TY - JOUR

T1 - Proteomic Signatures of Genetically Predicted and Pharmacologically Observed PCSK9 Inhibition

AU - Kraaijenhof, Jordan M.

AU - Cronjé, Héléne T.

AU - Hovingh, G. Kees

AU - Nurmohamed, Nick S.

AU - Gill, Dipender

AU - Zagkos, Loukas

PY - 2024

Y1 - 2024

N2 - 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.1Plasma 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.

AB - 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.1Plasma 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.

KW - low‐density lipoprotein cholesterol

KW - Mendelian randomization

KW - PCSK9

KW - proteomics

U2 - 10.1161/JAHA.123.033190

DO - 10.1161/JAHA.123.033190

M3 - Journal article

C2 - 38874077

AN - SCOPUS:85196582427

VL - 13

JO - Journal of the American Heart Association

JF - Journal of the American Heart Association

SN - 2047-9980

IS - 12

M1 - e033190

ER -