Mendelian randomisation implicates hyperlipidaemia as a risk factor for colorectal cancer.
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.
Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom.
Henry
H
Rodriguez-Broadbent
Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom.
Philip J
0000-0001-9663-4611
PJ
Law
Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom.
Amit
A
Sud
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.
Kimmo
K
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.
Sari
S
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.
Alexandra
A
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.
Ulrika A
UA
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.
Tatiana
T
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.
Tomas
T
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.
Johanna
J
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.
Eevi
E
Kaasinen
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
Antti-Pekka
AP
Sarin
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.
Samuli
S
Ripatti
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.
Johan G
JG
Eriksson
National Institute for Health and Welfare, Helsinki, Finland.
Harri
H
Rissanen
National Institute for Health and Welfare, Helsinki, Finland.
Paul
P
Knekt
Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer Research, Helsinki, Finland.|Faculty of Social Sciences, University of Tampere, Tampere, Finland.
Eero
E
Pukkala
National Institute for Health and Welfare, Helsinki, Finland.
Pekka
P
Jousilahti
National Institute for Health and Welfare, Helsinki, Finland.
Veikko
V
Salomaa
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.
Aarno
A
Palotie
Department of Surgery, Abdominal Center, Helsinki University Hospital, Helsinki, Finland.
Laura
L
Renkonen-Sinisalo
Department of Surgery, Abdominal Center, Helsinki University Hospital, Helsinki, Finland.
Anna
A
Lepistö
Department of Pathology, Central Finland Central Hospital, Jyväskylä, Finland.
Jan
J
Böhm
Department of Surgery, Jyväskylä Central Hospital, University of Eastern Finland, Jyväskylä, Finland.
Jukka-Pekka
JP
Mecklin
Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Nada A
NA
Al-Tassan
Wellcome Trust Centre for Human Genetics and NIHR Comprehensive Biomedical Research Centre, Oxford, United Kingdom.
Claire
C
Palles
Wellcome Trust Centre for Human Genetics and NIHR Comprehensive Biomedical Research Centre, Oxford, United Kingdom.
Lynn
L
Martin
Wellcome Trust Centre for Human Genetics and NIHR Comprehensive Biomedical Research Centre, Oxford, United Kingdom.
Ella
E
Barclay
Colon Cancer Genetics Group, University of Edinburgh and MRC Human Genetics Unit, Western General Hospital, Edinburgh, United Kingdom.
Susan M
SM
Farrington
Colon Cancer Genetics Group, University of Edinburgh and MRC Human Genetics Unit, Western General Hospital, Edinburgh, United Kingdom.
Maria N
MN
Timofeeva
Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Brian F
BF
Meyer
Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Salma M
SM
Wakil
Centre for Population Health Sciences, University of Edinburgh, Edinburgh, United Kingdom.
Harry
H
Campbell
Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, United Kingdom.
Christopher G
CG
Smith
Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, United Kingdom.
Shelley
S
Idziaszczyk
CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, United Kingdom.
Timothy S
TS
Maughan
MRC Clinical Trials Unit, Aviation House, London, United Kingdom.
Richard
R
Kaplan
Department of Oncology, Oxford Cancer Centre, University of Oxford, Churchill Hospital, Oxford, United Kingdom.
Rachel
R
Kerr
Nuffield Department of Clinical Laboratory Sciences, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.
David
D
Kerr
Department of Epidemiology, Geisel School of Medicine at Dartmouth, Dartmouth-Hitchcock Medical Center, Lebanon, NH.
Michael N
MN
Passarelli
Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA.|Keck School of Medicine, University of Southern California, Los Angeles, CA.
Jane C
JC
Figueiredo
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.
Daniel D
0000-0003-2225-6675
DD
Buchanan
Centre for Epidemiology and Biostatistics, The University of Melbourne, Victoria, Australia.
Aung K
0000-0002-2794-5261
AK
Win
Centre for Epidemiology and Biostatistics, The University of Melbourne, Victoria, Australia.
John L
JL
Hopper
Centre for Epidemiology and Biostatistics, The University of Melbourne, Victoria, Australia.
Mark A
MA
Jenkins
Department of Health Sciences Research, Mayo Clinic, Scottsdale, AZ.
Noralane M
NM
Lindor
Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA.
Polly A
PA
Newcomb
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.
Steven
S
Gallinger
Department of Preventive Medicine, University of Southern California, Los Angeles, CA.
David
D
Conti
Department of Preventive Medicine, University of Southern California, Los Angeles, CA.
Fred
F
Schumacher
Center for Public Health Genomics, University of Virginia, Charlottesville, VA.
Graham
G
Casey
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.
Lauri A
LA
Aaltonen
Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, United Kingdom.
Jeremy P
JP
Cheadle
Wellcome Trust Centre for Human Genetics and NIHR Comprehensive Biomedical Research Centre, Oxford, United Kingdom.
Ian P
IP
Tomlinson
Colon Cancer Genetics Group, University of Edinburgh and MRC Human Genetics Unit, Western General Hospital, Edinburgh, United Kingdom.
Malcolm G
MG
Dunlop
Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom.
Richard S
RS
Houlston
D002784:Cholesterol / Q000097:blood; D015179:Colorectal Neoplasms / Q000097:blood / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods / Q000706:statistics & numerical data; D006801:Humans; D006949:Hyperlipidemias / Q000097:blood / Q000235:genetics*; D008075:Lipoproteins, HDL / Q000097:blood; D008077:Lipoproteins, LDL / Q000097:blood; D016015:Logistic Models; D057182:Mendelian Randomization Analysis / Q000379:methods*; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D018570:Risk Assessment; D012307:Risk Factors; D014280:Triglycerides / Q000097:blood
D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D014280:Triglycerides; D002784:Cholesterol
Mendelian randomisation; cholesterol; colorectal cancer; hyperlipidaemia; risk