title: Blood lipids and prostate cancer: a Mendelian randomization analysis.
abstract: Genetic risk scores were used as unconfounded instruments for specific lipid traits (Mendelian randomization) to assess whether circulating lipids causally influence prostate cancer risk. Data from 22,249 prostate cancer cases and 22,133 controls from 22 studies within the international PRACTICAL consortium were analyzed. Allele scores based on single nucleotide polymorphisms (SNPs) previously reported to be uniquely associated with each of low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglyceride (TG) levels, were first validated in an independent dataset, and then entered into logistic regression models to estimate the presence (and direction) of any causal effect of each lipid trait on prostate cancer risk. There was weak evidence for an association between the LDL genetic score and cancer grade: the odds ratio (OR) per genetically instrumented standard deviation (SD) in LDL, comparing high- (≥7 Gleason score) versus low-grade (<7 Gleason score) cancers was 1.50 (95% CI: 0.92, 2.46; P = 0.11). A genetically instrumented SD increase in TGs was weakly associated with stage: the OR for advanced versus localized cancer per unit increase in genetic risk score was 1.68 (95% CI: 0.95, 3.00; P = 0.08). The rs12916-T variant in 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) was inversely associated with prostate cancer (OR: 0.97; 95% CI: 0.94, 1.00; P = 0.03). In conclusion, circulating lipids, instrumented by our genetic risk scores, did not appear to alter prostate cancer risk. We found weak evidence that higher LDL and TG levels increase aggressive prostate cancer risk, and that a variant in HMGCR (that mimics the LDL lowering effect of statin drugs) reduces risk. However, inferences are limited by sample size and evidence of pleiotropy.
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.|MRC/University of Bristol Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.|Integrative Cancer Epidemiology Programme, University of Bristol, Bristol, United Kingdom.|IGFs and Metabolic Endocrinology Group, School of Clinical Sciences North Bristol, University of Bristol, Bristol, BS10 5NB, United Kingdom.
authors.forename: Caroline J
authors.initials: CJ
authors.lastname: Bull
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.|MRC/University of Bristol Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.|Integrative Cancer Epidemiology Programme, University of Bristol, Bristol, United Kingdom.
authors.forename: Carolina
authors.initials: C
authors.lastname: Bonilla
authors.affiliation: Integrative Cancer Epidemiology Programme, University of Bristol, Bristol, United Kingdom.|IGFs and Metabolic Endocrinology Group, School of Clinical Sciences North Bristol, University of Bristol, Bristol, BS10 5NB, United Kingdom.
authors.forename: Jeff M P
authors.initials: JM
authors.lastname: Holly
authors.affiliation: Integrative Cancer Epidemiology Programme, University of Bristol, Bristol, United Kingdom.|IGFs and Metabolic Endocrinology Group, School of Clinical Sciences North Bristol, University of Bristol, Bristol, BS10 5NB, United Kingdom.
authors.forename: Claire M
authors.initials: CM
authors.lastname: Perks
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.|MRC/University of Bristol Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.|Integrative Cancer Epidemiology Programme, University of Bristol, Bristol, United Kingdom.
authors.forename: Neil
authors.initials: N
authors.lastname: Davies
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.|MRC/University of Bristol Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.|Integrative Cancer Epidemiology Programme, University of Bristol, Bristol, United Kingdom.
authors.forename: Philip
authors.initials: P
authors.lastname: Haycock
authors.affiliation: Department of Medicine, Division of Endocrinology, Epidemiology, Biostatistics and Occupational Health McGill University, Montreal, Quebec, Canada.
authors.forename: Oriana Hoi Yun
authors.initials: OH
authors.lastname: Yu
authors.affiliation: Department of Medicine, Division of Endocrinology, Epidemiology, Biostatistics and Occupational Health McGill University, Montreal, Quebec, Canada.|Department of Twin Research, King's College London, London, SE1 7EH, United Kingdom.
authors.forename: J Brent
authors.initials: JB
authors.lastname: Richards
authors.affiliation: The Institute of Cancer Research, London, SM2 5NG, United Kingdom.|The Royal Marsden NHS Foundation Trust, London, SW3 6JJ, United Kingdom.
authors.forename: Rosalind
authors.initials: R
authors.lastname: Eeles
authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Laboratory, Worts Causeway, Cambridge, United Kingdom.
authors.forename: Doug
authors.initials: D
authors.lastname: Easton
authors.affiliation: The Institute of Cancer Research, London, SM2 5NG, United Kingdom.
authors.forename: Zsofia
authors.initials: Z
authors.lastname: Kote-Jarai
authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Laboratory, Worts Causeway, Cambridge, United Kingdom.
authors.forename: Ali
authors.initials: A
authors.lastname: Amin Al Olama
authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Laboratory, Worts Causeway, Cambridge, United Kingdom.
authors.forename: Sara
authors.initials: S
authors.lastname: Benlloch
authors.affiliation: Integrative Cancer Epidemiology Programme, University of Bristol, Bristol, United Kingdom.|Warwick Medical School, University of Warwick, Coventry, CV4 7AL, United Kingdom.|Institute of Population Health, University of Manchester, Manchester, M13 9PL, United Kingdom.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Muir
authors.affiliation: Cancer Epidemiology Centre, The Cancer Council Victoria, 615 St Kilda Road, Melbourne, Victoria, Australia.|Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Victoria, Australia.
authors.forename: Graham G
authors.initials: GG
authors.lastname: Giles
authors.affiliation: Cancer Epidemiology Centre, The Cancer Council Victoria, 615 St Kilda Road, Melbourne, Victoria, Australia.|Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Victoria, Australia.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: MacInnis
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Wiklund
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
authors.forename: Henrik
authors.initials: H
authors.lastname: Gronberg
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Haiman
authors.affiliation: Department of Medical Biochemistry and Genetics, University of Turku and Tyks Microbiology and Genetics, Department of Medical Genetics, Turku University Hospital, Turku, Finland.|Institute of Biomedical Technology/BioMediTech, University of Tampere and FimLab Laboratories, Tampere, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Schleutker
authors.affiliation: Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev Ringvej 75, Herlev, DK-2730, Denmark.
authors.forename: Børge G
authors.initials: BG
authors.lastname: Nordestgaard
authors.affiliation: Cancer Epidemiology, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom.
authors.forename: Ruth C
authors.initials: RC
authors.lastname: Travis
authors.affiliation: Surgical Oncology (Uro-Oncology: S4), University of Cambridge, Addenbrooke's Hospital, Box 279, Hills Road, Cambridge, United Kingdom.|Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Cambridge, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Neal
authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Laboratory, Worts Causeway, Cambridge, United Kingdom.|Surgical Oncology (Uro-Oncology: S4), University of Cambridge, Addenbrooke's Hospital, Box 279, Hills Road, Cambridge, United Kingdom.|Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Cambridge, United Kingdom.|Department of Applied Health Research, University College London, 1-19 Torrington Place, London, WC1E 7HB, United Kingdom.
authors.forename: Nora
authors.initials: N
authors.lastname: Pashayan
authors.affiliation: Cambridge Institute of Public Health, University of Cambridge, Forvie Site, Robinson Way, Cambridge, CB2 0SR, United Kingdom.
authors.forename: Kay-Tee
authors.initials: KT
authors.lastname: Khaw
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.|Department of Epidemiology, School of Public Health, University of Washington, Seattle, Washington.
authors.forename: Janet L
authors.initials: JL
authors.lastname: Stanford
authors.affiliation: International Epidemiology Institute, 1455 Research Blvd., Suite 550, Rockville, 20850, Maryland.
authors.forename: William J
authors.initials: WJ
authors.lastname: Blot
authors.affiliation: Mayo Clinic, Rochester, Minnesota.
authors.forename: Stephen
authors.initials: S
authors.lastname: Thibodeau
authors.affiliation: Department of Urology, University Hospital, Ulm, Germany.|Institute of Human Genetics University Hospital, Ulm, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Maier
authors.affiliation: Brigham and Women's Hospital/Dana-Farber Cancer Institute, 45 Francis Street- ASB II-3, Boston, Massachusetts, 02115.|Washington University, St. Louis, Missouri.
authors.forename: Adam S
authors.initials: AS
authors.lastname: Kibel
authors.affiliation: International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
authors.forename: Cezary
authors.initials: C
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authors.affiliation: Division of Genetic Epidemiology, Department of Medicine, University of Utah School of Medicine, Salt Lake City, Utah.
authors.forename: Lisa
authors.initials: L
authors.lastname: Cannon-Albright
authors.affiliation: Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.|German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Brenner
authors.affiliation: Division of Cancer Prevention and Control, H. Lee Moffitt Cancer Center, Magnolia Dr., Tampa, Florida, 12902.
authors.forename: Jong
authors.initials: J
authors.lastname: Park
authors.affiliation: Molecular Medicine Center and Department of Medical Chemistry and Biochemistry, Medical University Sofia, 2 Zdrave St, Sofia, 1431, Bulgaria.
authors.forename: Radka
authors.initials: R
authors.lastname: Kaneva
authors.affiliation: Australian Prostate Cancer Research Centre-Qld, Institute of Health and Biomedical Innovation and School of Biomedical Sciences, Queensland University of Technology, Brisbane, Australia.
authors.forename: Jyotsna
authors.initials: J
authors.lastname: Batra
authors.affiliation: Department of Genetics, Portuguese Oncology Institute, Porto, Portugal.|Biomedical Sciences Institute (ICBAS), Porto University, Porto, Portugal.
authors.forename: Manuel R
authors.initials: MR
authors.lastname: Teixeira
authors.affiliation: The University of Surrey, Surrey, GU2 7XH, United Kingdom.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Micheal
authors.affiliation: The University of Surrey, Surrey, GU2 7XH, United Kingdom.
authors.forename: Hardev
authors.initials: H
authors.lastname: Pandha
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.|MRC/University of Bristol Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.
authors.forename: George Davey
authors.initials: GD
authors.lastname: Smith
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.|MRC/University of Bristol Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.|Integrative Cancer Epidemiology Programme, University of Bristol, Bristol, United Kingdom.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Lewis
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.|Integrative Cancer Epidemiology Programme, University of Bristol, Bristol, United Kingdom.|National Institute for Health Research, Bristol Nutrition Biomedical Research Unit, Bristol, United Kingdom.
authors.forename: Richard M
authors.initials: RM
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mesh_terms: D016022:Case-Control Studies; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D008055:Lipids / Q000097:blood*; D008297:Male; D057182:Mendelian Randomization Analysis; D015201:Meta-Analysis as Topic; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D011159:Population Surveillance; D011471:Prostatic Neoplasms / Q000097:blood* / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D019655:Quantitative Trait, Heritable
chemical_list: D008055:Lipids
keywords: Cholesterol; Mendelian randomization; prostate cancer; statins