Mendelian randomisation implicates hyperlipidaemia as a risk factor for colorectal cancer

Research output: Contribution to journalArticle

Authors

  • Henry Rodriguez-Broadbent
  • Philip J Law
  • Amit Sud
  • Kimmo Palin
  • Sari Tuupanen
  • Alexandra Gylfe
  • Ulrika A Hänninen
  • Tatiana Cajuso
  • Tomas Tanskanen
  • Johanna Kondelin
  • Eevi Kaasinen
  • Antti-Pekka Sarin
  • Samuli Ripatti
  • Johan G Eriksson
  • Harri Rissanen
  • Paul Knekt
  • Eero Pukkala
  • Pekka Jousilahti
  • Veikko Salomaa
  • Aarno Palotie
  • Laura Renkonen-Sinisalo
  • Anna Lepistö
  • Jan Böhm
  • Jukka-Pekka Mecklin
  • Nada A Al-Tassan
  • Lynn Martin
  • Ella Barclay
  • Susan M Farrington
  • Maria N Timofeeva
  • Brian F Meyer
  • Salma M Wakil
  • Harry Campbell
  • Christopher G Smith
  • Shelley Idziaszczyk
  • Timothy S Maughan
  • Richard Kaplan
  • Rachel Kerr
  • David Kerr
  • Michael N Passarelli
  • Jane C Figueiredo
  • Daniel D Buchanan
  • Aung K Win
  • John L Hopper
  • Mark A Jenkins
  • Noralane M Lindor
  • Polly A Newcomb
  • Steven Gallinger
  • David Conti
  • Fred Schumacher
  • Graham Casey
  • Lauri A Aaltonen
  • Jeremy P Cheadle
  • Ian P Tomlinson
  • Malcolm G Dunlop
  • Richard S Houlston

Colleges, School and Institutes

External organisations

  • Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom.
  • Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, 00014, Finland; Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, 00014, Finland.
  • Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
  • Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, 00014, Finland; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK; Department of Public Health, University of Helsinki, Helsinki, 00014, Finland.
  • National Institute for Health and Welfare, Helsinki, 00271, Finland; Folkhälsan Research Centre, Helsinki, 00250, Finland; Unit of General Practice and Primary Health Care, University of Helsinki and Helsinki University Hospital, Helsinki, 00014, Finland.
  • National Institute for Health and Welfare, Helsinki, Finland.
  • Faculty of Social Sciences, University of Tampere, Tampere, Finland.
  • Department of Neurology, Massachusetts General Hospital, Boston, MA.
  • Department of Surgery, Abdominal Center, Helsinki University Hospital, Helsinki, Finland.
  • Department of Pathology, Central Finland Central Hospital, Jyväskylä, Finland.
  • Department of Surgery, Jyväskylä Central Hospital, University of Eastern Finland, Jyväskylä, Finland.
  • Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
  • Wellcome Trust Centre for Human Genetics and NIHR Comprehensive Biomedical Research Centre, Oxford, United Kingdom.
  • Colon Cancer Genetics Group, University of Edinburgh and MRC Human Genetics Unit, Western General Hospital, Edinburgh, United Kingdom.
  • From the Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, United Kingdom (J.P.S., R.S., C.H., F.D.R.H., D.N., A.W., R.J.M.); Institute of Applied Health Research, Institute of Clinical Sciences, University of Birmingham, Birmingham, United Kingdom (P.G., U.M.); Family Practice Unit, Memorial University of Newfoundland, St John's, Newfoundland, NL, Canada (M.G.); Health Services Research Unit, Edinburgh Napier University, Edinburgh, United Kingdom (J.H.); Cambridge Institute of Public Health, University of Cambridge, Cambridge, United Kingdom (J.M.); Centre for Population Health Sciences, University of Edinburgh, Edinburgh, United Kingdom (B.M.); Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada (M.M.); and Institute of Cardiovascular Science, University College London, London, United Kingdom (B.W.). james.sheppard@phc.ox.ac.uk.
  • Cardiff University
  • 5. CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, United Kingdom.
  • MRC Clinical Trials Unit, , Aviation House, London, United Kingdom.
  • Oxford Cancer Centre, Department of Oncology, University of Oxford, Churchill Hospital, Oxford, United Kingdom.
  • Nuffield Department of Clinical Laboratory Sciences, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.
  • Department of Epidemiology, Geisel School of Medicine at Dartmouth, Dartmouth-Hitchcock Medical Center, Lebanon, NH, 03756, USA.
  • Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • Centre for Epidemiology and Biostatistics, The University of Melbourne, Victoria, Australia.
  • Department of Health Sciences Research, Mayo Clinic, Scottsdale, AZ, USA.
  • Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
  • Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.
  • Department of Preventive Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
  • Center for Public Health Genomics, University of Virginia, Charlottesville, VA.

Abstract

While elevated blood cholesterol has been associated with an increased risk of colorectal cancer (CRC) in observational studies, causality is uncertain. Here we apply a Mendelian randomisation (MR) analysis to examine the potential causal relationship between lipid traits and CRC risk. We used single nucleotide polymorphisms (SNPs) associated with blood levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) as instrumental variables (IV). We calculated MR estimates for each risk factor with CRC using SNP-CRC associations from 9,254 cases and 18,386 controls. Genetically predicted higher TC was associated with an elevated risk of CRC (odds ratios (OR) per unit SD increase = 1.46, 95% confidence interval [CI]: 1.20-1.79, p = 1.68 × 10-4 ). The pooled ORs for LDL, HDL, and TG were 1.05 (95% CI: 0.92-1.18, p = 0.49), 0.94 (95% CI: 0.84-1.05, p = 0.27), and 0.98 (95% CI: 0.85-1.12, p = 0.75) respectively. A genetic risk score for 3-hydoxy-3-methylglutaryl-coenzyme A reductase (HMGCR) to mimic the effects of statin therapy was associated with a reduced CRC risk (OR = 0.69, 95% CI: 0.49-0.99, p = 0.046). This study supports a causal relationship between higher levels of TC with CRC risk, and a further rationale for implementing public health strategies to reduce the prevalence of hyperlipidaemia.

Details

Original languageEnglish
Pages (from-to)2701-2708
Number of pages8
JournalInternational Journal of Cancer
Volume140
Issue number12
Early online date6 Apr 2017
Publication statusPublished - 15 Jun 2017

Keywords

  • Cholesterol, Colorectal Neoplasms, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Hyperlipidemias, Lipoproteins, HDL, Lipoproteins, LDL, Logistic Models, Mendelian Randomization Analysis, Odds Ratio, Polymorphism, Single Nucleotide, Risk Assessment, Risk Factors, Triglycerides, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't