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Assessing the role of insulin‐like growth factors and binding proteins in prostate cancer using Mendelian randomization: Genetic variants as instruments for circulating levels
Author(s) -
Bonilla Carolina,
Lewis Sarah J.,
Rowlands MariAnne,
Gaunt Tom R.,
Davey Smith George,
Gunnell David,
Palmer Tom,
Donovan Jenny L.,
Hamdy Freddie C.,
Neal David E.,
Eeles Rosalind,
Easton Doug,
KoteJarai Zsofia,
Al Olama Ali Amin,
Benlloch Sara,
Muir Kenneth,
Giles Graham G.,
Wiklund Fredrik,
Grönberg Henrik,
Haiman Christopher A.,
Schleutker Johanna,
Nordestgaard Børge G.,
Travis Ruth C.,
Pashayan Nora,
Khaw KayTee,
Stanford Janet L.,
Blot William J.,
Thibodeau Stephen,
Maier Christiane,
Kibel Adam S,
Cybulski Cezary,
CanAlbright Lisa,
Brenner Hermann,
Park Jong,
Kaneva Radka,
Batra Jyotsna,
Teixeira Manuel R.,
Pandha Hardev,
Lathrop Mark,
Martin Richard M.,
Holly Jeff M. P.
Publication year - 2016
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.30206
Subject(s) - mendelian randomization , igfbp3 , prostate cancer , single nucleotide polymorphism , medicine , prostate , oncology , genome wide association study , allele , pleiotropy , biology , insulin like growth factor , cancer , endocrinology , genetics , genotype , gene , growth factor , genetic variants , phenotype , receptor
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.