Revealing Causal Proteomic Signatures of Hypertension: Systematic Insights From Proteome-Wide Mendelian Randomization.

BACKGROUND: Hypertension is a major cardiovascular risk factor with an incompletely understood cause. We aimed to unravel its proteomic landscape and investigate potential molecular mechanisms underlying its risk related to modifiable exposures. METHODS: Leveraging protein quantitative trait loci from 3 biobank-scale studies (deCODE, Fenland, and UKB-PPP [UK Biobank Pharma Proteomics Project]) based on distinct proteomic platforms (SomaScan or Olink), we performed proteome-wide Mendelian randomization to identify and cross-platform validate proteins causally associated with hypertension and blood pressure (BP). Bayesian colocalization was applied to detect shared causal variants underpinning the identified associations. A broad range of modifiable risk factors were systematically assessed for their causal associations with hypertension/BP, followed by mediation analyses exploring potential proteomic pathways linking risk factors to hypertension/BP. RESULTS: The discovery Mendelian randomization analyses (deCODE) identified 190 significant causal associations between 118 proteins and hypertension/BP, which were overall consistent in the cross-platform replication analyses (Fenland and UKB-PPP). Fifty-four protein-hypertension/BP pairs were further supported by genetic colocalization. Triangulation of evidence from Mendelian randomization and colocalization prioritized 28 proteins as key causal signatures. Among these, 10 proteins (particularly ALDH2 [mitochondrial aldehyde dehydrogenase] and ULK3 [serine/threonine-protein kinase]) were found to mediate the associations of 8 genetically predicted modifiable risk factors with hypertension/BP, with ALDH2 emerging as a central hub across multiple causal pathways. CONCLUSIONS: This study systematically characterized the causal proteomic landscape of hypertension and highlighted proteins implicated in its modifiable risk. These findings provide novel insights into the molecular cause of hypertension and identify promising candidates for further therapeutic investigation.