Abstract
BACKGROUND: Hypertension affects one-third of adults worldwide and is largely idiopathic. Identifying protein biomarkers of hypertension may reveal underlying mechanisms and potential treatments. METHODS: We examined associations between 2922 plasma proteins and blood pressure (BP) traits (systolic BP [SBP] and diastolic BP [DBP], and prevalent hypertension) in 45 991 UK Biobank participants with validation in 5759 FHS (Framingham Heart Study) participants. Analysis of new-onset hypertension was performed in 3995 UK Biobank participants and validated in 3073 FHS participants. Functional enrichment analysis linked proteins to biological functions and diseases. Mendelian randomization assessed causal relations between proteins using cis-protein quantitative trait loci as exposures and BP traits as outcomes. RESULTS: In the UK Biobank, 342 proteins were associated (false discovery rate knockoff <0.1) with SBP, 276 with DBP, and 200 with prevalent hypertension (N=24 724). In the FHS, 115 proteins were validated (Bonferroni-corrected P<0.05) for SBP, 108 for DBP, and 102 for hypertension. New-onset hypertension was associated with 60 (17 validated) proteins. Mendelian randomization analyses revealed significant associations for 206, 210, and 82 proteins with SBP, DBP, and hypertension, respectively. Several of these proteins are involved in blood vessel and cardiac muscle morphogenesis, vasoconstriction, and inflammation. BP-related proteins are enriched for atherosclerotic cardiovascular, liver, and kidney diseases. NHERF2 (Na(+)/H(+) exchange regulatory cofactor 2) demonstrated putatively causal associations with SBP, DBP, and with prevalent and new-onset hypertension. CONCLUSIONS: This large-scale proteomic study revealed protein signatures of BP traits and hypertension risk, highlighting inflammation and cardiac and vascular remodeling processes; NHERF2 and several other proteins emerged as promising therapeutic targets.