Association of Aspirin and NSAID Use With Risk of Colorectal Cancer According to Genetic Variants | Colorectal Cancer | JAMA | JAMA Network
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Original Investigation
March 17, 2015

Association of Aspirin and NSAID Use With Risk of Colorectal Cancer According to Genetic Variants

Author Affiliations
  • 1Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis
  • 2Indiana University Melvin and Bren Simon Cancer Center, Indianapolis
  • 3National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland
  • 4Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
  • 5Epidemiology Research Program, American Cancer Society, Atlanta, Georgia
  • 6Huntsman Cancer Institute, University of Utah, Salt Lake City
  • 7Department of Epidemiology, University of Washington School of Public Health, Seattle
  • 8Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, Chapel Hill
  • 9Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
  • 10Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 11German Cancer Consortium (DKTK), Heidelberg, Germany
  • 12Division of Research, Kaiser Permanente Medical Care Program of Northern California, Oakland
  • 13Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles
  • 14Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany
  • 15Prevention and Cancer Control, Cancer Care Ontario, Toronto, Ontario, Canada
  • 16Genetic Basis of Human Disease Division, Translational Genomics Research Institute (TGen), Phoenix, Arizona
  • 17Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts
  • 18Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massacusetts
  • 19Division of Epidemiology, Department of Population Health, New York University School of Medicine, New York, New York
  • 20Melbourne School of Population Health, University of Melbourne, Victoria, Australia
  • 21Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
  • 22Ontario Institute for Cancer Research, Toronto, Ontario, Canada
  • 23Department of Health Sciences Research, Mayo Clinic, Scottsdale, Arizona
  • 24Epidemiology Program, University of Hawaii Cancer Center, Honolulu
  • 25Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts
  • 26Department of Epidemiology, Harvard School of Public Health, Boston, Masschusetts
  • 27Centre for Public Health Research, Massey University, Wellington, New Zealand
  • 28Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
  • 29Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City
  • 30Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
  • 31Department of Medical Genetics, Mayo Clinic, Rochester, Minnesota
  • 32Division of Biostatistics and Epidemiology, Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis
  • 33Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
  • 34Department of Biostatistics, University of Washington, Seattle
  • 35Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
JAMA. 2015;313(11):1133-1142. doi:10.1001/jama.2015.1815
Abstract

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 × 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% 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 Relevance  In 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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