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We aimed to assess the impact on AS and peak velocity across the aortic valve conferred by lifelong alterations in LDL-C levels mediated by protein-disrupting variants in 3 clinically significant genes for LDL (low-density lipoprotein) metabolism (\n              <jats:italic toggle=\"yes\">LDLR<\/jats:italic>\n              ,\n              <jats:italic toggle=\"yes\">APOB<\/jats:italic>\n              , and\n              <jats:italic toggle=\"yes\">PCSK9<\/jats:italic>\n              ).\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>METHODS:<\/jats:title>\n            <jats:p>We used sequencing data and electronic health records from UK Biobank (UKB) and All of Us and magnetic resonance imaging data from UKB. We identified predicted protein-disrupting variants with the Loss Of Function Transcript Effect Estimator (LOFTEE) and AlphaMissense algorithms and evaluated their associations with LDL-C and peak velocity across the aortic valve (UK Biobank), as well as diagnosed AS and aortic valve replacement (UK Biobank and All of Us).<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>RESULTS:<\/jats:title>\n            <jats:p>\n              We included 421\u2009049 unrelated participants (5621 with AS) in UKB and 195\u2009519 unrelated participants (1087 with AS) in All of Us. Carriers of protein-disrupting variants in\n              <jats:italic toggle=\"yes\">LDLR<\/jats:italic>\n              had higher mean LDL-C (UKB: +42.6 mg\/dL;\n              <jats:italic toggle=\"yes\">P<\/jats:italic>\n              =4.4e-237) and greater risk of AS (meta-analysis: odds ratio, 3.52 [95% CI, 2.39\u20135.20];\n              <jats:italic toggle=\"yes\">P<\/jats:italic>\n              =2.3e-10) and aortic valve replacement (meta-analysis: odds ratio, 3.78 [95% CI, 2.26\u20136.32];\n              <jats:italic toggle=\"yes\">P<\/jats:italic>\n              =4.0e-7). Carriers of protein-disrupting variants in\n              <jats:italic toggle=\"yes\">APOB<\/jats:italic>\n              or\n              <jats:italic toggle=\"yes\">PCSK9<\/jats:italic>\n              had lower mean LDL-C (UKB: \u201332.3 mg\/dL;\n              <jats:italic toggle=\"yes\">P<\/jats:italic>\n              &lt;5e-324) and lower risk of AS (meta-analysis: odds ratio, 0.49 [95% CI, 0.31\u20130.75];\n              <jats:italic toggle=\"yes\">P<\/jats:italic>\n              =0.001) and aortic valve replacement (meta-analysis: odds ratio, 0.54 [95% CI, 0.30\u20130.97];\n              <jats:italic toggle=\"yes\">P<\/jats:italic>\n              =0.04). Among 57\u2009371 UKB imaging substudy participants, peak velocities across the aortic valve were greater in carriers of protein-disrupting variants in\n              <jats:italic toggle=\"yes\">LDLR<\/jats:italic>\n              (+12.2 cm\/s;\n              <jats:italic toggle=\"yes\">P<\/jats:italic>\n              =1.6e-5) and lower in carriers of protein-disrupting variants in\n              <jats:italic toggle=\"yes\">PCSK9<\/jats:italic>\n              (\u20136.9 cm\/s;\n              <jats:italic toggle=\"yes\">P<\/jats:italic>\n              =0.022).\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>CONCLUSIONS:<\/jats:title>\n            <jats:p>Rare genetic variants that confer lifelong higher or lower LDL-C levels are associated with substantially increased and decreased risk of AS, respectively. Early and sustained lipid-lowering therapy may slow or prevent AS development.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circulationaha.124.070982","type":"journal-article","created":{"date-parts":[[2024,9,2]],"date-time":"2024-09-02T14:00:35Z","timestamp":1725285635000},"page":"1767-1780","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":25,"title":["Rare Genetic Variants in\n            <i>LDLR<\/i>\n            ,\n            <i>APOB<\/i>\n            , and\n            <i>PCSK9<\/i>\n            Are Associated With Aortic Stenosis"],"prefix":"10.1161","volume":"150","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6429-5149","authenticated-orcid":true,"given":"Joel T.","family":"R\u00e4m\u00f6","sequence":"first","affiliation":[{"name":"Cardiovascular Disease Initiative (J.T.R., S.J.J., S. Kany, X.W., S. Khurshid, P.T.E., J.P.P.), Cambridge, MA."},{"name":"Broad Institute of MIT and Harvard (J.T.R., S.J.J., S. Kany, X.W., S. Khurshid, P.T.E., J.P.P, A.N.S., S.F.F., M.M.), Cambridge, MA."},{"name":"Department of Medicine, Brigham and Women\u2019s Hospital, Boston, MA (J.T.R.)."},{"name":"Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki (J.T.R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1605-9782","authenticated-orcid":true,"given":"Sean J.","family":"Jurgens","sequence":"additional","affiliation":[{"name":"Cardiovascular Disease Initiative (J.T.R., S.J.J., S. Kany, X.W., S. Khurshid, P.T.E., J.P.P.), Cambridge, MA."},{"name":"Broad Institute of MIT and Harvard (J.T.R., S.J.J., S. Kany, X.W., S. Khurshid, P.T.E., J.P.P, A.N.S., S.F.F., M.M.), Cambridge, MA."},{"name":"Cardiovascular Research Center (J.T.R., S.J.J., S. Kany, S. Khurshid, P.T.E.), Massachusetts General Hospital, Boston."},{"name":"Department of Experimental Cardiology, Amsterdam Cardiovascular Sciences, Heart Failure &amp; Arrhythmias, Amsterdam University Medical Center, University of Amsterdam, The Netherlands (S.J.J.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8113-733X","authenticated-orcid":true,"given":"Shinwan","family":"Kany","sequence":"additional","affiliation":[{"name":"Cardiovascular Disease Initiative (J.T.R., S.J.J., S. Kany, X.W., S. Khurshid, P.T.E., J.P.P.), Cambridge, MA."},{"name":"Broad Institute of MIT and Harvard (J.T.R., S.J.J., S. Kany, X.W., S. Khurshid, P.T.E., J.P.P, A.N.S., S.F.F., M.M.), Cambridge, MA."},{"name":"Cardiovascular Research Center (J.T.R., S.J.J., S. Kany, S. Khurshid, P.T.E.), Massachusetts General Hospital, Boston."},{"name":"Department of Cardiology, University Heart and Vascular Center Hamburg-Eppendorf, Hamburg, Germany (S. 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