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The association between genetically elevated polyunsaturated fatty acids and risk of cancer.

Authors

Haycock PC, Borges MC, Burrows K, Lemaitre RN, Burgess S, Khankari NK, Tsilidis KK, Gaunt TR, Hemani G, Zheng J, Truong T, Birmann BM, OMara T, Spurdle AB, Iles MM, Law MH, Slager SL, Saberi Hosnijeh F, Mariosa D, Cotterchio M, ...show more Cerhan JR, Peters U, Enroth S, Gharahkhani P, Le Marchand L, Williams AC, Block RC, ACCC, CCFR-CORECT-GECCO, EPITHYR, InterLymph, MMAC, ECAC, ILCCO, PRACTICAL Consortium, PanScan, PanC4, Amos CI, Hung RJ, Zheng W, Gunter MJ, Smith GD, Relton C, Martin RM, Fatty Acids in Cancer Mendelian Randomization Collaboration

Affiliations

  • MRC Integrative Epidemiology Unit (IEU), Population Health Sciences, University of Bristol, Bristol, United Kingdom. Electronic address: philip.haycock@bristol.ac.uk.
  • MRC Integrative Epidemiology Unit (IEU), Population Health Sciences, University of Bristol, Bristol, United Kingdom.
  • Department of Medicine, Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA.
  • MRC Biostatistics Unit, University of Cambridge, USA.
  • Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
  • Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK; Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.
  • Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Université Paris-Saclay, UVSQ, Inserm, Gustave Roussy, Team "Exposome, Heredity, Cancer and Health", CESP, Villejuif, France.
  • Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • Genetics and Computational Biology Division, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; School of Medicine, Faculty of Health Sciences, University of Queensland, Australia.
...show more
  • Leeds Institute for Data Analytics, University of Leeds, Leeds, UK; NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
  • Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia; School of Biomedical Sciences, Faculty of Health, and Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, Queensland, Australia.
  • Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA.
  • Institute for Risk Assessment Sciences, Utrecht University, Netherlands.
  • Genomic Epidemiology Branch, International Agency for Research on Cancer (IARC/WHO), Lyon, France.
  • Dalla Lana School of Public Health, University of Toronto, Canada; Prevention and Cancer Control, Cancer Care Ontario, Ontario Health, Toronto, ON, Canada.
  • Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, USA; Department of Epidemiology, School of Public Health, University of Washington, Seattle, USA.
  • Department of Immunology, Genetics, and Pathology, Biomedical Center, Science for Life Laboratory (SciLifeLab) Uppsala, Uppsala University, Uppsala, Sweden.
  • Statistical Genetics Lab, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston QLD, 4006, Australia.
  • University of Hawaii Cancer Center, Honolulu, HI, USA.
  • School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK.
  • Department of Public Health Sciences, University of Rochester, NY, USA.
  • Dan L Duncan Comprehensive Cancer Center Baylor College of Medicine, USA.
  • Lunenfeld-Tanenbaum Research Institute Mount Sinai Hospital and University of Toronto, Canada.
  • Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
  • Section of Nutrition and Metabolism, International Agency for Research on Cancer (IARC), 150 Cours Albert Thomas, Lyon, France.
  • MRC Integrative Epidemiology Unit (IEU), Population Health Sciences, University of Bristol, Bristol, United Kingdom; The National Institute for Health Research (NIHR) Bristol Biomedical Research Centre, University Hospitals Bristol and Weston NHS Foundation Trust and University of Bristol, Bristol, United Kingdom; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom.

Abstract

BACKGROUND: The causal relevance of polyunsaturated fatty acids (PUFAs) for risk of site-specific cancers remains uncertain.

METHODS: Using a Mendelian randomization (MR) framework, we assessed the causal relevance of PUFAs for risk of cancer in European and East Asian ancestry individuals. We defined the primary exposure as PUFA desaturase activity, proxied by rs174546 at the FADS locus. Secondary exposures were defined as omega 3 and omega 6 PUFAs that could be proxied by genetic polymorphisms outside the FADS region. Our study used summary genetic data on 10 PUFAs and 67 cancers, corresponding to 562,871 cases and 1,619,465 controls, collected by the Fatty Acids in Cancer Mendelian Randomization Collaboration. We estimated odds ratios (ORs) for cancer per standard deviation increase in genetically proxied PUFA exposures.

FINDINGS: Genetically elevated PUFA desaturase activity was associated (P < 0.0007) with higher risk (OR [95% confidence interval]) of colorectal cancer (1.09 [1.07-1.11]), esophageal squamous cell carcinoma (1.16 [1.06-1.26]), lung cancer (1.06 [1.03-1.08]) and basal cell carcinoma (1.05 [1.02-1.07]). There was little evidence for associations with reproductive cancers (OR = 1.00 [95% CI: 0.99-1.01]; Pheterogeneity = 0.25), urinary system cancers (1.03 [0.99-1.06], Pheterogeneity = 0.51), nervous system cancers (0.99 [0.95-1.03], Pheterogeneity = 0.92) or blood cancers (1.01 [0.98-1.04], Pheterogeneity = 0.09). Findings for colorectal cancer and esophageal squamous cell carcinoma remained compatible with causality in sensitivity analyses for violations of assumptions. Secondary MR analyses highlighted higher omega 6 PUFAs (arachidonic acid, gamma-linolenic acid and dihomo-gamma-linolenic acid) as potential mediators. PUFA biosynthesis is known to interact with aspirin, which increases risk of bleeding and inflammatory bowel disease. In a phenome-wide MR study of non-neoplastic diseases, we found that genetic lowering of PUFA desaturase activity, mimicking a hypothetical intervention to reduce cancer risk, was associated (P < 0.0006) with increased risk of inflammatory bowel disease but not bleeding.

INTERPRETATION: The PUFA biosynthesis pathway may be an intervention target for prevention of colorectal cancer and esophageal squamous cell carcinoma but with potential for increased risk of inflammatory bowel disease.

FUNDING: Cancer Resesrch UK (C52724/A20138, C18281/A19169). UK Medical Research Council (MR/P014054/1). National Institute for Health Research (NIHR202411). UK Medical Research Council (MC_UU_00011/1, MC_UU_00011/3, MC_UU_00011/6, and MC_UU_00011/4). National Cancer Institute (R00 CA215360). National Institutes of Health (U01 CA164973, R01 CA60987, R01 CA72520, U01 CA74806, R01 CA55874, U01 CA164973 and U01 CA164973).

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Publication Details

PubMed ID
37086649

Digital Object Identifier
10.1016/j.ebiom.2023.104510

Publication
EBioMedicine. 2023 May; Volume 91: Pages 104510

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