Blood lipids and prostate cancer: a Mendelian randomization analysis

Genetic 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.

[1]  R. Barnard,et al.  Effects of life-style modification on serum lipids. , 1991, Archives of internal medicine.

[2]  Francesco Bettella,et al.  Shared common variants in prostate cancer and blood lipids. , 2014, International journal of epidemiology.

[3]  Hynek Pikhart,et al.  HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials , 2015, The Lancet.

[4]  P. Donnelly,et al.  A Flexible and Accurate Genotype Imputation Method for the Next Generation of Genome-Wide Association Studies , 2009, PLoS genetics.

[5]  N. Clarke,et al.  The differential effects of statins on the metastatic behaviour of prostate cancer , 2012, British Journal of Cancer.

[6]  Sara M. Willems,et al.  Risk Scores of Common Genetic Variants for Lipid Levels Influence Atherosclerosis and Incident Coronary Heart Disease , 2013, Arteriosclerosis, thrombosis, and vascular biology.

[7]  Michel Bolla,et al.  [EAU guidelines on prostate cancer]. , 2009, Actas urologicas espanolas.

[8]  M Bolla,et al.  EAU guidelines on prostate cancer. , 2001, European urology.

[9]  N. Sheehan,et al.  Mendelian randomization as an instrumental variable approach to causal inference , 2007, Statistical methods in medical research.

[10]  Inês Barroso,et al.  Genetic Variants Influencing Circulating Lipid Levels and Risk of Coronary Artery Disease , 2010, Arteriosclerosis, thrombosis, and vascular biology.

[11]  A. Butterworth,et al.  Mendelian Randomization Analysis With Multiple Genetic Variants Using Summarized Data , 2013, Genetic epidemiology.

[12]  Ali Amin Al Olama,et al.  Multiple newly identified loci associated with prostate cancer susceptibility , 2008, Nature Genetics.

[13]  C. Hart,et al.  Cholesterol and the risk of grade-specific prostate cancer incidence: evidence from two large prospective cohort studies with up to 37 years' follow up , 2012, BMC Cancer.

[14]  Barnard Rj.  Effects of Life-style Modification on Serum Lipids , 1991 .

[15]  Tanya M. Teslovich,et al.  Common variants associated with plasma triglycerides and risk for coronary artery disease , 2013, Nature Genetics.

[16]  S. Ebrahim,et al.  Mendelian randomization: can genetic epidemiology help redress the failures of observational epidemiology? , 2008, Human Genetics.

[17]  T. Tammela,et al.  The Importance of LDL and Cholesterol Metabolism for Prostate Epithelial Cell Growth , 2012, PloS one.

[18]  I. Thompson,et al.  Men with Low Serum Cholesterol Have a Lower Risk of High-Grade Prostate Cancer in the Placebo Arm of the Prostate Cancer Prevention Trial , 2009, Cancer Epidemiology, Biomarkers & Prevention.

[19]  G. Davey Smith,et al.  Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression , 2015, International journal of epidemiology.

[20]  Y. Furuya,et al.  Simvastatin inhibits the proliferation of human prostate cancer PC-3 cells via down-regulation of the insulin-like growth factor 1 receptor. , 2008, Biochemical and biophysical research communications.

[21]  S. Ebrahim,et al.  Mendelian randomization: prospects, potentials, and limitations. , 2004, International journal of epidemiology.

[22]  S. Gapstur,et al.  Plasma total, LDL, and HDL cholesterol and risk of aggressive prostate cancer in the Cancer Prevention Study II Nutrition Cohort , 2012, Cancer Causes & Control.

[23]  D. Lawlor,et al.  Cohort Profile: The ‘Children of the 90s’—the index offspring of the Avon Longitudinal Study of Parents and Children , 2012, International journal of epidemiology.

[24]  M. Freeman,et al.  Do the cholesterol-lowering properties of statins affect cancer risk? , 2008, Trends in Endocrinology & Metabolism.

[25]  C. Napoli,et al.  Statin effects beyond lipid lowering--are they clinically relevant? , 2003, European heart journal.

[26]  Douglas G. Altman,et al.  Metan: Fixed- and Random-Effects Meta-Analysis , 2008 .

[27]  S. Thompson,et al.  Use of allele scores as instrumental variables for Mendelian randomization , 2013, International journal of epidemiology.

[28]  Tanya M. Teslovich,et al.  Biological, Clinical, and Population Relevance of 95 Loci for Blood Lipids , 2010, Nature.

[29]  P. Kantoff,et al.  Statin Use at the Time of Initiation of Androgen Deprivation Therapy and Time to Progression in Patients With Hormone-Sensitive Prostate Cancer. , 2015, JAMA oncology.

[30]  P. O. Bonettia,et al.  Statin effects beyond lipid lowering—are they clinically relevant? , 2003 .

[31]  E. Rimm,et al.  Statin drugs and risk of advanced prostate cancer. , 2006, Journal of the National Cancer Institute.

[32]  Alex P. Reiner,et al.  Mendelian randomization of blood lipids for coronary heart disease , 2014, European heart journal.

[33]  R. Collins,et al.  Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90 056 participants in 14 randomised trials of statins , 2005, The Lancet.

[34]  L. Pengfei,et al.  Cholesterol Levels in Blood and the Risk of Prostate Cancer: A Meta-analysis of 14 Prospective Studies , 2015, Cancer Epidemiology, Biomarkers & Prevention.

[35]  Michelle M. Hill,et al.  Statins: protectors or pretenders in prostate cancer? , 2014, Trends in Endocrinology & Metabolism.

[36]  Tanya M. Teslovich,et al.  Discovery and refinement of loci associated with lipid levels , 2013, Nature Genetics.

[37]  S. Ebrahim,et al.  'Mendelian randomization': can genetic epidemiology contribute to understanding environmental determinants of disease? , 2003, International journal of epidemiology.

[38]  W. Howard.  Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90 056 participants in 14 randomised trials of statins , 2007 .

[39]  Richard M. Martin,et al.  Statins and risk of cancer: A systematic review and metaanalysis , 2007, International journal of cancer.

[40]  A. Bhansali,et al.  Type 2 diabetes and risk of prostate cancer: a meta-analysis of observational studies , 2012, Prostate Cancer and Prostatic Diseases.

[41]  F. Schifano,et al.  Statin Use and Risk of Prostate Cancer: A Meta-Analysis of Observational Studies , 2012, PloS one.