Assessing the role of insulin-like growth factors and binding proteins in prostate cancer using Mendelian randomization: Genetic variants as instruments for circulating levels

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 - Bonilla, Carolina

AU - Lewis, Sarah J

AU - Rowlands, Mari-Anne

AU - Gaunt, Tom R

AU - Davey-Smith, George

AU - Gunnell, David

AU - Palmer, Tom M

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

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-Seon

AU - Kaneva, Radka

AU - Batra, Jyotsna

AU - Teixeira, Manuel R

AU - Pandha, Hardev

AU - PRACTICAL consortium

AU - Lathrop, Mark

AU - Martin, Richard M

AU - Holly, Jeff M P

N1 - © 2016 UICC.

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 - Journal Article

U2 - 10.1002/ijc.30206

DO - 10.1002/ijc.30206

M3 - Journal article

C2 - 27225428

SN - 0020-7136

VL - 139

SP - 1520

EP - 1533

JO - Radiation Oncology Investigations

JF - Radiation Oncology Investigations

IS - 7

ER -