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

Research output: Contribution to journalArticle

5 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)1520-1533
Number of pages14
JournalInternational Journal of Cancer
Volume139
Issue number7
DOIs
StatePublished - Oct 1 2016

Fingerprint

Insulin-Like Growth Factor Binding Proteins
Insulin-Like Growth Factor II
Somatomedins
Random Allocation
Insulin-Like Growth Factor Binding Protein 3
Prostatic Neoplasms
Insulin-Like Growth Factor I
Single Nucleotide Polymorphism
Genetic Pleiotropy
Biomarkers
Insulin-Like Growth Factor Binding Protein 2
Peptides
Genome-Wide Association Study
Genes
Alleles
Mortality

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

@article{939eedae392541438cbed651863d79f7,
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",
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.",
keywords = "ALSPAC, IGFBP3, insulin-like growth factor-binding proteins, insulin-like growth factors, Mendelian randomization, PRACTICAL, prostate cancer, ProtecT, single nucleotide polymorphisms, UKHLS",
author = "{The PRACTICAL Consortium} and Carolina Bonilla and Lewis, {Sarah J.} and Rowlands, {Mari Anne} and Gaunt, {Tom R.} and {Davey Smith}, George and David Gunnell and Tom Palmer and Donovan, {Jenny L.} and Hamdy, {Freddie C.} and Neal, {David E.} and Rosalind Eeles and Doug Easton and Zsofia Kote-Jarai and {Al Olama}, {Ali Amin} and Sara Benlloch and Kenneth Muir and Giles, {Graham G.} and Fredrik Wiklund and Henrik Gr{\"o}nberg and Haiman, {Christopher A.} and Johanna Schleutker and Nordestgaard, {B{\o}rge G.} and Travis, {Ruth C.} and Nora Pashayan and Khaw, {Kay Tee} and Stanford, {Janet L.} and Blot, {William J.} and Thibodeau, {Stephen N} and Christiane Maier and Kibel, {Adam S.} and Cezary Cybulski and Lisa Cannon-Albright and Hermann Brenner and Jong Park and Radka Kaneva and Jyotsna Batra and Teixeira, {Manuel R.} and Hardev Pandha and Mark Lathrop and Martin, {Richard M.} and Holly, {Jeff M P}",
year = "2016",
month = "10",
day = "1",
doi = "10.1002/ijc.30206",
language = "English (US)",
volume = "139",
pages = "1520--1533",
journal = "International Journal of Cancer",
issn = "0020-7136",
publisher = "Wiley-Liss Inc.",
number = "7",

}

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 -