PCSK9 and breast cancer survival: a Mendelian Randomization study

BackgroundProprotein convertase subtilisin/kexin type 9 (PCSK9) is well known for its causal effects on the lipid metabolism. A recent study identified an association between rs562556 within PCSK9 and breast cancer survival (BCS). It was suggested that PCSK9 inhibition might allow for early intervention strategies to prevent metastasizing breast cancer. Here, we attempt to replicate these findings by using genome-wide association study (GWAS) summary statistics in three 2-sample Mendelian Randomization (MR) approaches. MethodsWe used publicly available GWAS summary statistics for PCSK9 and BCS from the Breast Cancer Association Consortium (N=99,217), and performed SNP association tests with BCS in the FinnGen study (N=4,648). First, we tested the MR-ratio using only the reported SNP rs562556, then tested the genetically proxied PCSK9 inhibition using the MR inverse variance weighted (IVW) approach, and finally adjusted for indirect effects of the lipid metabolism using multivariable MR (MVMR-IVW). Coronary artery disease and parental longevity were chosen as positive control outcomes. ResultsWe found no significant association between PCSK9 and BCS in neither the MR-ratio, MR-IVW nor MVMR-IVW approach. The positive controls were significant throughout. ConclusionA significant positive effect of PCSK9 on BCS could only be reproduced when using the outcome data from the recent study, but not when using independent, larger GWASs. ImpactPotential reasons for the discrepant results are different genetic models, sample selection criteria, and the time-variability of Hazard Ratio estimates. They should be explored before considering PCSK9 a therapeutic target in BC patients.