title: Association of aspirin and NSAID use with risk of colorectal cancer according to genetic variants.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  Genome-wide SNP data and information on regular use of aspirin and/or NSAIDs and other risk factors.
  
  
  METHODS
  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
  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.
authors.affiliation: Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis2Indiana University Melvin and Bren Simon Cancer Center, Indianapolis.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Nan
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Hutter
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Yi
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Epidemiology Research Program, American Cancer Society, Atlanta, Georgia.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Jacobs
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington6Huntsman Cancer Institute, University of Utah, Salt Lake City.
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: Ulrich
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington7Department of Epidemiology, University of Washington School of Public Health, Seattle.
authors.forename: Emily
authors.initials: E
authors.lastname: White
authors.affiliation: Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, Chapel Hill.
authors.forename: John A
authors.initials: JA
authors.lastname: Baron
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Sonja I
authors.initials: SI
authors.lastname: Berndt
authors.affiliation: Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany11German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Brenner
authors.affiliation: Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Butterbach
authors.affiliation: Division of Research, Kaiser Permanente Medical Care Program of Northern California, Oakland.
authors.forename: Bette J
authors.initials: BJ
authors.lastname: Caan
authors.affiliation: Epidemiology Research Program, American Cancer Society, Atlanta, Georgia.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Campbell
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Carlson
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles.
authors.forename: Graham
authors.initials: G
authors.lastname: Casey
authors.affiliation: Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Jenny
authors.initials: J
authors.lastname: Chang-Claude
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Chanock
authors.affiliation: Prevention and Cancer Control, Cancer Care Ontario, Toronto, Ontario, Canada.
authors.forename: Michelle
authors.initials: M
authors.lastname: Cotterchio
authors.affiliation: Genetic Basis of Human Disease Division, Translational Genomics Research Institute (TGen), Phoenix, Arizona.
authors.forename: David
authors.initials: D
authors.lastname: Duggan
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles.
authors.forename: Jane C
authors.initials: JC
authors.lastname: Figueiredo
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Charles S
authors.initials: CS
authors.lastname: Fuchs
authors.affiliation: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massacusetts.
authors.forename: Edward L
authors.initials: EL
authors.lastname: Giovannucci
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Jian
authors.initials: J
authors.lastname: Gong
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Haile
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Tabitha A
authors.initials: TA
authors.lastname: Harrison
authors.affiliation: Division of Epidemiology, Department of Population Health, New York University School of Medicine, New York, New York.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Hayes
authors.affiliation: Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Hoffmeister
authors.affiliation: Melbourne School of Population Health, University of Melbourne, Victoria, Australia.
authors.forename: John L
authors.initials: JL
authors.lastname: Hopper
authors.affiliation: Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada22Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Hudson
authors.affiliation: Melbourne School of Population Health, University of Melbourne, Victoria, Australia.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Jenkins
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Shuo
authors.initials: S
authors.lastname: Jiao
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Scottsdale, Arizona.
authors.forename: Noralane M
authors.initials: NM
authors.lastname: Lindor
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Lemire
authors.affiliation: Epidemiology Program, University of Hawaii Cancer Center, Honolulu.
authors.forename: Loic
authors.initials: L
authors.lastname: Le Marchand
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Polly A
authors.initials: PA
authors.lastname: Newcomb
authors.affiliation: 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.
authors.forename: Shuji
authors.initials: S
authors.lastname: Ogino
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Bethann M
authors.initials: BM
authors.lastname: Pflugeisen
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington27Centre for Public Health Research, Massey University, Wellington, New Zealand.
authors.forename: John D
authors.initials: JD
authors.lastname: Potter
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Conghui
authors.initials: C
authors.lastname: Qu
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Rosse
authors.affiliation: Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Rudolph
authors.affiliation: Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Schoen
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles.
authors.forename: Fredrick R
authors.initials: FR
authors.lastname: Schumacher
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Daniela
authors.initials: D
authors.lastname: Seminara
authors.affiliation: Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City.
authors.forename: Martha L
authors.initials: ML
authors.lastname: Slattery
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota31Department of Medical Genetics, Mayo Clinic, Rochester, Minnesota.
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Thibodeau
authors.affiliation: Division of Biostatistics and Epidemiology, Department of Preventive Medicine, University of Tennessee Healthy Science Center, Memphis.
authors.forename: Fridtjof
authors.initials: F
authors.lastname: Thomas
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Mark
authors.initials: M
authors.lastname: Thornquist
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Greg S
authors.initials: GS
authors.lastname: Warnick
authors.affiliation: Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
authors.forename: Brent W
authors.initials: BW
authors.lastname: Zanke
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles.
authors.forename: W James
authors.initials: WJ
authors.lastname: Gauderman
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington7Department of Epidemiology, University of Washington School of Public Health, Seattle.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Peters
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington34Department of Biostatistics, University of Washington, Seattle.
authors.forename: Li
authors.initials: L
authors.lastname: Hsu
authors.affiliation: 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.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Chan
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D001241:Aspirin / Q000627:therapeutic use*; D016022:Case-Control Studies; D002881:Chromosomes, Human, Pair 12; D002884:Chromosomes, Human, Pair 15; D015179:Colorectal Neoplasms / Q000235:genetics / Q000517:prevention & control*; D005260:Female; D059647:Gene-Environment Interaction; D005819:Genetic Markers; D005838:Genotype; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D005819:Genetic Markers; D001241:Aspirin