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Background Numerous epidemiological studies have investigated the role of blood lipids in prostate cancer (PCa) risk though findings remain inconclusive to date. The ongoing research has mainly involved observational studies which are often prone to confounding. This study aimed to identify the relationship between genetically predicted blood lipid concentrations and PCa. Methods and Findings Data for low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides (TG), apolipoprotein A (apoA) and B (apoB), lipoprotein A (Lp(a)) and PCa were acquired from genome-wide association studies in UK Biobank and the PRACTICAL consortium, respectively. We used a two-sample Mendelian randomisation (MR) approach with both univariable and multivariable (MVMR) models and utilised a variety of robust methods and sensitivity analyses to assess the possibility of MR assumptions violation. No association was observed between genetically predicted concentrations of HDL, TG, apoA and apoB and PCa risk. Genetically predicted LDL concentration was positively associated with total PCa in the univariable analysis but adjustment for HDL, TG and Lp(a) led to a null association. Genetically predicted concentration of Lp(a) was associated with higher total PCa risk in the univariable (OR weighted median per sd = 1.091; 95% CI 1.028-1.157; P=0.004) and MVMR analyses after adjustment for the other lipid traits (OR IVW per sd = 1.068; 95% CI 1.005-1.134; P = 0.034). Genetically predicted Lp(a) was also associated with advanced (MVMR OR IVW per sd = 1.078; 95% CI 0.999-1.163; P=0.055) and early age onset PCa (MVMR OR IVW per sd = 1.150; 95% CI 1.015,1.303; P = 0.028). Although multiple estimation methods were utilized to minimize the effect of pleiotropic traits, the presence of any unmeasured pleiotropy cannot be excluded and may limit our findings. Conclusions We observed that genetically predicted Lp(a) concentrations are associated with an increased PCa risk. Future studies are required to understand the underlying biological pathways of this finding, as it may inform PCa prevention through Lp(a)-lowering strategies.

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