Association between genetically proxied PCSK9 inhibition and prostate cancer risk: A Mendelian randomisation study

Abstract

Background Prostate cancer (PrCa) is the second most prevalent malignancy in men worldwide. Observational studies have linked the use of low-density lipoprotein cholesterol (LDL-c) lowering therapies with reduced risk of PrCa, which may potentially be attributable to confounding factors. In this study, we performed a drug target Mendelian randomisation (MR) analysis to evaluate the association of genetically proxied inhibition of LDL-c-lowering drug targets on risk of PrCa. Methods and findings Single-nucleotide polymorphisms (SNPs) associated with LDL-c (P Conclusions Our study supports a strong association between genetically proxied inhibition of PCSK9 and a lower risk of total and early-onset PrCa, potentially through an alternative mechanism other than the on-target effect on LDL-c. Further evidence from clinical studies is needed to confirm this finding as well as the putative mediatory role of Lp(a). Si Fang and colleagues use drug target Mendelian randomization to examine the association between lipid lowering drug targets and the risk of prostate cancer. Author summary Why was this study done? Prostate cancer is the second most diagnosed malignancy in men globally. Previous studies have provided conflicting evidence regarding a relationship between elevated low-density lipoprotein (LDL) cholesterol and prostate cancer risk. The aim of this study was to examine the association between genetically proxied inhibition of lipid-lowering drug targets (i.e., PCSK9, NPC1L1, HMGCR) and prostate cancer using evidence from multiple datasets and analytical methods. What did the researchers do and find? Using genetic variants associated with LDL cholesterol, liver-derived gene expression, and plasma protein levels, the researchers applied drug target Mendelian randomisation (MR) and colocalization to examine the association between lipid-lowering drug targets and the risk of overall, early-onset, and advanced prostate cancer. Additional MR analyses were conducted to explore putative mediators of drug effects. This study provided evidence of an association between genetically proxied PCSK9 inhibition and lower risk of overall and early-onset prostate cancer supported by both MR and colocalization approaches. Follow-up analyses of genetically proxied PCSK9 inhibition highlighted a potential mediatory role for Lp(a) along the causal pathway to lower prostate cancer risk. What do these findings mean? PCSK9 inhibition may be involved in biological mechanisms that reduce the risk of overall and early-onset prostate cancer, potentially through the regulation of Lp(a). However, functional validation is necessary to confirm these findings, as well as future research to further evaluate the relationship between lipid-lowering drug targets and advanced prostate cancer risk.