Dual site proteomic analyses reveal potential drug targets for cardiovascular disease

Background: While genome-wide association studies (GWAS) hold great promise for unravelling disease pathophysiology, the translation of disease-associated genetic loci into clinically actionable information remains a challenge. Mendelian randomisation (MR), using expressed proteins as exposures and disease as an outcome, stands as a powerful analytical approach for leveraging GWAS data to identify potential drug-targets--at scale--in a data-driven manner. Cardiovascular disease (CVD) is a major health burden worldwide, and therefore is an important outcome for which to establish and prioritise potential therapeutic targets. Methods: In this study, we utilised generalised summary-data-based MR (GSMR) with novel mass-spectrometry-based isoform-specific protein groups measured from peripheral-blood mononuclear cell (PBMC) obtained from Generation Scotland and antibody-based plasma protein measures from UK Biobank as exposures, and two CVD and three CVD-related risk-factors from UK Biobank as outcomes. Further, we used colocalisation to assess support for a shared causal variant between the proteins and the disease outcomes providing further evidence supporting a causal link. Results: We evaluate expression of 5,114 isoform-specific protein groups in PBMCs from 862 individuals. GSMR analysis, using this data, found 16 putative causal proteins across three of the CVD/CVD-related risk-factors with seven supported by colocalisation analysis. Within the plasma GSMR analysis, 761 putative causal proteins were identified, of which 145 were supported by colocalisation. In addition, we go on to examine enrichment amongst the results and find enrichment of pathways which relate to cholesterol metabolism and platelet function. There was an overlap of three proteins between significant GSMR results in PBMCs and plasma, with two proteins (COMT and SWAP70) identifying opposite directions of effect of the relevant outcome, and one identifying a concordant direction of effect (HLA-DRA). Discussion: This study identifies a number of proteins and pathways that may be involved in CVD pathogenesis. It also demonstrates the importance of the location of protein measurement and the methods by which it is quantified. Our research contributes to ongoing efforts to bridge the gap between genotype and phenotype.