@article{939eedae392541438cbed651863d79f7,
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.",
keywords = "ALSPAC, IGFBP3, Mendelian randomization, PRACTICAL, ProtecT, UKHLS, insulin-like growth factor-binding proteins, insulin-like growth factors, prostate cancer, single nucleotide polymorphisms",
author = "{The PRACTICAL Consortium} and Carolina Bonilla and Lewis, {Sarah J.} and Rowlands, {Mari Anne} and Gaunt, {Tom R.} and {Davey Smith}, George and David Gunnell and Tom Palmer and Donovan, {Jenny L.} and Hamdy, {Freddie C.} and Neal, {David E.} and Rosalind Eeles and Doug Easton and Zsofia Kote-Jarai and {Al Olama}, {Ali Amin} and Sara Benlloch and Kenneth Muir and Giles, {Graham G.} and Fredrik Wiklund and Henrik Gr{\"o}nberg and Haiman, {Christopher A.} and Johanna Schleutker and Nordestgaard, {B{\o}rge G.} and Travis, {Ruth C.} and Nora Pashayan and Khaw, {Kay Tee} and Stanford, {Janet L.} and Blot, {William J.} and Stephen Thibodeau and Christiane Maier and Kibel, {Adam S.} and Cezary Cybulski and Lisa Cannon-Albright and Hermann Brenner and Jong Park and Radka Kaneva and Jyotsna Batra and Teixeira, {Manuel R.} and Hardev Pandha and Mark Lathrop and Martin, {Richard M.} and Holly, {Jeff M.P.}",
note = "Funding Information: The authors thank the tremendous contribution of all members of the ProtecT study research group, and especially the following who were involved in this research (Prasad Bollina, Sue Bonnington, Lynn Bradshaw, James Catto, Debbie Cooper, Michael Davis, Liz Down, Andrew Doble, Alan Doherty, Garrett Durkan, Emma Elliott, David Gillatt, Pippa Herbert, Peter Holding, Joanne Howson, Mandy Jones, Roger Kockelbergh, Howard Kynaston, Teresa Lennon, Norma Lyons, Hing Leung, Malcolm Mason, Hilary Moody, Philip Powell, Alan Paul, Stephen Prescott, Derek Rosario, Patricia O'Sullivan, Pauline Thompson, Sarah Tidball). They thank Gemma Marsden and Luke Marsden, who processed the blood samples at the biorepository, and Rajeev Kumar, data manager. They also thank the Center National de G?notypage, Evry, France for genotyping the ProtecT samples. The authors are grateful for the provision of the additional epidemiological data by the NHS R&D Directorate supported Prodigal study and the ProMPT (Prostate Mechanisms of Progression and Treatment) collaboration which is supported by the National Cancer Research Institute (NCRI) formed by the Department of Health, the Medical Research Council and Cancer Research UK (G0500966/75466). The authors are extremely grateful to all the families who took part in the ALSPAC study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. The UK Medical Research Council and the Wellcome Trust (Grant ref: 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. GWAS data was generated by Sample Logistics and Genotyping Facilities at the Wellcome Trust Sanger Institute and LabCorp (Laboratory Corportation of America) using support from 23andMe. The Collaborative Oncological Gene-environment Study (COGS), within which the PRACTICAL consortium was assembled, would not have been possible without the contributions of the following: Per Hall (COGS), Douglas F. Easton, Paul Pharoah, Kyriaki Michailidou, Manjeet K. Bolla, Qin Wang (BCAC), Andrew Berchuck (OCAC), Rosalind A. Eeles, Douglas F. Easton, Ali Amin Al Olama, Zsofia Kote-Jarai, Sara Benlloch (PRACTICAL), Georgia Chenevix-Trench, Antonis Antoniou, Lesley McGuffog, Fergus Couch, Ken Offit (CIMBA), Joe Dennis, Alison M. Dunning, Andrew Lee, Ed Dicks, Craig Luccarini and the staff of the Centre for Genetic Epidemiology Laboratory, Javier Benitez, Anna Gonzalez-Neira and the staff of the CNIO genotyping unit, Jacques Simard and Daniel C. Tessier, Francois Bacot, Daniel Vincent, Sylvie LaBoissi?re, Frederic Robidoux and the staff of the McGill University and G?nome Qu?bec Innovation Centre, Stig E. Bojesen, Sune F. Nielsen, Maren Weischer, B?rge G. Nordestgaard and the staff of the Copenhagen DNA laboratory, and Julie M. Cunningham, Sharon A. Windebank, Christopher A. Hilker, Jeffrey Meyer and the staff of the Mayo Clinic Genotyping Core Facility. The UK Household Longitudinal Study is led by the Institute for Social and Economic Research at the University of Essex and funded by the Economic and Social Research Council. The data were collected by NatCen. The authors acknowledge support from the NIHR to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Publisher Copyright: {\textcopyright} 2016 UICC",
year = "2016",
month = oct,
day = "1",
doi = "10.1002/ijc.30206",
language = "English (US)",
volume = "139",
pages = "1520--1533",
journal = "International Journal of Cancer",
issn = "0020-7136",
publisher = "Wiley-Liss Inc.",
number = "7",
}