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

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. Single-nucleotide polymorphisms (SNPs) associated with LDL-c (P < 5 × 10-8) from the Global Lipids Genetics Consortium genome-wide association study (GWAS) (N = 1,320,016) and located in and around the HMGCR, NPC1L1, and PCSK9 genes were used to proxy the therapeutic inhibition of these targets. Summary-level data regarding the risk of total, advanced, and early-onset PrCa were obtained from the PRACTICAL consortium. Validation analyses were 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 two-sample MR using the inverse-variance weighted approach 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) = 0.85, 95% confidence interval (CI) = 0.76 to 0.96, P = 9.15 × 10-3) and early-onset PrCa (OR = 0.70, 95% CI = 0.52 to 0.95, P = 0.023). Genetically proxied HMGCR inhibition provided a similar central effect estimate on PrCa risk, although with a wider 95% CI (OR = 0.83, 95% CI = 0.62 to 1.13, P = 0.244), whereas genetically proxied NPC1L1 inhibition had an effect on higher PrCa risk with a 95% CI that likewise included the null (OR = 1.34, 95% CI = 0.87 to 2.04, P = 0.180). Analyses using male-stratified instruments provided consistent results. Secondary MR analyses supported a genetically proxied effect of liver-specific PCSK9 expression (OR = 0.90 per SD reduction in PCSK9 expression, 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 protein levels, 95% CI = 0.87 to 0.997, P = 0.04) on PrCa risk. Coloc