Journal
JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION
Volume 313, Issue 11, Pages 1133-1142Publisher
AMER MEDICAL ASSOC
DOI: 10.1001/jama.2015.1815
Keywords
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Categories
Funding
- National Cancer Institute (NCI), National Institutes of Health (NIH), US Department of Health and Human Services [U01 CA137088, RO1 CA059045]
- NIH [RFA CA-95-011, R01 CA48998, P01 CA 055075, UM1 CA167552, R01137178, R01 CA137178, P01 CA 087969, RO1 CA151993, P50 CA 127003, U01 CA074783, R01 CA076366, K05 CA154337]
- NCI, NIH [U01 CA122839]
- NIH: Australasian Colorectal Cancer Family Registry [U01 CA097735]
- Ontario Registry for Studies of Familial Colorectal Cancer [U01 CA074783]
- Seattle Colorectal Cancer Family Registry [U01 CA074794]
- German Research Council (Deutsche Forschungsgemeinschaft) [BR 1704/6-1, BR 1704163, BR 1704/6-4, CH 117/1-1]
- German Federal Ministry of Education and Research [01KH0404, 01ER0814]
- Ontario Research Fund [GL2]
- Canadian Institutes of Health Research
- Cancer Risk Evaluation (CaRE) Program grant from the Canadian Cancer Society Research Institute
- Ontario Institute for Cancer Research through Ontario Ministry of Research and Innovation
- Division of Cancer Epidemiology and Genetics
- Division of Cancer Prevention, NCI, NIH, Department of Health and Human Services
- National Heart, Lung, and Blood Institute, NIH, US Department of Health and Human Services [HHSN268201100046C, HH5N268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C]
- [K24 DK098311]
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IMPORTANCE Use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with lower risk of colorectal cancer. OBJECTIVE To identify common genetic markers that may confer differential benefit from aspirin or NSAID chemoprevention, we tested gene x 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 PARTICIPANTS Case-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. EXPOSURES Genome-wide SNP data and information on regular use of aspirin and/or NSAIDs and other risk factors. MAIN OUTCOMES AND MEASURES Colorectal cancer. RESULTS Regular use of aspirin and/or NSAIDs was associated with lower risk of colorectal cancer (prevalence, 28% vs 38%; odds ratio [OR], 0.69 [95% Cl, 0.64-0.74]; P = 6.2 x 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 x 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 x 10(-33)) but with a higher risk among those with rare (4%) TA or AA genotypes (prevalence, 35% vs 29%; OR, 1.89 [95% Cl, 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 x 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 x 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% Cl, 0.78-1.20]; P = .76). CONCLUSIONS AND RELEVANCE In this genome-wide investigation of gene x 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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