{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T15:08:49Z","timestamp":1783955329310,"version":"3.55.0"},"reference-count":40,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"7","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["ATVB"],"published-print":{"date-parts":[[2023,7]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>\n              Lower plasma levels of LDL (low-density lipoprotein) cholesterol (LDL-C) can reduce the risk of atherosclerotic cardiovascular disease. The loss-of-function mutations in\n              <jats:italic>PCSK9<\/jats:italic>\n              (proprotein convertase subtilisin\/kexin type 9) have been known to associate with low LDL-C in many human populations. PCSK9 genetic variants in Chinese Uyghurs who are at high risk of atherosclerotic cardiovascular disease due to their dietary habits have not been reported.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>The study involved the whole-exome and target sequencing of college students from Uyghur and other ethnic groups in Xinjiang, China, for the association of PCSK9 loss-of-function mutations with low plasma levels of LDL-C. The mechanisms by which the identified mutations affect the function of PCSK9 were investigated in cultured cells using biochemical and cell assays. The causal effects of the identified PCSK9 mutations on LDL-C levels were verified in mice injected with adeno-associated virus expressing different forms of PCSK9 and fed a high-cholesterol diet.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              We identified 2 PCSK9 mutations\u2014E144K and C378W\u2014in Chinese Uyghurs with low plasma levels of LDL-C. The E144K and C378W mutations impaired the maturation and secretion of the PCSK9 protein, respectively. Adeno-associated virus\u2013mediated expression of E144K and C378W mutants in\n              <jats:italic>Pcsk9<\/jats:italic>\n              KO (knockout) mice fed a high-cholesterol diet also hampered PCSK9 secretion into the serum, resulting in elevated levels of LDL receptor in the liver and reduced levels of LDL-C in the serum.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>Our study shows that E144K and C378W are PCSK9 loss-of-function mutations causing low LDL-C levels in mice and probably in humans as well.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/atvbaha.122.318839","type":"journal-article","created":{"date-parts":[[2023,5,11]],"date-time":"2023-05-11T09:01:40Z","timestamp":1683795700000},"page":"1219-1233","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":26,"title":["New Loss-of-Function Mutations in PCSK9 Reduce 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Z.-Y.F.), First Affiliated Hospital of Xinjiang Medical University, China."},{"name":"State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Heart Center (F.-H.M., S.L., Y.-T.M., Z.-Y.F.), First Affiliated Hospital of Xinjiang Medical University, China."},{"name":"College of Life Sciences, Taikang Center for Life and Medical Sciences, Hubei Key Laboratory of Cell Homeostasis, Wuhan University, China (F.-H.M., S.L., J.X., Y.-X.Z., L.-W.D., Y.-F.L., Y.-Q.Z., W.-H.L., J.-Q.W., Y.W., B.-L.S., J.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Xiao","sequence":"additional","affiliation":[{"name":"College of Life Sciences, Taikang Center for Life and Medical Sciences, Hubei Key Laboratory of Cell Homeostasis, Wuhan University, China (F.-H.M., S.L., J.X., Y.-X.Z., L.-W.D., Y.-F.L., Y.-Q.Z., W.-H.L., J.-Q.W., Y.W., B.-L.S., 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