Year: 2026
Type: article
Study design: Observational Study
Abstract: BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) affects lipid metabolism. A recent study identified an association between rs562556 within the PCSK9 gene and breast cancer survival (BCS), suggesting PCSK9 inhibition as an early intervention strategy to prevent metastasizing breast cancer. We attempt to replicate these findings using genome-wide association study (GWAS) data and Mendelian Randomization (MR). METHODS: We used GWAS data from the Breast Cancer Association Consortium (BCAC, N = 91,686) and performed analyses in the FinnGen study (N = 4,648; additive and recessive model). First, we tested the association of the single variant rs562556, then genetically proxied PCSK9 inhibition using multiple variants, and finally adjusted for the indirect effects of lipid metabolism using multivariable MR. Coronary artery disease was chosen as a positive control outcome. RESULTS: Estimates are scaled as log hazard ratios (logHR) per 1 SD higher PCSK9 levels. We found no significant association between PCSK9 variants and BCS in any MR approach with any replication data: single variant [BCAC: logHR = 2.37, P = 0.066; FinnGen additive: logHR = 0.58, P = 0.91; FinnGen recessive: logHR = -2.75, P = 0.87], multiple variants [BCAC: logHR = -0.22, P = 0.30; FinnGen: logHR = -0.40, P = 0.54], or multivariable [BCAC: logHR = 0.42, P = 0.65; FinnGen: logHR = 1.23, P = 0.75]. Positive control analyses were significant throughout. CONCLUSIONS: A significant association of PCSK9 variants with BCS could only be reproduced using outcome data from the original study but not when using independent, larger GWASs. IMPACT: Potential reasons for the discrepant results are different genetic models, sample selection criteria, and the time variability of HR estimates. They should be explored before considering PCSK9, a therapeutic target in patients with breast cancer.
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Funders: Wellcome Trust, Scottish Government, National Institute for Health and Care Research, British Heart Foundation, Department of Health and Social Care, Public Health Agency, Chief Scientist Office, Scottish Government Health and Social Care Directorate, Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Health and Social Care Research and Development Division, NIHR Cambridge Biomedical Research Centre, Cambridge BHF Centre of Research Excellence, Health Data Research UK
Awards: G1211085472, G1351194392, G192668546, Large-scale integrative genomic studies of high-dimensional traits in cardiovascular diseases (renewal), G2493601830, G2537968379, Research Excellence (round 3), G4493023864, G4753630297, New horizons in Mendelian randomization, Large-scale integrative molecular studies of CVDs in multi-ethnic cohorts, The BHF Chair of Epidemiology and Medicine
OpenAlex ID: W7140123403
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