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 and Lewis, Sarah J. and Rowlands, Mari-Anne and Gaunt, Tom R. and Smith, George Davey and Gunnell, David and Palmer, Tom and Donovan, Jenny L. and Hamdy, Freddie C. and Neal, David E. and Eeles, Rosalind and Easton, Doug and Kote-Jarai, Zsofia and Olama, Ali Amin Al and Benlloch, Sara and Muir, Kenneth and Giles, Graham G. and Wiklund, Fredrik and Gronberg, Henrik and Haiman, Christopher A. and Schleutker, Johanna and Nordestgaard, Børge G. and Travis, Ruth C. and Pashayan, Nora and Khaw, Kay-Tee and Stanford, Janet L. and Blot, William J. and Thibodeau, Stephen and Maier, Christiane and Kibel, Adam S. and Cybulski, Cezary and Cannon-Albright, Lisa and Brenner, Hermann and Park, Jong and Kaneva, Radka and Batra, Jyotsna and Teixeira, Manuel R. and Pandha, Hardev and Lathrop, Mark and Martin, Richard M. and Holly, Jeff M. P. and , PRACTICAL consortium (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. ISSN 0020-7136

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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. This article is protected by copyright. All rights reserved.

Item Type:
Journal Article
Journal or Publication Title:
International Journal of Cancer
Additional Information:
This is the peer reviewed version of the following article: Bonilla, C., Lewis, S. J., Rowlands, M.-A., Gaunt, T. R., Davey Smith, G., Gunnell, D., Palmer, T., Donovan, J. L., Hamdy, F. C., Neal, D. E., Eeles, R., Easton, D., Kote-Jarai, Z., Al Olama, A. A., Benlloch, S., Muir, K., Giles, G. G., Wiklund, F., Grönberg, H., Haiman, C. A., Schleutker, J., Nordestgaard, B. G., Travis, R. C., Pashayan, N., Khaw, K.-T., Stanford, J. L., Blot, W. J., Thibodeau, S., Maier, C., Kibel, A. S., Cybulski, C., Cannon-Albright, L., Brenner, H., Park, J., Kaneva, R., Batra, J., Teixeira, M. R., Pandha, H., the PRACTICAL consortium, Lathrop, M., Martin, R. M. and Holly, J. M. P. (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. Int. J. Cancer, 139: 1520–1533. doi: 10.1002/ijc.30206 which has been published in final form at http://onlinelibrary.wiley.com/doi/10.1111/jpim.12206/abstract This article may be used for non-commercial purposes in accordance With Wiley Terms and Conditions for self-archiving.
Uncontrolled Keywords:
/dk/atira/pure/subjectarea/asjc/1300/1306
Subjects:
ID Code:
79777
Deposited By:
Deposited On:
31 May 2016 15:34
Refereed?:
Yes
Published?:
Published
Last Modified:
29 Sep 2020 02:57