{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T22:49:34Z","timestamp":1784328574054,"version":"3.55.0"},"reference-count":51,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Genomic and Precision Medicine"],"published-print":{"date-parts":[[2018,5]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>Inhibition of PCSK9 (proprotein convertase subtilisin\/kexin type 9) is a novel strategy to treat hypercholesterolemia and reduce cardiovascular events. However, the potential role of circulating plasma PCSK9 concentrations as a diagnostic and predictive biomarker remains uncertain as of now. Here, we aimed to identify genetic variants associated with plasma PCSK9 and investigate possible causal effects on atherosclerotic vascular disease phenotypes.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>We performed the first genome-wide association study of plasma PCSK9 levels in a cohort of suspected and confirmed coronary artery disease (LIFE-Heart; n=3290).<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              Several independent variants at the\n              <jats:italic>PCSK9<\/jats:italic>\n              gene locus were associated with circulating PCSK9 levels at genome-wide significance (lead SNP rs11591147, PCSK9-R46L;\n              <jats:italic>P<\/jats:italic>\n              =1.94\u00d710\n              <jats:sup>\u221217<\/jats:sup>\n              ). We discovered 4 independent\n              <jats:italic>PCSK9<\/jats:italic>\n              SNPs explaining 4.4% of the variance of plasma PCSK9. In addition, we identified a genome-wide significant locus at chromosome 7p22.1 (rs6957201;\n              <jats:italic>P<\/jats:italic>\n              =7.01\u00d710\n              <jats:sup>\u22129<\/jats:sup>\n              ) and 7 suggestive hits (\n              <jats:italic>P<\/jats:italic>\n              &lt;1\u00d710\n              <jats:sup>\u22126<\/jats:sup>\n              ). Using MR (Mendelian Randomization), we detected significant causal effects of circulating PCSK9 on coronary artery disease status and severity, carotid plaques, and intima-media thickness.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>\n              Variants at the\n              <jats:italic>PCSK9<\/jats:italic>\n              gene locus seem to be the major genetic determinants of plasma PCSK9 levels with 4 independent variants at the\n              <jats:italic>PCSK9<\/jats:italic>\n              gene locus expressing allelic heterogeneity. The detected MR estimates support the hypothesis of a causal effect of PCSK9 on coronary artery disease and other vascular phenotypes. Other observed genetic associations for PCSK9 require validation in independent cohorts.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Clinical Trial Registration:<\/jats:title>\n            <jats:p>\n              URL:\n              <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"http:\/\/www.clinicaltrials.gov\">http:\/\/www.clinicaltrials.gov<\/jats:ext-link>\n              . Unique Identifier: NCT00497887.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circgen.117.001992","type":"journal-article","created":{"date-parts":[[2018,10,9]],"date-time":"2018-10-09T08:09:51Z","timestamp":1539072591000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":47,"title":["Genetic Regulation of PCSK9 (Proprotein Convertase Subtilisin\/Kexin Type 9) Plasma Levels and Its Impact on Atherosclerotic Vascular Disease Phenotypes"],"prefix":"10.1161","volume":"11","author":[{"given":"Janne","family":"Pott","sequence":"first","affiliation":[{"name":"Institute for Medical Informatics, Statistics and Epidemiology, Leipzig, Germany (J.P., K.H., H.K., M.L., M.S.)"},{"name":"LIFE Research Center for Civilization Diseases, University of Leipzig, Germany (J.P., V.S., A.T., H.K., C.B., M.L., J.T., R.B., 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