{"doi":"10.1161/circulationaha.124.070982","title":"Rare Genetic Variants in <i>LDLR</i> , <i>APOB</i> , and <i>PCSK9</i> Are Associated With Aortic Stenosis","abstract":"BACKGROUND: Despite a proposed causal role for LDL-C (low-density lipoprotein cholesterol) in aortic stenosis (AS), randomized controlled trials of lipid-lowering therapy failed to prevent severe AS. 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 ( LDLR , APOB , and PCSK9 ). METHODS: 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). RESULTS: We included 421 049 unrelated participants (5621 with AS) in UKB and 195 519 unrelated participants (1087 with AS) in All of Us. Carriers of protein-disrupting variants in LDLR had higher mean LDL-C (UKB: +42.6 mg/dL; P =4.4e-237) and greater risk of AS (meta-analysis: odds ratio, 3.52 [95% CI, 2.39–5.20]; P =2.3e-10) and aortic valve replacement (meta-analysis: odds ratio, 3.78 [95% CI, 2.26–6.32]; P =4.0e-7). Carriers of protein-disrupting variants in APOB or PCSK9 had lower mean LDL-C (UKB: –32.3 mg/dL; P &lt;5e-324) and lower risk of AS (meta-analysis: odds ratio, 0.49 [95% CI, 0.31–0.75]; P =0.001) and aortic valve replacement (meta-analysis: odds ratio, 0.54 [95% CI, 0.30–0.97]; P =0.04). Among 57 371 UKB imaging substudy participants, peak velocities across the aortic valve were greater in carriers of protein-disrupting variants in LDLR (+12.2 cm/s; P =1.6e-5) and lower in carriers of protein-disrupting variants in PCSK9 (–6.9 cm/s; P =0.022). CONCLUSIONS: 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.","journal":"Circulation","year":2024,"id":426144,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":18,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9578,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":888,"name":"Sean J. Jurgens","orcid":"0000-0002-1605-9782","position":1,"is_corresponding":false},{"id":885,"name":"Shinwan Kany","orcid":"0000-0001-8113-733X","position":2,"is_corresponding":false},{"id":24713,"name":"Seung Hoan Choi","orcid":"0000-0002-2797-3190","position":3,"is_corresponding":false},{"id":852753,"name":"Xin Wang","orcid":"0000-0002-0322-8970","position":4,"is_corresponding":false},{"id":984554,"name":"Andrey N. Smirnov","orcid":"0000-0002-4450-0408","position":5,"is_corresponding":false},{"id":236909,"name":"Sam Friedman","orcid":"0000-0002-0688-2169","position":6,"is_corresponding":false},{"id":464218,"name":"Mahnaz Maddah","orcid":"0000-0002-9837-6000","position":7,"is_corresponding":false},{"id":552483,"name":"Shaan Khurshid","orcid":"0000-0002-2840-4539","position":8,"is_corresponding":false},{"id":896,"name":"Patrick T. Ellinor","orcid":"0000-0002-2067-0533","position":9,"is_corresponding":false},{"id":902,"name":"James P. Pirruccello","orcid":"0000-0001-6088-4037","position":10,"is_corresponding":false},{"id":886,"name":"Joel Rämö","orcid":"0000-0002-6429-5149","position":0,"is_corresponding":true}],"reference_count":36,"raw_metadata":null,"created_at":"2026-07-19T01:58:37.924718Z","pmid":"39222019","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}