Assessing the role of insulin-like growth factors and binding proteins in prostate cancer using Mendelian randomization: Genetic variants as instruments for circulating levels.
![Thumbnail](/bitstream/handle/internal/230/Bonilla_et_al-2016-International_Journal_of_Cancer.pdf.jpg?sequence=9&isAllowed=y)
View/ Open
Date
2016-10-01Author
Bonilla, C
Lewis, SJ
Rowlands, M-A
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
Grönberg, H
Haiman, CA
Schleutker, J
Nordestgaard, BG
Travis, RC
Pashayan, N
Khaw, K-T
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, H
PRACTICAL consortium,
Lathrop, M
Martin, RM
Holly, JMP
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
PRACTICAL consortium
Humans
Prostatic Neoplasms
Somatomedins
Insulin-Like Growth Factor Binding Proteins
Neoplasm Staging
Case-Control Studies
Longitudinal Studies
Polymorphism, Single Nucleotide
Aged
Middle Aged
Male
Genome-Wide Association Study
Mendelian Randomization Analysis
Neoplasm Grading
United Kingdom
Research team
Oncogenetics
Language
eng
Date accepted
2016-04-07
License start date
2016-10
Citation
International journal of cancer, 2016, 139 (7), pp. 1520 - 1533
Publisher
WILEY