title: Assessing the role of insulin-like growth factors and binding proteins in prostate cancer using Mendelian randomization: Genetic variants as instruments for circulating levels.
abstract: Circulating insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) are associated with prostate cancer. Using genetic variants as instruments for IGF peptides, we investigated whether these associations are likely to be causal. We identified from the literature 56 single nucleotide polymorphisms (SNPs) in the IGF axis previously associated with biomarker levels (8 from a genome-wide association study [GWAS] and 48 in reported candidate genes). In ∼700 men without prostate cancer and two replication cohorts (N ∼ 900 and ∼9,000), we examined the properties of these SNPS as instrumental variables (IVs) for IGF-I, IGF-II, IGFBP-2 and IGFBP-3. Those confirmed as strong IVs were tested for association with prostate cancer risk, low (< 7) vs. high (≥ 7) Gleason grade, localised vs. advanced stage, and mortality, in 22,936 controls and 22,992 cases. IV analysis was used in an attempt to estimate the causal effect of circulating IGF peptides on prostate cancer. Published SNPs in the IGFBP1/IGFBP3 gene region, particularly rs11977526, were strong instruments for IGF-II and IGFBP-3, less so for IGF-I. Rs11977526 was associated with high (vs. low) Gleason grade (OR per IGF-II/IGFBP-3 level-raising allele 1.05; 95% CI: 1.00, 1.10). Using rs11977526 as an IV we estimated the causal effect of a one SD increase in IGF-II (∼265 ng/mL) on risk of high vs. low grade disease as 1.14 (95% CI: 1.00, 1.31). Because of the potential for pleiotropy of the genetic instruments, these findings can only causally implicate the IGF pathway in general, not any one specific biomarker.
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: Carolina
authors.initials: C
authors.lastname: Bonilla
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: Sarah J
authors.initials: SJ
authors.lastname: Lewis
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: Mari-Anne
authors.initials: MA
authors.lastname: Rowlands
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: Tom R
authors.initials: TR
authors.lastname: Gaunt
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
authors.initials: G
authors.lastname: Davey Smith
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Gunnell
authors.affiliation: Department of Mathematics and Statistics, Lancaster University, Lancaster, United Kingdom.
authors.forename: Tom
authors.initials: T
authors.lastname: Palmer
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: Jenny L
authors.initials: JL
authors.lastname: Donovan
authors.affiliation: Nuffield Department of Surgery, University of Oxford, Oxford, United Kingdom.
authors.forename: Freddie C
authors.initials: FC
authors.lastname: Hamdy
authors.affiliation: Nuffield Department of Surgery, University of Oxford, Oxford, United Kingdom.|Surgical Oncology (Uro-Oncology: S4), University of Cambridge, Box 279, Addenbrooke's Hospital, Hills Road, Cambridge, United Kingdom.
authors.forename: David E
authors.initials: DE
authors.lastname: Neal
authors.affiliation: The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey, SM2 5NG, United Kingdom.|Royal Marsden NHS Foundation Trust, Fulham and Sutton, London and Surrey, 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 Research Laboratory, Worts Causeway, Cambridge, United Kingdom.
authors.forename: Doug
authors.initials: D
authors.lastname: Easton
authors.affiliation: The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey, 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 Research Laboratory, Worts Causeway, Cambridge, United Kingdom.
authors.forename: Ali Amin
authors.initials: AA
authors.lastname: Al Olama
authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge, United Kingdom.
authors.forename: Sara
authors.initials: S
authors.lastname: Benlloch
authors.affiliation: University of Warwick, Coventry, 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: The Cancer Council Victoria, 615 St. Kilda Road, Melbourne, Victoria, 3004, Australia.|Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, the University of Melbourne, Victoria, 3010, Australia.
authors.forename: Graham G
authors.initials: GG
authors.lastname: Giles
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: Grönberg
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, 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 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 Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom.
authors.forename: Ruth C
authors.initials: RC
authors.lastname: Travis
authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, 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: Forvie Site, Cambridge Institute of Public Health, University of Cambridge, 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, 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, Massachussets.|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
authors.lastname: Cybulski
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), 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, 12902 Magnolia Dr, Tampa, Florida.
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, Guildford, Surrey, GU2 7XH, United Kingdom.
authors.forename: Hardev
authors.initials: H
authors.lastname: Pandha
authors.affiliation: Commissariat à L'Energie Atomique, Center National De Génotypage, Evry, France.|McGill University-Génome Québec Innovation Centre, Montreal, Canada.
authors.forename: Mark
authors.initials: M
authors.lastname: Lathrop
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.|NIHR Bristol Biomedical Research Unit in Nutrition, Bristol, United Kingdom.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Martin
authors.affiliation: NIHR Bristol Biomedical Research Unit in Nutrition, Bristol, United Kingdom.|IGFs and Metabolic Endocrinology Group, School of Clinical Sciences North Bristol, University of Bristol, Bristol, United Kingdom.
authors.forename: Jeff M P
authors.initials: JM
authors.lastname: Holly
mesh_terms: D000368:Aged; D016022:Case-Control Studies; D055106:Genome-Wide Association Study; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D008137:Longitudinal Studies; D008297:Male; D057182:Mendelian Randomization Analysis / Q000379:methods; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000097:blood* / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D013002:Somatomedins / Q000235:genetics* / Q000378:metabolism*; D006113:United Kingdom / Q000453:epidemiology
chemical_list: D018969:Insulin-Like Growth Factor Binding Proteins; D013002:Somatomedins
keywords: ALSPAC; IGFBP3; Mendelian randomization; PRACTICAL; ProtecT; UKHLS; insulin-like growth factor-binding proteins; insulin-like growth factors; prostate cancer; single nucleotide polymorphisms