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Mendelian Randomization of Circulating Polyunsaturated Fatty Acids and Colorectal Cancer Risk.
Pubmed ID
32051193 (View this publication on the PubMed website)
Digital Object Identifier
Cancer Epidemiol. Biomarkers Prev. 2020 Feb 12
Khankari NK, Banbury BL, Borges MC, Haycock P, Albanes D, Arndt V, Berndt SI, Bézieau S, Brenner H, Campbell PT, Casey G, Chan AT, Chang-Claude J, Conti DV, Cotterchio M, English DR, Figueiredo JC, Giles GG, Giovannucci EL, Gunter MJ, more Hampe J, Hoffmeister M, Hopper JL, Jenkins MA, Joshi AD, Marchand LL, Lemire M, Li CI, Li L, Lindblom A, Martín V, Moreno V, Newcomb PA, Offit K, Pharoah PDP, Rennert G, Sakoda LC, Schafmayer C, Schmit SL, Slattery ML, Song M, Thibodeau SN, Ulrich CM, Weinstein SJ, White E, Win AK, Wolk A, Woods MO, Wu AH, Cai Q, Denny JC, Edwards TL, Murff HJ, Gruber SB, Peters U, Zheng W
  • Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.
  • Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
  • Medical Research Council (MRC) Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.
  • Division of Cancer Epidemiology and Genetics, NCI, NIH, Bethesda, Maryland.
  • Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Service de Génétique Médicale, Centre Hospitalier Universitaire (CHU) Nantes, Nantes, France.
  • Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, Georgia.
  • Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia.
  • Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
  • University Medical Centre Hamburg-Eppendorf, University Cancer Centre Hamburg (UCCH), Hamburg, Germany. more
  • Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California.
  • Prevention and Cancer Control, Cancer Care Ontario, Toronto, Ontario, Canada.
  • Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
  • Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
  • Nutrition and Metabolism Section, International Agency for Research on Cancer, World Health Organization, Lyon, France.
  • Department of Medicine, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany.
  • Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
  • University of Hawaii Cancer Center, Honolulu, Hawaii.
  • PanCuRx Translational Research Initiative, Ontario, Institute for Cancer Research, Toronto, Ontario, Canada.
  • Department of Family Medicine, University of Virginia, Charlottesville, Virginia.
  • Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
  • Área de Medicina Preventiva y Salud Publica, Universidad de León, León, Spain.
  • Cancer Prevention and Control Program, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
  • Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York.
  • Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
  • Department of Community Medicine and Epidemiology, Lady Davis Carmel Medical Center, Haifa, Israel.
  • Department of General and Thoracic Surgery, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
  • Division of Epidemiology, Department of Internal Medicine, University of Utah, Salt Lake City, Utah.
  • Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
  • Huntsman Cancer Institute and Department of Population Health Sciences, University of Utah, Salt Lake City, Utah.
  • Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
  • Discipline of Genetics, Memorial University of Newfoundland, St. John's, Newfoundland, Canada.
  • Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.
  • Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, Tennessee.
  • Department of Medical Oncology, City of Hope National Medical Center, Duarte, California.

BACKGROUND: Results from epidemiologic studies examining polyunsaturated fatty acids (PUFAs) and colorectal cancer (CRC) risk are inconsistent. Mendelian randomization may strengthen causal inference from observational studies. Given their shared metabolic pathway, examining the combined effects of aspirin/NSAID use with PUFAs could help elucidate an association between PUFAs and CRC risk.

METHODS: Information was leveraged from GWAS regarding PUFA-associated single nucleotide polymorphisms (SNPs) to create weighted genetic scores (wGSs) representing genetically-predicted circulating blood PUFAs for 11,016 non-Hispanic white CRC cases and 13,732 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Associations per standard deviation increase in the wGS were estimated using unconditional logistic regression. Interactions between PUFA wGSs and aspirin/NSAID use on CRC risk were also examined.

RESULTS: Modest CRC risk reductions were observed per standard deviation increase in circulating linoleic acid (ORLA=0.96; 95% CI=0.93-0.98; p=5.2x10-4), α-linolenic acid (ORALA=0.95; 95% CI=0.92-0.97; p=5.4x10-5); whereas modest increased risks were observed for arachidonic acid (ORAA=1.06; 95% CI=1.03-1.08; p=3.3x10-5), eicosapentaenoic (OREPA=1.04; 95% CI=1.01-1.07; p=2.5x10-3), and docosapentaenoic acids (ORDPA=1.03; 95% CI=1.01-1.06; p=1.2x10-2. Each of these effects were stronger among aspirin/NSAID non-users in the stratified analyses.

CONCLUSIONS: Our study suggests that higher circulating shorter-chain PUFAs (i.e., LA and ALA) were associated with reduced CRC risk, whereas longer-chain PUFAs (i.e., AA, EPA, and DPA) were associated with an increased CRC risk.

IMPACT: The interaction of PUFAs with aspirin/NSAID use indicates a shared CRC inflammatory pathway. Future research should continue to improve PUFA genetic instruments to elucidate the independent effects of PUFAs on CRC.

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