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
AU - Rowlands, Mari-Anne
AU - Gaunt, Tom
AU - Davey Smith, George
AU - Gunnell, David
AU - Palmer, Tom
AU - Donovan, Jenny
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 - Gronberg, 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
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 - The PRACTICAL, Consortium
AU - Lathrop, Mark
AU - Martin, Richard
AU - Holly, Jeffrey
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 - Insulin-like growth factors
KW - insulin-like growth factor-binding proteins;
KW - prostate cancer
KW - Mendelian randomization
KW - single nucleotide polymorphisms
KW - IGFBP3
KW - ProtecT
KW - PRACTICAL
KW - ALSPAC
KW - UKHLS
UR - http://www.scopus.com/inward/record.url?scp=84978264652&partnerID=8YFLogxK
U2 - 10.1002/ijc.30206
DO - 10.1002/ijc.30206
M3 - Article (Academic Journal)
C2 - 27225428
SN - 0020-7136
VL - 139
SP - 1520
EP - 1533
JO - International Journal of Cancer
JF - International Journal of Cancer
IS - 7
ER -