Genetically proxied PCSK9 inhibition provides indication of lower prostate cancer risk: a Mendelian randomization study

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 randomization (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) in and around HMGCR, NPC1L1 and PCSK9 genes associated with LDL-c (P<5×10 −8 ) from the Global Lipids Genetics Consortium genome-wide association study (GWAS) (N=173,082) were used to proxy the therapeutic inhibition of these targets. Association estimates for the risk of total, advanced and early-onset PrCa were obtained from the PRACTICAL consortium. Replication was performed using genetic instruments from an LDL-c GWAS conducted on male UK Biobank participants of European ancestry (N=201,678), as well as instruments selected based on liver-derived gene expression and circulation plasma levels of targets. We also investigated whether putative mediators may play a role in findings for traits previously implicated in PrCa risk (i.e., lipoprotein a (Lp(a)), body mass index (BMI) and testosterone). Applying MR using the inverse-variance weighted approach accounting for genetic correlations between instruments provided strong evidence supporting an effect of genetically proxied inhibition of PCSK9 (equivalent to a standard deviation (SD) reduction in LDL-c) on lower risk of total PrCa (odds ratio (OR)=0.84, 95% confidence interval (CI)=0.74 to 0.96, P=7.86×10 −3 ) and early-onset PrCa OR=0.70, 95% CI=0.52 to 0.95, P=0.021. Analyses using male-stratified instruments provided consistent results. In contrast, there was little evidence of an association of genetically proxied HMGCR (OR=0.83, 95% CI=0.67 to 1.03, P=0.093) or NPC1L1 (OR=1.27, 95% CI=0.87 to 1.87, P=0.218) inhibition on PrCa risk. Secondary analyses supported a genetically proxied effect of liver-specific PCSK9 expression (OR=0.90, 95% CI=0.86 to 0.95, P=5.50×10 −5 ) and circulating plasma levels of PCSK9 (OR=0.93 per SD reduction in PCSK9, 95% CI=0.87 to 0.997, P=0.04) on PrCa risk. Colocalization using eCAVIAR identified evidence (colocalization posterior probability=0.103) of a shared genetic variant (rs553741) between liver-derived PCSK9 expression and PrCa risk. Moreover, genetically proxied PCSK9 inhibition was strongly associated with Lp(a) levels (Beta= -0.07, 95% CI= -0.10 to -0.03, P=1.44×10 −4 ), but not BMI or testosterone, indicating a putative mediatory role of Lp(a). Conclusions Our study supports a strong association between genetically proxied inhibition of PCSK9 and a lower risk of total and early-onset PrCa. Further evidence from clinical studies is needed to confirm this finding as well as the putative mediatory role of Lp(a).