Assessing the role of insulin-like growth factors and binding proteins in prostate cancer using Mendelian randomization: Genetic variants as instruments for circulating levels
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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. / Bonilla, Carolina; Lewis, Sarah J; Rowlands, Mari-Anne; Gaunt, Tom R; Davey-Smith, George; Gunnell, David; Palmer, Tom M; Donovan, Jenny L; Hamdy, Freddie C; Neal, David E; Eeles, Rosalind; Easton, Doug; Kote-Jarai, Zsofia; Al Olama, Ali Amin; Benlloch, Sara; Muir, Kenneth; Giles, Graham; Wiklund, Fredrik; Grönberg, Henrik; Haiman, Christopher A; Schleutker, Johanna; Nordestgaard, Børge G; Travis, Ruth C; Pashayan, Nora; Khaw, Kay-Tee; Stanford, Janet L; Blot, William J; Thibodeau, Stephen N; Maier, Christiane; Kibel, Adam S; Cybulski, Cezary; Cannon-Albright, Lisa; Brenner, Hermann; Park, Jong-Seon; Kaneva, Radka; Batra, Jyotsna; Teixeira, Manuel R; Pandha, Hardev; PRACTICAL consortium; Lathrop, Mark; Martin, Richard M; Holly, Jeff M P.
In: International Journal of Cancer, Vol. 139, No. 7, 01.10.2016, p. 1520-1533.Research output: Contribution to journal › Journal article › Research › peer-review
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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
VL - 139
SP - 1520
EP - 1533
JO - International Journal of Cancer
JF - International Journal of Cancer
SN - 0020-7136
IS - 7
ER -
ID: 177496127