Mendelian randomisation implicates hyperlipidaemia as a risk factor for colorectal cancer
Henry Rodriguez-Broadbent
Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom
H.R.-B., P.J.L., and A.S contributed equally to this work
Search for more papers by this authorPhilip J. Law
Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom
H.R.-B., P.J.L., and A.S contributed equally to this work
Search for more papers by this authorAmit Sud
Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom
H.R.-B., P.J.L., and A.S contributed equally to this work
Search for more papers by this authorKimmo Palin
Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland
Search for more papers by this authorSari Tuupanen
Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland
Search for more papers by this authorAlexandra Gylfe
Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland
Search for more papers by this authorUlrika A. Hänninen
Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland
Search for more papers by this authorTatiana Cajuso
Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland
Search for more papers by this authorTomas Tanskanen
Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland
Search for more papers by this authorJohanna Kondelin
Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland
Search for more papers by this authorEevi Kaasinen
Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland
Search for more papers by this authorAntti-Pekka Sarin
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
Search for more papers by this authorSamuli Ripatti
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom
Department of Public Health, University of Helsinki, Helsinki, Finland
Search for more papers by this authorJohan G. Eriksson
National Institute for Health and Welfare, Helsinki, Finland
Folkhälsan Research Centre, Helsinki, Finland
Unit of General Practice and Primary Health Care, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
Search for more papers by this authorHarri Rissanen
National Institute for Health and Welfare, Helsinki, Finland
Search for more papers by this authorPaul Knekt
National Institute for Health and Welfare, Helsinki, Finland
Search for more papers by this authorEero Pukkala
Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer Research, Helsinki, Finland
Faculty of Social Sciences, University of Tampere, Tampere, Finland
Search for more papers by this authorPekka Jousilahti
National Institute for Health and Welfare, Helsinki, Finland
Search for more papers by this authorVeikko Salomaa
National Institute for Health and Welfare, Helsinki, Finland
Search for more papers by this authorAarno Palotie
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA
Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA
Department of Neurology, Massachusetts General Hospital, Boston, MA
Search for more papers by this authorLaura Renkonen-Sinisalo
Department of Surgery, Abdominal Center, Helsinki University Hospital, Helsinki, Finland
Search for more papers by this authorAnna Lepistö
Department of Surgery, Abdominal Center, Helsinki University Hospital, Helsinki, Finland
Search for more papers by this authorJan Böhm
Department of Pathology, Central Finland Central Hospital, Jyväskylä, Finland
Search for more papers by this authorJukka-Pekka Mecklin
Department of Surgery, Jyväskylä Central Hospital, University of Eastern Finland, Jyväskylä, Finland
Search for more papers by this authorNada A. Al-Tassan
Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
Search for more papers by this authorClaire Palles
Wellcome Trust Centre for Human Genetics and NIHR Comprehensive Biomedical Research Centre, Oxford, United Kingdom
Search for more papers by this authorLynn Martin
Wellcome Trust Centre for Human Genetics and NIHR Comprehensive Biomedical Research Centre, Oxford, United Kingdom
Search for more papers by this authorElla Barclay
Wellcome Trust Centre for Human Genetics and NIHR Comprehensive Biomedical Research Centre, Oxford, United Kingdom
Search for more papers by this authorSusan M. Farrington
Colon Cancer Genetics Group, University of Edinburgh and MRC Human Genetics Unit, Western General Hospital, Edinburgh, United Kingdom
Search for more papers by this authorMaria N. Timofeeva
Colon Cancer Genetics Group, University of Edinburgh and MRC Human Genetics Unit, Western General Hospital, Edinburgh, United Kingdom
Search for more papers by this authorBrian F. Meyer
Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
Search for more papers by this authorSalma M. Wakil
Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
Search for more papers by this authorHarry Campbell
Centre for Population Health Sciences, University of Edinburgh, Edinburgh, United Kingdom
Search for more papers by this authorChristopher G. Smith
Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, United Kingdom
Search for more papers by this authorShelley Idziaszczyk
Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, United Kingdom
Search for more papers by this authorTimothy S. Maughan
CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, United Kingdom
Search for more papers by this authorRichard Kaplan
MRC Clinical Trials Unit, Aviation House, London, United Kingdom
Search for more papers by this authorRachel Kerr
Department of Oncology, Oxford Cancer Centre, University of Oxford, Churchill Hospital, Oxford, United Kingdom
Search for more papers by this authorDavid Kerr
Nuffield Department of Clinical Laboratory Sciences, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
Search for more papers by this authorMichael N. Passarelli
Department of Epidemiology, Geisel School of Medicine at Dartmouth, Dartmouth-Hitchcock Medical Center, Lebanon, NH
Search for more papers by this authorJane C. Figueiredo
Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA
Keck School of Medicine, University of Southern California, Los Angeles, CA
Search for more papers by this authorDaniel D. Buchanan
Department of Pathology, Colorectal Oncogenomics Group, Genetic Epidemiology Laboratory, The University of Melbourne, Victoria, Australia
Centre for Epidemiology and Biostatistics, The University of Melbourne, Victoria, Australia
Search for more papers by this authorAung K. Win
Centre for Epidemiology and Biostatistics, The University of Melbourne, Victoria, Australia
Search for more papers by this authorJohn L. Hopper
Centre for Epidemiology and Biostatistics, The University of Melbourne, Victoria, Australia
Search for more papers by this authorMark A. Jenkins
Centre for Epidemiology and Biostatistics, The University of Melbourne, Victoria, Australia
Search for more papers by this authorNoralane M. Lindor
Department of Health Sciences Research, Mayo Clinic, Scottsdale, AZ
Search for more papers by this authorPolly A. Newcomb
Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA
Search for more papers by this authorSteven Gallinger
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
Search for more papers by this authorDavid Conti
Department of Preventive Medicine, University of Southern California, Los Angeles, CA
Search for more papers by this authorFred Schumacher
Department of Preventive Medicine, University of Southern California, Los Angeles, CA
Search for more papers by this authorGraham Casey
Center for Public Health Genomics, University of Virginia, Charlottesville, VA
Search for more papers by this authorLauri A. Aaltonen
Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland
Search for more papers by this authorJeremy P. Cheadle
Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, United Kingdom
Search for more papers by this authorIan P. Tomlinson
Wellcome Trust Centre for Human Genetics and NIHR Comprehensive Biomedical Research Centre, Oxford, United Kingdom
Search for more papers by this authorMalcolm G. Dunlop
Colon Cancer Genetics Group, University of Edinburgh and MRC Human Genetics Unit, Western General Hospital, Edinburgh, United Kingdom
Search for more papers by this authorCorresponding Author
Richard S. Houlston
Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom
Correspondence to: Richard S. Houlston, Division of Genetics and Epidemiology, The Institute of Cancer Research, 15 Cotswold Road, London SM2 5NG, UK, Tel.: +44-(0)-208-722-4175, Fax: +44-(0)-722-4365, E-mail: [email protected]Search for more papers by this authorHenry Rodriguez-Broadbent
Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom
H.R.-B., P.J.L., and A.S contributed equally to this work
Search for more papers by this authorPhilip J. Law
Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom
H.R.-B., P.J.L., and A.S contributed equally to this work
Search for more papers by this authorAmit Sud
Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom
H.R.-B., P.J.L., and A.S contributed equally to this work
Search for more papers by this authorKimmo Palin
Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland
Search for more papers by this authorSari Tuupanen
Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland
Search for more papers by this authorAlexandra Gylfe
Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland
Search for more papers by this authorUlrika A. Hänninen
Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland
Search for more papers by this authorTatiana Cajuso
Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland
Search for more papers by this authorTomas Tanskanen
Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland
Search for more papers by this authorJohanna Kondelin
Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland
Search for more papers by this authorEevi Kaasinen
Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland
Search for more papers by this authorAntti-Pekka Sarin
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
Search for more papers by this authorSamuli Ripatti
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom
Department of Public Health, University of Helsinki, Helsinki, Finland
Search for more papers by this authorJohan G. Eriksson
National Institute for Health and Welfare, Helsinki, Finland
Folkhälsan Research Centre, Helsinki, Finland
Unit of General Practice and Primary Health Care, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
Search for more papers by this authorHarri Rissanen
National Institute for Health and Welfare, Helsinki, Finland
Search for more papers by this authorPaul Knekt
National Institute for Health and Welfare, Helsinki, Finland
Search for more papers by this authorEero Pukkala
Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer Research, Helsinki, Finland
Faculty of Social Sciences, University of Tampere, Tampere, Finland
Search for more papers by this authorPekka Jousilahti
National Institute for Health and Welfare, Helsinki, Finland
Search for more papers by this authorVeikko Salomaa
National Institute for Health and Welfare, Helsinki, Finland
Search for more papers by this authorAarno Palotie
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA
Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA
Department of Neurology, Massachusetts General Hospital, Boston, MA
Search for more papers by this authorLaura Renkonen-Sinisalo
Department of Surgery, Abdominal Center, Helsinki University Hospital, Helsinki, Finland
Search for more papers by this authorAnna Lepistö
Department of Surgery, Abdominal Center, Helsinki University Hospital, Helsinki, Finland
Search for more papers by this authorJan Böhm
Department of Pathology, Central Finland Central Hospital, Jyväskylä, Finland
Search for more papers by this authorJukka-Pekka Mecklin
Department of Surgery, Jyväskylä Central Hospital, University of Eastern Finland, Jyväskylä, Finland
Search for more papers by this authorNada A. Al-Tassan
Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
Search for more papers by this authorClaire Palles
Wellcome Trust Centre for Human Genetics and NIHR Comprehensive Biomedical Research Centre, Oxford, United Kingdom
Search for more papers by this authorLynn Martin
Wellcome Trust Centre for Human Genetics and NIHR Comprehensive Biomedical Research Centre, Oxford, United Kingdom
Search for more papers by this authorElla Barclay
Wellcome Trust Centre for Human Genetics and NIHR Comprehensive Biomedical Research Centre, Oxford, United Kingdom
Search for more papers by this authorSusan M. Farrington
Colon Cancer Genetics Group, University of Edinburgh and MRC Human Genetics Unit, Western General Hospital, Edinburgh, United Kingdom
Search for more papers by this authorMaria N. Timofeeva
Colon Cancer Genetics Group, University of Edinburgh and MRC Human Genetics Unit, Western General Hospital, Edinburgh, United Kingdom
Search for more papers by this authorBrian F. Meyer
Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
Search for more papers by this authorSalma M. Wakil
Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
Search for more papers by this authorHarry Campbell
Centre for Population Health Sciences, University of Edinburgh, Edinburgh, United Kingdom
Search for more papers by this authorChristopher G. Smith
Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, United Kingdom
Search for more papers by this authorShelley Idziaszczyk
Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, United Kingdom
Search for more papers by this authorTimothy S. Maughan
CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, United Kingdom
Search for more papers by this authorRichard Kaplan
MRC Clinical Trials Unit, Aviation House, London, United Kingdom
Search for more papers by this authorRachel Kerr
Department of Oncology, Oxford Cancer Centre, University of Oxford, Churchill Hospital, Oxford, United Kingdom
Search for more papers by this authorDavid Kerr
Nuffield Department of Clinical Laboratory Sciences, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
Search for more papers by this authorMichael N. Passarelli
Department of Epidemiology, Geisel School of Medicine at Dartmouth, Dartmouth-Hitchcock Medical Center, Lebanon, NH
Search for more papers by this authorJane C. Figueiredo
Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA
Keck School of Medicine, University of Southern California, Los Angeles, CA
Search for more papers by this authorDaniel D. Buchanan
Department of Pathology, Colorectal Oncogenomics Group, Genetic Epidemiology Laboratory, The University of Melbourne, Victoria, Australia
Centre for Epidemiology and Biostatistics, The University of Melbourne, Victoria, Australia
Search for more papers by this authorAung K. Win
Centre for Epidemiology and Biostatistics, The University of Melbourne, Victoria, Australia
Search for more papers by this authorJohn L. Hopper
Centre for Epidemiology and Biostatistics, The University of Melbourne, Victoria, Australia
Search for more papers by this authorMark A. Jenkins
Centre for Epidemiology and Biostatistics, The University of Melbourne, Victoria, Australia
Search for more papers by this authorNoralane M. Lindor
Department of Health Sciences Research, Mayo Clinic, Scottsdale, AZ
Search for more papers by this authorPolly A. Newcomb
Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA
Search for more papers by this authorSteven Gallinger
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
Search for more papers by this authorDavid Conti
Department of Preventive Medicine, University of Southern California, Los Angeles, CA
Search for more papers by this authorFred Schumacher
Department of Preventive Medicine, University of Southern California, Los Angeles, CA
Search for more papers by this authorGraham Casey
Center for Public Health Genomics, University of Virginia, Charlottesville, VA
Search for more papers by this authorLauri A. Aaltonen
Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland
Search for more papers by this authorJeremy P. Cheadle
Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, United Kingdom
Search for more papers by this authorIan P. Tomlinson
Wellcome Trust Centre for Human Genetics and NIHR Comprehensive Biomedical Research Centre, Oxford, United Kingdom
Search for more papers by this authorMalcolm G. Dunlop
Colon Cancer Genetics Group, University of Edinburgh and MRC Human Genetics Unit, Western General Hospital, Edinburgh, United Kingdom
Search for more papers by this authorCorresponding Author
Richard S. Houlston
Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom
Correspondence to: Richard S. Houlston, Division of Genetics and Epidemiology, The Institute of Cancer Research, 15 Cotswold Road, London SM2 5NG, UK, Tel.: +44-(0)-208-722-4175, Fax: +44-(0)-722-4365, E-mail: [email protected]Search for more papers by this authorAbstract
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.
Abstract
What's new?
While observational studies have suggested an association between blood cholesterol levels and colorectal cancer (CRC), they do not establish causality and may be influenced by confounding factors. Here the authors used Mendelian randomization, the relationship between genetic risk scores for lipid traits and CRC, to provide new evidence for a causal link between both. Their results point to hyperlipidaemia as an important target for CRC prevention in the population.
Supporting Information
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