Association between genetically proxied PCSK9 inhibition and prostate cancer risk: A Mendelian randomisation study
Open accessAbstract
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 < 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. Colocalization analyses identified strong evidence (posterior probability (PPA) = 81.3%) of a shared genetic variant (rs553741) between liver-derived PCSK9 expression and PrCa risk, whereas weak evidence was found for HMGCR (PPA = 0.33%) and NPC1L1 expression (PPA = 0.38%). Moreover, genetically proxied PCSK9 inhibition was strongly associated with Lp(a) levels (Beta = −0.08, 95% CI = −0.12 to −0.05, P = 1.00 × 10−5), but not BMI or testosterone, indicating a possible role for Lp(a) in the biological mechanism underlying the association between PCSK9 and PrCa. Notably, we emphasise that our estimates are based on a lifelong exposure that makes direct comparisons with trial results challenging. 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).
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Drug target MR uses genetic variants in genes encoding drug targets to mimic the actions of drugs and estimate therapeutic potential.
“As an extension of MR, drug target MR has emerged as efficient way to estimate therapeutic potential by using genetic variants in genes encoding drug targets (referred to as cis variants) to mimic the actions of drugs.”
From Genetic insights into causal effects of lipids and lipid-modifying targets on calcific aortic valve stenosis: a Mendelian randomized study (2025) · cites this paper as [15]
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- Authors
- Fang, S., Yarmolinsky, J., Gill, D., Bull, C. J., Perks, C. M., the PRACTICAL Consortium, Davey Smith, G., Gaunt, T. R., & Richardson, T. G.
- Affiliations
- University of Bristol (GB)
- Novo Nordisk (Denmark) (DK)
- Southmead Hospital (GB)
- Corresponding author
- Fang, Si
- Richardson, Tom G.
- ORCID
- Venue
- PLOS Medicine
- Publisher
- Public Library of Science (PLoS)
- Published
- 2023-01-03
- Volume
- 20
- Issue
- 1
- Pages
- e1003988
- ISSN
- 1549-1277 (ISSN-L)
- 1549-1676
- PMC
- PMC9810198
- OpenAlex
- W4313461963
- Cited by
- 55
- References
- 78
- Citations by year
- 2026: 9 · 2025: 19 · 2024: 18 · 2023: 8
- FWCI
- 8.96
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS Medicine (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Bristol Research (University of Bristol) (submittedVersion, cc-by)
- Explore Bristol Research (submittedVersion, cc-by)
- Funders
- Medical Research Council (MC_UU_00011/1, MC_UU_00011/4)
- Wellcome Trust (108902/Z/15/Z)
- Cancer Research UK (C68933/A28534)
- World Cancer Research Fund (IIG_2019_2009)
- University Hospitals Bristol NHS Foundation Trust
- University of Bristol
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- prostate cancer risk, PCSK9 inhibition, LDL cholesterol lowering, HMGCR, NPC1L1, statins, early-onset prostate cancer, genetic instruments, lipoprotein(a), body mass index, testosterone, mediation analysis, confounding by treatment, PRACTICAL consortium, UK Biobank
- MeSH terms
- Proprotein Convertase 9, Humans, Cholesterol, LDL, Male, Prostatic Neoplasms, Testosterone, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Mendelian Randomization Analysis
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