{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T17:37:39Z","timestamp":1792690659549,"version":"4.5.0"},"reference-count":51,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"8","license":[{"start":{"date-parts":[[2025,8,1]],"date-time":"2025-08-01T00:00:00Z","timestamp":1754006400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Stroke"],"published-print":{"date-parts":[[2025,8]]},"abstract":"<jats:sec>\n            <jats:title>BACKGROUND:<\/jats:title>\n            <jats:p>Analyses of genomic and proteomics data in prospective biobank studies in diverse populations may discover novel or repurposing drug targets for stroke.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>METHODS:<\/jats:title>\n            <jats:p>\n              We extracted individual\n              <jats:italic toggle=\"yes\">cis<\/jats:italic>\n              -protein quantitative trait locus for 2923 proteins measured using Olink Explore panel from a genome-wide association study in prospective China Kadoorie Biobank and UK Biobank, both established \u224820 years ago. These\n              <jats:italic toggle=\"yes\">cis<\/jats:italic>\n              -protein quantitative trait loci were used in ancestry-specific 2-sample Mendelian randomization analyses of ischemic stroke (IS) in East Asians (n=22\u2005664 cases) and Europeans (n=62\u2005100 cases). We further undertook colocalization analyses to examine the shared causal variants of\n              <jats:italic toggle=\"yes\">cis<\/jats:italic>\n              -protein quantitative trait locus with stroke, along with various downstream analyses (eg, phenome-wide association study, drug development lookups) to clarify mechanisms of action and druggability.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>RESULTS:<\/jats:title>\n            <jats:p>In Mendelian randomization analyses, the genetically predicted plasma levels of 10 proteins were significantly associated with IS in East Asians (n=2) and Europeans (n=9), with 6 proteins (FGF5 [fibroblast growth factor 5], TMPRSS5 [transmembrane protease serine 5], FURIN, F11 [coagulation factor XI], ALDH2 [aldehyde dehydrogenase 2], and ABO [histo-blood group ABO system transferase]) showing positive and 4 (GRK5 [G protein-coupled receptor kinase 5], KIAA0319 [dyslexia-associated protein KIAA0319], PROCR [endothelial protein C receptor], and MMP12 [macrophage metalloelastase 12]) showing inverse associations, all directionally consistent between East Asians and Europeans. Colocalization analyses provided strong evidence (posterior probabilities for the H4 hypothesis \u22650.7) of shared genetic variants with IS for 9 out of 10 proteins (except ABO). Moreover, 8 proteins were also causally associated, in the expected directions, with systolic blood pressure (positive\/inverse: 4\/2), low-density lipoprotein cholesterol (1 positive), body mass index (1 inverse), type 2 diabetes (2\/1), or atrial fibrillation (3\/1). Phenome-wide association study analyses and lookups in knock-out mouse models confirmed their importance for IS or stroke-related traits (eg, hematologic phenotypes). Of these 10 proteins, 1 was not druggable (ABO), 3 had known primary (F11) or potentially repurposed (ALDH2, MMP12) drug targets for stroke, and 6 (PROCR, GRK5, FGF5, FURIN, KIAA0319, and TMPRSS5) had no evidence of any drug targets.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>CONCLUSIONS:<\/jats:title>\n            <jats:p>Proteogenomic investigation in diverse ancestry populations identified the causal relevance of 10 proteins for IS, with several being potentially novel or repurposed targets that could be prioritized for further investigation.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/strokeaha.125.050982","type":"journal-article","created":{"date-parts":[[2025,4,30]],"date-time":"2025-04-30T05:00:51Z","timestamp":1745989251000},"page":"2147-2158","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":15,"title":["Proteome-Wide Genetic Study in East Asians and Europeans Identified Multiple Therapeutic Targets for Ischemic Stroke"],"prefix":"10.1161","volume":"56","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6875-7435","authenticated-orcid":true,"given":"Pang","family":"Yao","sequence":"first","affiliation":[{"name":"Clinical Trial Service Unit &amp; Epidemiological Studies Unit (P.Y., M.M., A.P., A.I., N.W., K.L., I.Y.M., H.F., C.K., Y.C., L.Y., H.D., D.A., D.S.-V., M.H., D.A.B., R.G.W., R.C., Z.C.), Nuffield Department of Population Health, University of Oxford, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-9392-4074","authenticated-orcid":true,"given":"Mohsen","family":"Mazidi","sequence":"additional","affiliation":[{"name":"Clinical Trial Service Unit &amp; Epidemiological Studies Unit (P.Y., M.M., A.P., A.I., N.W., K.L., I.Y.M., H.F., C.K., Y.C., L.Y., H.D., D.A., D.S.-V., M.H., D.A.B., R.G.W., R.C., Z.C.), Nuffield Department of Population Health, University of Oxford, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfred","family":"Pozarickij","sequence":"additional","affiliation":[{"name":"Clinical Trial Service Unit &amp; Epidemiological Studies Unit (P.Y., M.M., A.P., A.I., N.W., K.L., I.Y.M., H.F., C.K., Y.C., L.Y., H.D., D.A., D.S.-V., M.H., D.A.B., R.G.W., R.C., Z.C.), Nuffield Department of Population Health, University of Oxford, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8042-9672","authenticated-orcid":true,"given":"Andri","family":"Iona","sequence":"additional","affiliation":[{"name":"Clinical Trial Service Unit &amp; Epidemiological Studies Unit (P.Y., M.M., A.P., A.I., N.W., K.L., I.Y.M., H.F., C.K., Y.C., L.Y., H.D., D.A., D.S.-V., M.H., D.A.B., R.G.W., R.C., Z.C.), Nuffield Department of Population Health, University of Oxford, United Kingdom."},{"name":"Medical Research Council Health Research Unit (I.Y.M., H.F., C.K., Y.C., L.Y., H.D., 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