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

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 p...

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Main Authors:	Bonilla, Carolina, Lewis, Sarah J., Rowlands, Mari‐Anne, Gaunt, Tom R., Davey Smith, George, Gunnell, David, Palmer, Tom, Donovan, Jenny L., Hamdy, Freddie C., Neal, David E., Eeles, Rosalind, Easton, Doug, Kote‐Jarai, Zsofia, Al Olama, Ali Amin, Benlloch, Sara, Muir, Kenneth, Giles, Graham G., Wiklund, Fredrik, Grönberg, Henrik, Haiman, Christopher A., Schleutker, Johanna, Nordestgaard, Børge G., Travis, Ruth C., Pashayan, Nora, Khaw, Kay‐Tee, Stanford, Janet L., Blot, William J., Thibodeau, Stephen, Maier, Christiane, Kibel, Adam S, Cybulski, Cezary, Cannon‐Albright, Lisa, Brenner, Hermann, Park, Jong, Kaneva, Radka, Batra, Jyotsna, Teixeira, Manuel R., Pandha, Hardev, Lathrop, Mark, Martin, Richard M., Holly, Jeff M. P.
Format:	Online
Language:	English
Published:	John Wiley and Sons Inc. 2016
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4957617/

id	pubmed-4957617
recordtype	oai_dc
spelling	pubmed-49576172016-08-05 Assessing the role of insulin‐like growth factors and binding proteins in prostate cancer using Mendelian randomization: Genetic variants as instruments for circulating levels Bonilla, Carolina Lewis, Sarah J. Rowlands, Mari‐Anne Gaunt, Tom R. Davey Smith, George Gunnell, David Palmer, Tom Donovan, Jenny L. Hamdy, Freddie C. Neal, David E. Eeles, Rosalind Easton, Doug Kote‐Jarai, Zsofia Al Olama, Ali Amin Benlloch, Sara Muir, Kenneth Giles, Graham G. Wiklund, Fredrik Grönberg, Henrik Haiman, Christopher A. Schleutker, Johanna Nordestgaard, Børge G. Travis, Ruth C. Pashayan, Nora Khaw, Kay‐Tee Stanford, Janet L. Blot, William J. Thibodeau, Stephen Maier, Christiane Kibel, Adam S Cybulski, Cezary Cannon‐Albright, Lisa Brenner, Hermann Park, Jong Kaneva, Radka Batra, Jyotsna Teixeira, Manuel R. Pandha, Hardev Lathrop, Mark Martin, Richard M. Holly, Jeff M. P. Cancer Epidemiology 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. John Wiley and Sons Inc. 2016-06-23 2016-10-01 /pmc/articles/PMC4957617/ /pubmed/27225428 http://dx.doi.org/10.1002/ijc.30206 Text en © 2016 UICC This is an open access article under the terms of the Creative Commons Attribution (http://creativecommons.org/licenses/by/3.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Bonilla, Carolina Lewis, Sarah J. Rowlands, Mari‐Anne Gaunt, Tom R. Davey Smith, George Gunnell, David Palmer, Tom Donovan, Jenny L. Hamdy, Freddie C. Neal, David E. Eeles, Rosalind Easton, Doug Kote‐Jarai, Zsofia Al Olama, Ali Amin Benlloch, Sara Muir, Kenneth Giles, Graham G. Wiklund, Fredrik Grönberg, Henrik Haiman, Christopher A. Schleutker, Johanna Nordestgaard, Børge G. Travis, Ruth C. Pashayan, Nora Khaw, Kay‐Tee Stanford, Janet L. Blot, William J. Thibodeau, Stephen Maier, Christiane Kibel, Adam S Cybulski, Cezary Cannon‐Albright, Lisa Brenner, Hermann Park, Jong Kaneva, Radka Batra, Jyotsna Teixeira, Manuel R. Pandha, Hardev Lathrop, Mark Martin, Richard M. Holly, Jeff M. P.
spellingShingle	Bonilla, Carolina Lewis, Sarah J. Rowlands, Mari‐Anne Gaunt, Tom R. Davey Smith, George Gunnell, David Palmer, Tom Donovan, Jenny L. Hamdy, Freddie C. Neal, David E. Eeles, Rosalind Easton, Doug Kote‐Jarai, Zsofia Al Olama, Ali Amin Benlloch, Sara Muir, Kenneth Giles, Graham G. Wiklund, Fredrik Grönberg, Henrik Haiman, Christopher A. Schleutker, Johanna Nordestgaard, Børge G. Travis, Ruth C. Pashayan, Nora Khaw, Kay‐Tee Stanford, Janet L. Blot, William J. Thibodeau, Stephen Maier, Christiane Kibel, Adam S Cybulski, Cezary Cannon‐Albright, Lisa Brenner, Hermann Park, Jong Kaneva, Radka Batra, Jyotsna Teixeira, Manuel R. Pandha, Hardev Lathrop, Mark Martin, Richard M. Holly, Jeff M. P. Assessing the role of insulin‐like growth factors and binding proteins in prostate cancer using Mendelian randomization: Genetic variants as instruments for circulating levels
author_facet	Bonilla, Carolina Lewis, Sarah J. Rowlands, Mari‐Anne Gaunt, Tom R. Davey Smith, George Gunnell, David Palmer, Tom Donovan, Jenny L. Hamdy, Freddie C. Neal, David E. Eeles, Rosalind Easton, Doug Kote‐Jarai, Zsofia Al Olama, Ali Amin Benlloch, Sara Muir, Kenneth Giles, Graham G. Wiklund, Fredrik Grönberg, Henrik Haiman, Christopher A. Schleutker, Johanna Nordestgaard, Børge G. Travis, Ruth C. Pashayan, Nora Khaw, Kay‐Tee Stanford, Janet L. Blot, William J. Thibodeau, Stephen Maier, Christiane Kibel, Adam S Cybulski, Cezary Cannon‐Albright, Lisa Brenner, Hermann Park, Jong Kaneva, Radka Batra, Jyotsna Teixeira, Manuel R. Pandha, Hardev Lathrop, Mark Martin, Richard M. Holly, Jeff M. P.
author_sort	Bonilla, Carolina
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
title_short	Assessing the role of insulin‐like growth factors and binding proteins in prostate cancer using Mendelian randomization: Genetic variants as instruments for circulating levels
title_full	Assessing the role of insulin‐like growth factors and binding proteins in prostate cancer using Mendelian randomization: Genetic variants as instruments for circulating levels
title_fullStr	Assessing the role of insulin‐like growth factors and binding proteins in prostate cancer using Mendelian randomization: Genetic variants as instruments for circulating levels
title_full_unstemmed	Assessing the role of insulin‐like growth factors and binding proteins in prostate cancer using Mendelian randomization: Genetic variants as instruments for circulating levels
title_sort	assessing the role of insulin‐like growth factors and binding proteins in prostate cancer using mendelian randomization: genetic variants as instruments for circulating levels
description	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.
publisher	John Wiley and Sons Inc.
publishDate	2016
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4957617/
_version_	1613613716685717504

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

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