BACKGROUND　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.METHODS　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.RESULTS　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.CONCLUSIONS　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.