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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, C, Lewis, SJ, Rowlands, M, Gaunt, TR, Davey Smith, G, Gunnell, D, Palmer, T, Donovan, JL, Hamdy, FC, Neal, DE , Eeles, R, Easton, D, Kote-Jarai, Z, Al Olama, AA, Benlloch, S, Muir, K, Giles, GG, Wiklund, F, Gronberg, H, Haiman, CA, Schleutker, J, Nordestgaard, BG, Travis, RC, Pashayan, N, Khaw, K, Stanford, JL, Blot, WJ, Thibodeau, S, Maier, C, Kibel, AS, Cybulski, C, Cannon-Albright, L, Brenner, H, Park, J, Kaneva, R, Batra, J, Teixeira, MR, Pandha, HS, PRACTICAL consortium, , Lathrop, M, Martin, RM and Holly, JMP (2016) Assessing the role of insulin-like growth factors and binding proteins in prostate cancer using Mendelian randomization: genetic variants as instruments for circulating levels International Journal of Cancer, 139 (7). pp. 1520-1533.

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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.

Item Type: Article
Subjects : Medical Science
Divisions : Faculty of Health and Medical Sciences > School of Biosciences and Medicine
Authors :
NameEmailORCID
Bonilla, C
Lewis, SJ
Rowlands, M
Gaunt, TR
Davey Smith, G
Gunnell, D
Palmer, T
Donovan, JL
Hamdy, FC
Neal, DE
Eeles, R
Easton, D
Kote-Jarai, Z
Al Olama, AA
Benlloch, S
Muir, K
Giles, GG
Wiklund, F
Gronberg, H
Haiman, CA
Schleutker, J
Nordestgaard, BG
Travis, RC
Pashayan, N
Khaw, K
Stanford, JL
Blot, WJ
Thibodeau, S
Maier, C
Kibel, AS
Cybulski, C
Cannon-Albright, L
Brenner, H
Park, J
Kaneva, R
Batra, J
Teixeira, MR
Pandha, HS
PRACTICAL consortium,
Lathrop, M
Martin, RM
Holly, JMP
Date : 1 October 2016
Identification Number : 10.1002/ijc.30206
Copyright Disclaimer : © 2016 The Authors International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Depositing User : Symplectic Elements
Date Deposited : 17 Aug 2016 10:42
Last Modified : 31 Oct 2017 18:35
URI: http://epubs.surrey.ac.uk/id/eprint/811728

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