Proteome-wide Mendelian randomization identifies drug targets for atrial fibrillation/flutter

Developing effective and safe drug targets for atrial fibrillation/flutter (AF/AFL) is a critical clinical need. As the plasma proteome represents a major source of druggable targets, this study aimed to identify causal protein targets for AF/AFL and assess their potential side effects. A two-sample Mendelian Randomization (MR) study was conducted to evaluate the causal effects of plasma proteins from the UK Biobank Pharma Proteomics Project (UKB-PPP) and the deCODE database on the risk of AF/AFL. The MR findings were further confirmed through Bayesian colocalization and Transcriptome-Wide Association Studies (TWAS) analyses. Furthermore, phenome-wide association study (PheWAS) was conducted to depict potential side effects of druggable targets, and Multivariable MR (MVMR) explored the potential mediators. MR analysis identified 44 plasma proteins from the UKB-PPP database and 14 from the deCODE database significantly associated with AF/AFL, and only 3 proteins (NFKB1, PGD, PCSK9) were overlapped. Colocalization analysis further identified only PCSK9 (Proprotein convertase subtilisin/kexin type 9) shared a causative genetic variant with AF/AFL (PP.H4 > 0.8). TWAS analysis also provided strong evidence to the association between PCSK9 and risks of AF/AFL. PheWAS have shown several potential side effects of PCSK9 inhibition (p_fdr < 0.05). Moreover, MVMR analysis revealed that LDL-C, systolic/diastolic blood pressure, and inflammatory factors may exert partial mediation effects on the causal relationship between PCSK9 and AF/AFL. This study identifies PCSK9 as a promising therapeutic target for AF/AFL, supported by consisitent evidence from MR, Bayesian colocalization, and TWAS analysis. And LDL-C, blood pressure, and inflammatory factors may exert partial mediation effects on the causal relationship between PCSK9 and AF/AFL.