BACKGROUND: Colorectal cancer (CRC) is a common, fatal cancer. Identifying subgroups who may benefit more from intervention is of critical public health importance. Previous studies have assessed multiplicative interaction between genetic risk scores and environmental factors, but few have assessed additive interaction, the relevant public health measure. METHODS: Using resources from CRC consortia, including 45,247 CRC cases and 52,671 controls, we assessed multiplicative and additive interaction (relative excess risk due to interaction, RERI) using logistic regression between 13 harmonized environmental factors and genetic risk score, including 141 variants associated with CRC risk. RESULTS: There was no evidence of multiplicative interaction between environmental factors and genetic risk score. There was additive interaction where, for individuals with high genetic susceptibility, either heavy drinking (RERI = 0.24, 95% confidence interval [CI] = 0.13, 0.36), ever smoking (0.11 [0.05, 0.16]), high body mass index (female 0.09 [0.05, 0.13], male 0.10 [0.05, 0.14]), or high red meat intake (highest versus lowest quartile 0.18 [0.09, 0.27]) was associated with excess CRC risk greater than that for individuals with average genetic susceptibility. Conversely, we estimate those with high genetic susceptibility may benefit more from reducing CRC risk with aspirin/nonsteroidal anti-inflammatory drugs use (-0.16 [-0.20, -0.11]) or higher intake of fruit, fiber, or calcium (highest quartile versus lowest quartile -0.12 [-0.18, -0.050]; -0.16 [-0.23, -0.09]; -0.11 [-0.18, -0.05], respectively) than those with average genetic susceptibility. CONCLUSIONS: Additive interaction is important to assess for identifying subgroups who may benefit from intervention. The subgroups identified in this study may help inform precision CRC prevention.

Bioinformatics and Data Science Research Center Bina Nusantara University Jakarta Indonesia

BioRealm LLC Walnut CA

Broad Institute of Harvard and MIT Cambridge MA

Broad Institute of MIT and Harvard Cambridge MA

Cancer Epidemiology Division Cancer Council Victoria Melbourne Victoria Australia

Center for Cancer Research Medical University of Vienna Vienna Austria

Center for Gastrointestinal Biology and Disease University of North Carolina Chapel Hill NC

Center for Public Health Genomics University of Virginia Charlottesville VA

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

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

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

Colorectal Cancer Group ONCOBELL Program Bellvitge Biomedical Research Institute L'Hospitalet de Llobregat Barcelona Spain

Computer Science Department School of Computer Science Bina Nusantara University Jakarta Indonesia

Consortium for Biomedical Research in Epidemiology and Public Health Madrid Spain

Department of Biostatistics University of Washington Seattle WA

Department of Cancer Medicine The University of Texas MD Anderson Cancer Center Houston TX

Department of Clinical Sciences Faculty of Medicine and health Sciences and Universitat de Barcelona Institute of Complex Systems L'Hospitalet de Llobregat Barcelona Spain

Department of Computer Science Stanford University Stanford CA

Department of Epidemiology and Biostatistics Imperial College London School of Public Health London UK

Department of Epidemiology and Population Health Albert Einstein College of Medicine Bronx NY

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

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

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

Department of Epidemiology University of Washington Seattle WA

Department of Family Medicine University of Virginia Charlottesville VA

Department of Genetics Stanford University Stanford CA

Department of Hygiene and Epidemiology University of Ioannina School of Medicine Ioannina Greece

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

Department of Medical Oncology and Therapeutics Research City of Hope National Medical Center Duarte CA

Department of Medical Oncology Dana Farber Cancer Institute Boston MA

Department of Medicine Brigham and Women's Hospital Harvard Medical School Boston MA

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

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

Department of Nutrition Harvard T H Chan School of Public Health Harvard University Boston MA

Department of Nutritional Sciences University of Michigan School of Public Health Ann Arbor MI

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

Department of Population Health Sciences University of Utah Salt Lake City UT

Department of Population Science American Cancer Society Atlanta GA

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

Department of Radiation Sciences Oncology Unit Umeå University Umeå Sweden

Departments of Epidemiology and Nutrition Harvard TH Chan School of Public Health Boston MA

Departments of Medicine and Epidemiology University of Pittsburgh Medical Center Pittsburgh PA

Digestive Diseases and Microbiota Group Girona Biomedical Research Institute Salt Girona Spain

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

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

Division of Cancer Epidemiology German Cancer Research Center Heidelberg Germany

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

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

Division of Human Nutrition and Health Wageningen University and Research Wageningen The Netherlands

Division of Preventive Oncology German Cancer Research Center Heidelberg Germany

Division of Research Kaiser Permanente Northern California Oakland CA

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

From the Public Health Sciences Division Fred Hutchinson Cancer Center Seattle WA

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

German Cancer Consortium Heidelberg Germany

Harvard TH Chan School of Public Health

Huntsman Cancer Institute Salt Lake City UT

Institute for Health Research Kaiser Permanente Colorado Aurora CO

Institute of Biology and Medical Genetics 1st Faculty of Medicine Charles University Prague Czech Republic

Institute of Environmental Medicine Karolinska Institutet Stockholm Sweden

Leeds Institute of Medical Research University of Leeds Leeds UK

Memorial University of Newfoundland Discipline of Genetics St John's Canada

Norris Comprehensive Cancer Center University of Southern California Los Angeles CA

Novo Nordisk Foundation Center for Basic Metabolic Research Faculty of Health and Medical Sciences University of Copenhagen Denmark

Nutrition and Metabolism Branch International Agency for Research on Cancer Lyon France

ONCOBELL Program Bellvitge Biomedical Research Institute L'Hospitalet de Llobregat Barcelona Spain

School of Public Health Capital Medical University Beijing China

Service de Génétique Médicale Centre Hospitalier Universitaire Nantes Nantes France

Slone Epidemiology Center at Boston University Boston MA

SWOG Statistical Center Fred Hutchinson Cancer Center Seattle WA

Unit of Biomarkers and Suceptibility L'Hospitalet del Llobregat Barcelona Spain

University Medical Centre Hamburg Eppendorf University Cancer Centre Hamburg Hamburg Germany

University of Hawaii Cancer Center Honolulu HI

University of Southern California Department of Population and Public Health Sciences Los Angeles CA

Wallenberg Centre for Molecular Medicine Umeå University Umeå Sweden

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