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JAMA. 2015 Mar 17;313(11):1133-42. doi: 10.1001/jama.2015.1815.

Association of aspirin and NSAID use with risk of colorectal cancer according to genetic variants.

Author information

1
Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis2Indiana University Melvin and Bren Simon Cancer Center, Indianapolis.
2
National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
3
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
4
Epidemiology Research Program, American Cancer Society, Atlanta, Georgia.
5
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington6Huntsman Cancer Institute, University of Utah, Salt Lake City.
6
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington7Department of Epidemiology, University of Washington School of Public Health, Seattle.
7
Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, Chapel Hill.
8
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
9
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany11German Cancer Consortium (DKTK), Heidelberg, Germany.
10
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
11
Division of Research, Kaiser Permanente Medical Care Program of Northern California, Oakland.
12
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles.
13
Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany.
14
Prevention and Cancer Control, Cancer Care Ontario, Toronto, Ontario, Canada.
15
Genetic Basis of Human Disease Division, Translational Genomics Research Institute (TGen), Phoenix, Arizona.
16
Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts.
17
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massacusetts.
18
Division of Epidemiology, Department of Population Health, New York University School of Medicine, New York, New York.
19
Melbourne School of Population Health, University of Melbourne, Victoria, Australia.
20
Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada22Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
21
Department of Health Sciences Research, Mayo Clinic, Scottsdale, Arizona.
22
Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
23
Epidemiology Program, University of Hawaii Cancer Center, Honolulu.
24
Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts25Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts26Department of Epidemiology, Harvard School of Public Health, Boston, Masschusetts.
25
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington27Centre for Public Health Research, Massey University, Wellington, New Zealand.
26
Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
27
Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City.
28
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota31Department of Medical Genetics, Mayo Clinic, Rochester, Minnesota.
29
Division of Biostatistics and Epidemiology, Department of Preventive Medicine, University of Tennessee Healthy Science Center, Memphis.
30
Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
31
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington34Department of Biostatistics, University of Washington, Seattle.
32
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massacusetts35Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.

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.

PMID:
25781442
PMCID:
PMC4382867
DOI:
10.1001/jama.2015.1815
[Indexed for MEDLINE]
Free PMC Article

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