CSK9 (proprotein convertase subtilisin/kexin type 9) inhibition has proven an efficacious strategy for lowering low‐density lipoprotein cholesterol and thereby reducing cardiovascular disease risk. Drug target Mendelian randomization (MR) has the potential to offer insight into all stages of drug development, thereby significantly improving time and cost efficiency.1 Genetic variants in the PCSK9 gene have been shown previously to mimic the effect of pharmacological PCSK9 inhibition, rendering this target amenable to study using MR.1
Plasma proteomics represents an intermediary phenotype for disease and offers insights into pathophysiology and the identification of biomarkers of pharmacological target engagement. Two targeted proteomic techniques are increasingly used high‐throughput platforms: Olink, which employs antibody‐paired coupling, and SomaScan, which uses an aptamer‐based approach. In this study, we used an MR approach1 to determine if the proteomic signature of genetically proxied PCSK9 inhibition varied between Olink and SomaScan methods, and to ascertain if the proteomic changes observed with genetically proxied inhibition paralleled those with pharmacologically lowered PCSK9. Such findings are pivotal in assessing the viability of MR in predicting proteomic profiles in pharmacological research.