Bonilla, C;
Lewis, SJ;
Rowlands, MA;
Gaunt, TR;
Davey Smith, G;
Gunnell, D;
Palmer, T;
... Holly, JMP; + view all
(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.
10.1002/ijc.30206.
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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.
| Type: | Article |
|---|---|
| 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 |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1002/ijc.30206 |
| Publisher version: | http://dx.doi.org/10.1002/ijc.30206 |
| Language: | English |
| Additional information: | 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. Further details about CC BY licenses are available at http://creativecommons.org/ licenses/by/4.0. |
| Keywords: | ALSPAC, IGFBP3, Mendelian randomization, PRACTICAL, ProtecT, UKHLS, insulin-like growth factor-binding proteins, insulin-like growth factors, prostate cancer, single nucleotide polymorphisms |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Epidemiology and Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Epidemiology and Health > Applied Health Research |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1478270 |
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