Citations 2
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. , Smith, George Davey , Palmer, Tom , Donovan, Jenny , Hamdy, Freddie C. , Neal, David E. , Eeles, Rosalind A. , Easton, Doug , Olama, Ali Amin Al , Benlloch, Sara, Muir, Kenneth , Giles, Graham G. , Grönberg, Henrik , Haiman, Christopher A. , Schleutker, Johanna , Nordestgaard, Børge G. , Travis, Ruth C. , Pashayan, Nora , Stanford, Janet L. , Blot, William J. , Thibodeau, Stephen N. , Maier, Christiane, Kibel, Adam S. , Cannon‐Albright, Lisa , Brenner, Hermann , Kaneva, Radka , Batra, Jyotsna , Teixeira, Manuel R. , Pandha, Hardev , Lathrop, Mark , Martin, Richard M. , Holly, Jeff M.P. , Thibodeau, Stephen, Gunnell, David , Kote‐Jarai, Zsofia , Wiklund, Fredrik E. , Khaw, Kay‐Tee , Cybulski, Cezary , Park, Jong Moon , Giles, Graham G , Teixeira, Manuel R , Eeles, Rosalind A , Donovan, Jenny L , Muir, Kenneth , Schleutker, Johanna , Travis, Ruth C , Pashayan, Nora , Cannon-Albright, Lisa A , Brenner, Hermann , Martin, Richard M , Batra, Jyotsna , Davey Smith, George
International Journal of Cancer | May 26, 2016 | Volume: 139 | Issue: 7 | Pages: 1520-1533
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.
Blood lipids and prostate cancer: a Mendelian randomization analysis
Bonilla, Carolina , Holly, Jeff M.P. , Perks, Claire M. , Davies, Neil M , Haycock, Philip , Richards, J. Brent , Eeles, Rosalind A. , Easton, Doug , Olama, Ali Amin Al , Benlloch, Sara, MacInnis, Robert J. , Grönberg, Henrik , Haiman, Christopher A. , Schleutker, Johanna , Nordestgaard, Børge G. , Travis, Ruth C. , Neal, David E. , Pashayan, Nora , Stanford, Janet L. , Blot, William J. , Thibodeau, Stephen N. , Maier, Christiane, Kibel, Adam S. , Brenner, Hermann , Park, Jong, Kaneva, Radka , Batra, Jyotsna , Teixeira, Manuel R. , Micheal, Agnieszka, Pandha, Hardev , Smith, George Davey , Lewis, Sarah J. , Martin, Richard M. , Thibodeau, Stephen, Bull, Caroline J. , Yu, Oriana Hoi Yun , Kote‐Jarai, Zsofia , Muir, Kenneth , Giles, Graham G. , Wiklund, Fredrik E. , Khaw, Kay‐Tee , Cybulski, Cezary , Cannon‐Albright, Lisa , Teixeira, Manuel R , Eeles, Rosalind A , Schleutker, Johanna , Travis, Ruth C , Pashayan, Nora , Maclnnis, Robert , Haycock, Philip , Brenner, Hermann , Martin, Richard M , Batra, Jyotsna , Davey Smith, George
Cancer Medicine | March 19, 2016 | Volume: 5 | Issue: 6 | Pages: 1125-1136
AbstractGenetic risk scores were used as unconfounded instruments for specific lipid traits (Mendelian randomization) to assess whether circulating lipids causally influence prostate cancer risk. Data from 22,249 prostate cancer cases and 22,133 controls from 22 studies within the international PRACTICAL consortium were analyzed. Allele scores based on single nucleotide polymorphisms (SNPs) previously reported to be uniquely associated with each of low‐density lipoprotein (LDL), high‐density lipoprotein (HDL), and triglyceride (TG) levels, were first validated in an independent dataset, and then entered into logistic regression models to estimate the presence (and direction) of any causal effect of each lipid trait on prostate cancer risk. There was weak evidence for an association between the LDL genetic score and cancer grade: the odds ratio (OR) per genetically instrumented standard deviation (SD) in LDL, comparing high‐ (≥7 Gleason score) versus low‐grade (<7 Gleason score) cancers was 1.50 (95% CI: 0.92, 2.46; P = 0.11). A genetically instrumented SD increase in TGs was weakly associated with stage: the OR for advanced versus localized cancer per unit increase in genetic risk score was 1.68 (95% CI: 0.95, 3.00; P = 0.08). The rs12916‐T variant in 3‐hydroxy‐3‐methylglutaryl‐CoA reductase (HMGCR) was inversely associated with prostate cancer (OR: 0.97; 95% CI: 0.94, 1.00; P = 0.03). In conclusion, circulating lipids, instrumented by our genetic risk scores, did not appear to alter prostate cancer risk. We found weak evidence that higher LDL and TG levels increase aggressive prostate cancer risk, and that a variant in HMGCR (that mimics the LDL lowering effect of statin drugs) reduces risk. However, inferences are limited by sample size and evidence of pleiotropy.