkins, Shuo Jiao, Noralane M Lindor, Mathieu Lemire, Loic Le Marchand, Polly A Newcomb, Shuji Ogino, Bethann M Pflugeisen, John D Potter, Conghui Qu, Stephanie A Rosse, Anja Rudolph, Robert E Schoen, Fredrick R Schumacher, Daniela Seminara, Martha L Slattery, Stephen N Thibodeau, Fridtjof Thomas, Mark Thornquist, Greg S Warnick, Brent W Zanke, W James Gauderman, Ulrike Peters, Li Hsu, Andrew T Chan, CCFR, and GECCO.
• Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis2Indiana University Melvin and Bren Simon Cancer Center, Indianapolis.
• JAMA. 2015 Mar 17; 313 (11): 113311421133-42.

ImportanceUse of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with lower risk of colorectal cancer.ObjectiveTo identify common genetic markers that may confer differential benefit from aspirin or NSAID chemoprevention, we tested gene × environment interactions between regular use of aspirin and/or NSAIDs and single-nucleotide polymorphisms (SNPs) in relation to risk of colorectal cancer.Design, Setting, And ParticipantsCase-control study using data from 5 case-control and 5 cohort studies initiated between 1976 and 2003 across the United States, Canada, Australia, and Germany and including colorectal cancer cases (n=8634) and matched controls (n=8553) ascertained between 1976 and 2011. Participants were all of European descent.ExposuresGenome-wide SNP data and information on regular use of aspirin and/or NSAIDs and other risk factors.Main Outcomes And MeasuresColorectal cancer.ResultsRegular use of aspirin and/or NSAIDs was associated with lower risk of colorectal cancer (prevalence, 28% vs 38%; odds ratio [OR], 0.69 [95% CI, 0.64-0.74]; P = 6.2 × 10(-28)) compared with nonregular use. In the conventional logistic regression analysis, the SNP rs2965667 at chromosome 12p12.3 near the MGST1 gene showed a genome-wide significant interaction with aspirin and/or NSAID use (P = 4.6 × 10(-9) for interaction). Aspirin and/or NSAID use was associated with a lower risk of colorectal cancer among individuals with rs2965667-TT genotype (prevalence, 28% vs 38%; OR, 0.66 [95% CI, 0.61-0.70]; P = 7.7 × 10(-33)) but with a higher risk among those with rare (4%) TA or AA genotypes (prevalence, 35% vs 29%; OR, 1.89 [95% CI, 1.27-2.81]; P = .002). In case-only interaction analysis, the SNP rs16973225 at chromosome 15q25.2 near the IL16 gene showed a genome-wide significant interaction with use of aspirin and/or NSAIDs (P = 8.2 × 10(-9) for interaction). Regular use was associated with a lower risk of colorectal cancer among individuals with rs16973225-AA genotype (prevalence, 28% vs 38%; OR, 0.66 [95% CI, 0.62-0.71]; P = 1.9 × 10(-30)) but was not associated with risk of colorectal cancer among those with less common (9%) AC or CC genotypes (prevalence, 36% vs 39%; OR, 0.97 [95% CI, 0.78-1.20]; P = .76).Conclusions And RelevanceIn this genome-wide investigation of gene × environment interactions, use of aspirin and/or NSAIDs was associated with lower risk of colorectal cancer, and this association differed according to genetic variation at 2 SNPs at chromosomes 12 and 15. Validation of these findings in additional populations may facilitate targeted colorectal cancer prevention strategies.

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