Integrative multi-omics genomics prioritizes causal therapeutic targets for salt sensitive of blood pressure

Hypertension remains a primary modifiable risk factor for cardiovascular disease (CVD). Salt sensitivity of blood pressure (SSBP) represents a critical yet mechanistically undefined phenotype influencing hypertension development. Current evidence lacks robust causal links between genetic determinants and SSBP pathogenesis. This study employs integrative genomics to identify causal genes and druggable targets for SSBP.

We integrated cis-expression quantitative trait loci (cis-eQTLs) from the eQTLGen Consortium and protein quantitative trait loci (pQTLs) from deCODE project. Genome-wide association study (GWAS) of SSBP was performed in 1684 participants from the Systematic Epidemiological Study of Salt Sensitivity (EpiSS) cohort. Summary-data-based Mendelian randomization (SMR) identified causal gene-SSBP relationships, with Bayesian colocalization confirming shared causal variants. Functional enrichment and drug prediction were performed to validate the identified target genes. We established 68 genes exhibiting significant causal associations with SSBP risk. Fifteen high-confidence therapeutic targets were prioritized through colocalization evidence and protein abundance concordance. These targets functionally converge on immune regulation, cytosolic localization, and protein methyltransferase activity, with enrichment in MAPK signaling pathways. PRKCB emerged as a promising pharmacological target through computational screening.

This multi-omics investigation provides evidence for causal roles of 15 genes in SSBP pathogenesis. Our findings reveal novel biological mechanisms and deliver actionable targets for precision interventions in salt-sensitive individuals.