{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T16:54:16Z","timestamp":1780073656374,"version":"3.54.0"},"reference-count":92,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Genomic and Precision Medicine"],"published-print":{"date-parts":[[2022,12]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>\n              A key goal of precision medicine is to disaggregate common, complex diseases into discrete molecular subtypes. Rare coding variants in the low-density lipoprotein receptor gene (\n              <jats:italic>LDLR<\/jats:italic>\n              ) are identified in 1% to 2% of coronary artery disease (CAD) patients, defining a molecular subtype with risk driven by hypercholesterolemia.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>To search for additional subtypes, we compared the frequency of rare, predicted loss-of-function and damaging missense variants aggregated within a given gene in 41 081 CAD cases versus 217 115 controls.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              Rare variants in\n              <jats:italic>LDLR<\/jats:italic>\n              were most strongly associated with CAD, present in 1% of cases and associated with 4.4-fold increased CAD risk. A second subtype was characterized by variants in endothelial nitric oxide synthase gene (\n              <jats:italic>NOS3<\/jats:italic>\n              ), a key enzyme regulating vascular tone, endothelial function, and platelet aggregation. A rare predicted loss-of-function or damaging missense variants in\n              <jats:italic>NOS3<\/jats:italic>\n              was present in 0.6% of cases and associated with 2.42-fold increased risk of CAD (95% CI, 1.80\u20133.26;\n              <jats:italic>P<\/jats:italic>\n              =5.50\u00d710\n              <jats:sup>\u22129<\/jats:sup>\n              ). These variants were associated with higher systolic blood pressure (+3.25 mm Hg; [95% CI, 1.86\u20134.65];\n              <jats:italic>P<\/jats:italic>\n              =5.00\u00d710\n              <jats:sup>\u22126<\/jats:sup>\n              ) and increased risk of hypertension (adjusted odds ratio 1.31; [95% CI, 1.14\u20131.51];\n              <jats:italic>P<\/jats:italic>\n              =2.00\u00d710\n              <jats:sup>\u22124<\/jats:sup>\n              ) but not circulating cholesterol concentrations, suggesting that, beyond lipid pathways, nitric oxide synthesis is a key nonlipid driver of CAD risk.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>\n              Beyond\n              <jats:italic>LDLR<\/jats:italic>\n              , we identified an additional nonlipid molecular subtype of CAD characterized by rare variants in the\n              <jats:italic>NOS3<\/jats:italic>\n              gene.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circgen.121.003598","type":"journal-article","created":{"date-parts":[[2022,10,10]],"date-time":"2022-10-10T16:04:17Z","timestamp":1665417857000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":8,"title":["Gene Sequencing Identifies Perturbation in Nitric Oxide Signaling as a Nonlipid Molecular Subtype of Coronary Artery Disease"],"prefix":"10.1161","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6535-5839","authenticated-orcid":true,"given":"Amit V.","family":"Khera","sequence":"first","affiliation":[{"name":"Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA (A.V.K.)"},{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, (A.V.K., M.W., C.A.E., S.K.)"},{"name":"Department of Medicine, Harvard Medical School, Boston, MA (A.V.K., C.A.E., S.K.)"},{"name":"Cardiology 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