Assessing the role of insulin‐like growth factors and binding proteins in prostate cancer using Mendelian randomization: Genetic variants as instruments for circulating levels - Institut de Biologie François JACOB Access content directly
Journal Articles International Journal of Cancer Year : 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

Tom Palmer
  • Function : Author
Freddie C Hamdy
  • Function : Author
Zsofia Kote‐jarai
  • Function : Author
Ali Amin Al Olama
  • Function : Author
Kay‐tee Khaw
  • Function : Author
Janet L Stanford
  • Function : Author
William J Blot
  • Function : Author
Stephen Thibodeau
  • Function : Author
Adam S Kibel
  • Function : Author
Cezary Cybulski
  • Function : Author
Lisa Cannon‐albright
  • Function : Author
Jong Park
  • Function : Author
Radka Kaneva
  • Function : Author
Jyotsna Batra
  • Function : Author
Manuel R Teixeira
  • Function : Author
Hardev Pandha
  • Function : Author

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.
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cea-04551327 , version 1 (18-04-2024)

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Carolina Bonilla, Sarah J Lewis, Mari‐anne Rowlands, Tom R Gaunt, George Davey Smith, et al.. 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, 2016, 139 (7), pp.1520 - 1533. ⟨10.1002/ijc.30206⟩. ⟨cea-04551327⟩
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