Blood plasma proteome-wide association study implicates novel proteins in the pathogenesis of multiple cardiovascular diseases

Cardiovascular diseases (CVD) are the leading cause of global mortality, but current treatments are only effective in a subset of individuals. To identify new potential treatment targets, we present here the first PWAS for 26 CVDs using plasma proteomics data of the largest cohort to date (53,022 individuals from the UK Biobank Pharma Proteomics Project (UKB-PPP) project). The GWAS summary data for 26 CVDs spanning 3 categories (16 cardiac diseases, 5 venous diseases, 5 cerebrovascular diseases, up to 1,308,460 individuals). We also conducted replication analyses leveraging two other independent human plasma proteomics datasets, encompassing 7,213 participants from the Atherosclerosis Risk in Communities (ARIC) study and 3,301 individuals from the INTERVAL study. We identified 94 genes that are consistent with being causal in CVD, acting via their cis-regulated plasma protein abundance. 34 of 45 genes were replicated in at least one of the replication datasets. 41 of the 94 genes are novel genes not implicated in original GWAS. 91.48% (86/94) proteins are category-specific, only two proteins (ABO, PROCR) were associated with diseases in all three CVD categories. Longitudinal analysis revealed that 37 proteins exhibit stable expression in plasma. In addition, PBMC scRNA-seq data analysis showed that 23 of the 94 genes were stably expressed in CD14+ monocytes, implicating their potential utility as biomarkers for CVD disease status. Drug repurposing analyses showed that 39 drugs targeting 23 genes for treating diseases from other systems might be considered in further research. In conclusion, our findings provide new insights into the pathogenic mechanisms of CVD and offering promising targets for further mechanistic and therapeutic studies.