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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1520-1533 |
| Number of pages | 14 |
| Journal | International Journal of Cancer |
| Volume | 139 |
| Issue number | 7 |
| DOIs | |
| State | Published - Oct 1 2016 |
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Keywords
- ALSPAC
- IGFBP3
- insulin-like growth factor-binding proteins
- insulin-like growth factors
- Mendelian randomization
- PRACTICAL
- prostate cancer
- ProtecT
- single nucleotide polymorphisms
- UKHLS
ASJC Scopus subject areas
- Medicine(all)
- Oncology
- Cancer Research
Cite this
Assessing the role of insulin-like growth factors and binding proteins in prostate cancer using Mendelian randomization : Genetic variants as instruments for circulating levels. / The PRACTICAL Consortium.
In: International Journal of Cancer, Vol. 139, No. 7, 01.10.2016, p. 1520-1533.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Assessing the role of insulin-like growth factors and binding proteins in prostate cancer using Mendelian randomization
T2 - Genetic variants as instruments for circulating levels
AU - The PRACTICAL Consortium
AU - Bonilla, Carolina
AU - Lewis, Sarah J.
AU - Rowlands, Mari Anne
AU - Gaunt, Tom R.
AU - Davey Smith, George
AU - Gunnell, David
AU - Palmer, Tom
AU - Donovan, Jenny L.
AU - Hamdy, Freddie C.
AU - Neal, David E.
AU - Eeles, Rosalind
AU - Easton, Doug
AU - Kote-Jarai, Zsofia
AU - Al Olama, Ali Amin
AU - Benlloch, Sara
AU - Muir, Kenneth
AU - Giles, Graham G.
AU - Wiklund, Fredrik
AU - Grönberg, Henrik
AU - Haiman, Christopher A.
AU - Schleutker, Johanna
AU - Nordestgaard, Børge G.
AU - Travis, Ruth C.
AU - Pashayan, Nora
AU - Khaw, Kay Tee
AU - Stanford, Janet L.
AU - Blot, William J.
AU - Thibodeau, Stephen N
AU - Maier, Christiane
AU - Kibel, Adam S.
AU - Cybulski, Cezary
AU - Cannon-Albright, Lisa
AU - Brenner, Hermann
AU - Park, Jong
AU - Kaneva, Radka
AU - Batra, Jyotsna
AU - Teixeira, Manuel R.
AU - Pandha, Hardev
AU - Lathrop, Mark
AU - Martin, Richard M.
AU - Holly, Jeff M P
PY - 2016/10/1
Y1 - 2016/10/1
N2 - 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.
AB - 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.
KW - ALSPAC
KW - IGFBP3
KW - insulin-like growth factor-binding proteins
KW - insulin-like growth factors
KW - Mendelian randomization
KW - PRACTICAL
KW - prostate cancer
KW - ProtecT
KW - single nucleotide polymorphisms
KW - UKHLS
UR - http://www.scopus.com/inward/record.url?scp=84978264652&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84978264652&partnerID=8YFLogxK
U2 - 10.1002/ijc.30206
DO - 10.1002/ijc.30206
M3 - Article
C2 - 27225428
AN - SCOPUS:84978264652
VL - 139
SP - 1520
EP - 1533
JO - International Journal of Cancer
JF - International Journal of Cancer
SN - 0020-7136
IS - 7
ER -