Genetically determined levels of ACE, AGT, and NPPA are causally related to hypertension, highlighting them as promising therapeutic targets.
Do genetically determined levels of specific plasma proteins causally affect the risk of hypertension?
Mendelian randomization and colocalization analyses identify ACE, AGT, and NPPA as genetically supported therapeutic targets for hypertension.
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Background: Hypertension, a major risk factor for cardiovascular disease morbidity and mortality, remains poorly controlled in many patients despite available treatments. There are many patients with poorly managed blood pressure despite the availability of treatments. We employed Mendelian Randomization (MR) and colocalization analyses of plasma proteins and hypertension to identify genetically supported drug targets. Methods: We investigated genetic associations between plasma protein quantitative trait loci (pQTLs) and hypertension GWAS data from FinnGen using two-sample MR, enrichment analysis, and Protein-Protein Interaction (PPI) analysis. Colocalization verified shared causal variants between identified proteins and hypertension. Drug prediction and molecular docking were used to assess therapeutic potential. Results: In the MR analysis, 12 plasma proteins were found to be associated with hypertension, three of which (ACE, AGT, and NPPA) were supported by colocalization. Among these, ACE and AGT are established drug targets, whereas NPPA remains relatively underexplored. Drug prediction and molecular docking results indicated that several candidate drugs exhibited highly stable interactions and strong binding affinities with the screened proteins. Discussion: Our findings confirm the centrality of the renin-angiotensin system (ACE, AGT) and highlight NPPA as a novel, genetically supported protective target. While the study benefits from robust MR and colocalization methods, the focus on European ancestry warrants validation in diverse populations. Experimental and clinical studies are needed to translate these targets into therapies. Conclusion: This proteome-wide MR analysis demonstrates a causal relationship between genetically determined levels of ACE, AGT, and NPPA and hypertension. These proteins represent promising targets for the development of novel hypertension therapeutics.
Wang et al. (Mon,) reported a other. Genetically determined levels of ACE, AGT, and NPPA are causally related to hypertension, highlighting them as promising therapeutic targets.