Assessing the role of insulin‐like growth factors and binding proteins in prostate cancer using Mendelian randomization: Genetic variants as instruments for circulating levels期刊界 All Journals 搜尽天下杂志传播学术成果专业期刊搜索期刊信息化学术搜索

Assessing the role of insulin‐like growth factors and binding proteins in prostate cancer using Mendelian randomization: Genetic variants as instruments for circulating levels

Authors:	Carolina Bonilla Sarah J. Lewis Mari‐Anne Rowlands Tom R. Gaunt George Davey Smith David Gunnell Tom Palmer Jenny L. Donovan Freddie C. Hamdy David E. Neal Rosalind Eeles Doug Easton Zsofia Kote‐Jarai Ali Amin Al Olama Sara Benlloch Kenneth Muir Graham G. Giles Fredrik Wiklund Henrik Grönberg Christopher A. Haiman Johanna Schleutker Børge G. Nordestgaard Ruth C. Travis Nora Pashayan Kay‐Tee Khaw Janet L. Stanford William J. Blot Stephen Thibodeau Christiane Maier Adam S Kibel Cezary Cybulski Lisa Cannon‐Albright Hermann Brenner Jong Park Radka Kaneva Jyotsna Batra Manuel R. Teixeira Hardev Pandha the PRACTICAL consortium Mark Lathrop Jeff M. P. Holly

Affiliation:	1. School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom;2. MRC/University of Bristol Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom;3. Department of Mathematics and Statistics, Lancaster University, Lancaster, United Kingdom;4. Nuffield Department of Surgery, University of Oxford, Oxford, United Kingdom;5. Surgical Oncology (Uro‐Oncology: S4), University of Cambridge, Cambridge, United Kingdom;6. The Institute of Cancer Research, Sutton, Surrey, United Kingdom;7. Royal Marsden NHS Foundation Trust, Fulham and Sutton, London and Surrey, United Kingdom;8. Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge, United Kingdom;9. University of Warwick, Coventry, United Kingdom;10. Institute of Population Health, University of Manchester, Manchester, United Kingdom;11. The Cancer Council Victoria, Melbourne, Victoria, Australia;12. Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, the University of Melbourne, Victoria, Australia;13. Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden;14. Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California;15. Department of Medical Biochemistry and Genetics, University of Turku, Turku, Finland;16. Institute of Biomedical Technology/BioMediTech, University of Tampere and FimLab Laboratories, Tampere, Finland;17. Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev, DK, Denmark;18. Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom;19. Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, United Kingdom;20. Department of Applied Health Research, University College London, London, United Kingdom;21. Forvie Site, Cambridge Institute of Public Health, University of Cambridge, Cambridge, United Kingdom;22. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington;23. Department of Epidemiology, School of Public Health, University of Washington, Seattle, Washington;24. International Epidemiology Institute, Rockville, Maryland;25. Mayo Clinic, Rochester, Minnesota;26. Department of Urology, University Hospital Ulm, Germany;27. Institute of Human Genetics, University Hospital Ulm, Germany;28. Brigham and Women's Hospital/Dana‐Farber Cancer Institute, Boston, Massachussets;29. Washington University, St Louis, Missouri;30. International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland;31. Division of Genetic Epidemiology, Department of Medicine, University of Utah School of Medicine, Salt Lake City, Utah;32. Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany;33. Division of Preventive Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany;34. German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany;35. Division of Cancer Prevention and Control, H. Lee Moffitt Cancer Center, Tampa, Florida;36. Molecular Medicine Center and Department of Medical Chemistry and Biochemistry, Medical University ‐ Sofia, Sofia, Bulgaria;37. Australian Prostate Cancer Research Centre‐Qld, Institute of Health and Biomedical Innovation and School of Biomedical Sciences, Queensland University of Technology, Brisbane, Australia;38. Department of Genetics, Portuguese Oncology Institute, Porto, Portugal;39. Biomedical Sciences Institute (ICBAS), Porto University, Porto, Portugal;40. The University of Surrey, Guildford, Surrey, United Kingdom;41. Commissariat à L'Energie Atomique, Center National De Génotypage, Evry, France;42. McGill University‐Génome Québec Innovation Centre, Montreal, Canada

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:	insulin‐like growth factors insulin‐like growth factor‐binding proteins prostate cancer Mendelian randomization single nucleotide polymorphisms IGFBP3 ProtecT PRACTICAL ALSPAC UKHLS

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