Salicylic acid (SA) has observationally been shown to decrease colorectal cancer (CRC) risk. Aspirin (acetylsalicylic acid, that rapidly deacetylates to SA) is an effective primary and secondary chemopreventive agent. Through a Mendelian randomization (MR) approach, we aimed to address whether levels of SA affected CRC risk, stratifying by aspirin use. A two-sample MR analysis was performed using GWAS summary statistics of SA (INTERVAL and EPIC-Norfolk, N = 14,149) and CRC (CCFR, CORECT, GECCO and UK Biobank, 55,168 cases and 65,160 controls). The DACHS study (4410 cases and 3441 controls) was used for replication and stratification of aspirin-use. SNPs proxying SA were selected via three methods: (1) functional SNPs that influence the activity of aspirin-metabolising enzymes; (2) pathway SNPs present in enzymes' coding regions; and (3) genome-wide significant SNPs. We found no association between functional SNPs and SA levels. The pathway and genome-wide SNPs showed no association between SA and CRC risk (OR: 1.03, 95% CI: 0.84-1.27 and OR: 1.08, 95% CI: 0.86-1.34, respectively). Results remained unchanged upon aspirin use stratification. We found little evidence to suggest that an SD increase in genetically predicted SA protects against CRC risk in the general population and upon stratification by aspirin use.

British Heart Foundation Cardiovascular Epidemiology Unit Department of Public Health and Primary Care University of Cambridge Cambridge CB1 8RN UK

British Heart Foundation Centre of Research Excellence Division of Cardiovascular Medicine University of Cambridge Cambridge CB2 0QQ UK

Broad Institute of Harvard and MIT Cambridge MA 02142 USA

Cancer Epidemiology Division Cancer Council Victoria Melbourne VIC 3004 Australia

Cancer Epidemiology Program University of Hawaii Cancer Center Honolulu HI 96813 USA

Center for Gastrointestinal Biology and Disease School of Medicine University of North Carolina Chapel Hill NC 27599 7555 USA

Center for Public Health Genomics Department of Public Health Sciences University of Virginia Charlottesville VA 22908 USA

Centre for Epidemiology and Biostatistics Melbourne School of Population and Global Health The University of Melbourne Melbourne VIC 3053 Australia

Channing Division of Network Medicine Brigham and Women's Hospital and Harvard Medical School Boston MA 02115 USA

CIBER Epidemiología y Salud Pública 28029 Madrid Spain

Clalit National Cancer Control Center Haifa 3436212 Israel

Clinical and Translational Epidemiology Unit Massachusetts General Hospital and Harvard Medical School Boston MA 02114 USA

Colorectal Oncogenomics Group Department of Clinical Pathology The University of Melbourne Parkville VIC 3010 Australia

Department of Clinical Genetics Karolinska University Hospital 171 64 Solna Sweden

Department of Clinical Sciences Faculty of Medicine University of Barcelona 08007 Barcelona Spain

Department of Community Medicine and Epidemiology Lady Davis Carmel Medical Center Haifa 3448516 Israel

Department of Epidemiology Harvard T H Chan School of Public Health Harvard University Boston MA 02115 USA

Department of Epidemiology Institute of Health and Environment School of Public Health Seoul National University Seoul 08826 Korea

Department of Epidemiology Johns Hopkins Bloomberg School of Public Health Baltimore MD 21205 USA

Department of Epidemiology University of Washington School of Public Health Seattle WA 98195 USA

Department of Family Medicine University of Virginia Charlottesville VA 22903 USA

Department of General Surgery University Hospital Rostock 18057 Rostock Germany

Department of Health Science Research Mayo Clinic Scottsdale AZ 85259 USA

Department of Immunology and Infectious Diseases Harvard T H Chan School of Public Health Harvard University Boston MA 02115 USA

Department of Internal Medicine University of Utah Salt Lake City UT 84112 USA

Department of Medicine and Epidemiology University of Pittsburgh Medical Center Pittsburgh PA 15261 USA

Department of Medicine Samuel Oschin Comprehensive Cancer Institute Cedars Sinai Medical Center Los Angeles CA 90048 USA

Department of Medicine School of Medicine University of North Carolina Chapel Hill NC 27516 USA

Department of Molecular Biology of Cancer Institute of Experimental Medicine of the Czech Academy of Sciences 142 20 Prague Czech Republic

Department of Molecular Medicine and Surgery Karolinska Institutet 171 64 Solna Sweden

Department of Oncology Haematology and BMT University Medical Centre Hamburg Eppendorf University Cancer Centre Hamburg 20251 Hamburg Germany

Department of Population and Public Health Sciences Keck School of Medicine University of Southern California Los Angeles CA 90032 USA

Department of Population Science American Cancer Society Atlanta GA 30303 USA

Department of Preventive Medicine and USC Norris Comprehensive Cancer Center Keck School of Medicine University of Southern California Los Angeles CA 90033 USA

Department of Preventive Medicine Chonnam National University Medical School Gwangju 61186 Korea

Department of Preventive Medicine Keck School of Medicine University of Southern California Los Angeles CA 0032 USA

Department of Public Health and Primary Care University of Cambridge Cambridge CB1 8RN UK

Department of Radiation Sciences Oncology Unit Umeå University 901 87 Umeå Sweden

Department of Surgery Chonnam National University Hwasun Hospital and Medical School Hwasun 58128 Korea

Department of Surgical Sciences Uppsala University 751 85 Uppsala Sweden

Discipline of Genetics Faculty of Medicine Memorial University of Newfoundland St John's NL A1B 3V6 Canada

Division of Cancer Epidemiology and Genetics National Cancer Institute National Institutes of Health Bethesda MD 20814 USA

Division of Cancer Epidemiology German Cancer Research Center 69120 Heidelberg Germany

Division of Clinical Epidemiology and Aging Research German Cancer Research Center 69120 Heidelberg Germany

Division of Epidemiology Department of Medicine Vanderbilt Ingram Cancer Center Vanderbilt Epidemiology Center Vanderbilt University School of Medicine Nashville TN 37232 USA

Division of Gastroenterology Massachusetts General Hospital and Harvard Medical School Boston MA 02114 USA

Division of Human Genetics Department of Internal Medicine The Ohio State University Comprehensive Cancer Center Columbus OH 43210 USA

Division of Human Nutrition and Health Department of Agrotechnology and Food Sciences Wageningen University and Research 6700 HB Wageningen The Netherlands

Division of Preventive Oncology German Cancer Research Center 69120 Heidelberg Germany

Division of Research Kaiser Permanente Northern California Oakland CA 94612 USA

Faculty of Medicine and Biomedical Center in Pilsen Charles University 323 00 Pilsen Czech Republic

Gastroenterology Department Hospital Clínic Institut d'Investigacions Biomèdiques August Pi i Sunyer University of Barcelona 08036 Barcelona Spain

Genetic Medicine and Family Cancer Clinic The Royal Melbourne Hospital Parkville VIC 3000 Australia

German Cancer Consortium 69120 Heidelberg Germany

Health Data Research UK Cambridge Wellcome Genome Campus and University of Cambridge Cambridge CB10 1SA UK

Huntsman Cancer Institute Department of Population Health Sciences University of Utah Salt Lake City UT 84112 USA

Institute of Biology and Medical Genetics 1st Faculty of Medicine Charles University Nové Město 121 08 Prague Czech Republic

Institute of Cancer Research Department of Medicine 1 Medical University Vienna 1090 Vienna Austria

Institute of Environmental Medicine Karolinska Institutet 171 64 Solna Sweden

Institute of Medical Biometry and Informatics Medical Faculty University of Heidelberg Im Neuenheimer Feld 130 3 69120 Heidelberg Germany

Integrative Cancer Epidemiology Programme Integrative Epidemiology Unit Bristol Medical School University of Bristol Bristol BS8 2BN UK

Jeonnam Regional Cancer Center Chonnam National University Hwasun Hospital Hwasun 58128 Korea

Leeds Institute of Cancer and Pathology School of Medicine University of Leeds Leeds LS2 9JT UK

Lunenfeld Tanenbaum Research Institute Mount Sinai Hospital Faculty of Medicine University of Toronto Toronto ON M5G 1X5 Canada

Melbourne Medical School University of Melbourne Centre for Cancer Research Victorian Comprehensive Cancer Centre Parkville VIC 3010 Australia

Memorial Sloan Kettering Cancer Center Department of Medicine New York NY 10065 USA

MRC Epidemiology Unit School of Clinical Medicine University of Cambridge Cambridge CB2 0SL UK

National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics University of Cambridge Cambridge CB2 1TN UK

National Institute for Health Research Cambridge Biomedical Research Centre Cambridge Biomedical Campus University of Cambridge Cambridge University Hospitals Cambridge CB2 0QQ UK

Nutrition and Metabolism Section International Agency for Research on Cancer World Health Organization 69372 Lyon France

ONCOBEL Program Bellvitge Biomedical Research Institute 08908 Barcelona Spain

Oncology Data Analytics Program Catalan Institute of Oncology IDIBELL 08908 Barcelona Spain

Precision Medicine School of Clinical Sciences at Monash Health Monash University Clayton VIC 3168 Australia

Public Health Sciences Division Fred Hutchinson Cancer Research Center Seattle WA 98109 1024 USA

Ruth and Bruce Rappaport Faculty of Medicine Technion Israel Institute of Technology Haifa 3200003 Israel

School of Cellular and Molecular Medicine University of Bristol Bristol BS8 1TD UK

School of Public Health University of Washington Seattle WA 98195 USA

Wallenberg Centre for Molecular Medicine Department of Biomedical and Clinical Sciences Umeå University 901 87 Umeå Sweden

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