Potential Therapeutic Drug Targets for Hypertension Identified Using Proteomics and Mendelian Randomization

Hypertension (HT) is the most prevalent risk factor for cardiovascular disease (CVD) worldwide. Despite being a highly heritable trait, the underlying mechanisms of HT remain elusive due to its complex genetic architecture. Discovering disease-associated proteins with causal genetic evidence offers a potential strategy for identifying therapeutic targets for HT.

We analyzed the plasma proteome of 4,657 plasma proteins from 7,213 European American participants in the Atherosclerosis risk in Communities study. Genome-wide association study data for HT were sourced from FinnGen R10, which includes 102,864 cases and 289,117 controls. Cis-Mendelian randomization was conducted to assess the causal effect of circulating proteins on the risk of HT. A multiverse sensitivity analysis was performed to evaluate the robustness of these causal relationships. Colocalization analysis was conducted to determine whether these features share the same associated single nucleotide polymorphisms. The causal effects of HT-associated proteins were then validated using cis-protein quantitative trait loci (Cis-pQTL) genetic instruments from the deCODE database.

Among 1,788 proteins, genetically predicted levels of 18 plasma proteins were associated with HT in the discovery stage. Seven of these proteins showed strong support for colocalization. After replication, only ERAP1 and ACVRL1 were validated as therapeutic candidates for HT, demonstrating a negative correlation with the risk of HT.

By combining cis-MR analysis with colocalization analysis, we identified ERAP1 and ACVRL1 as potential targets for interventions in the primary prevention of HT, with ERAP1 emerging as a particularly promising drug target after further validation.