{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T01:33:13Z","timestamp":1789522393099,"version":"build-2803163510"},"reference-count":16,"publisher":"American Medical Association (AMA)","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Cardiol"],"published-print":{"date-parts":[[2026,4,1]]},"abstract":"\n Importance<\/jats:title>\n Familial hypercholesterolemia (FH) is a common genetic condition that causes hypercholesterolemia and increased risk for premature atherosclerotic cardiovascular disease (ASCVD). The prevalence, management, and consequences of genetically confirmed FH across the US are poorly understood.<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n To identify genotype-positive FH in a national US cohort and describe its prevalence, consequences, and lipid-lowering management.<\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n In the All of Us (AoU) cohort study, whole-genome sequencing and phenotypic data from US adult participants enrolled between May 2018 and July 2022 were analyzed to identify and study genotype-positive FH. Data were analyzed between May 2024 and May 2025.<\/jats:p>\n <\/jats:sec>\n \n Exposure<\/jats:title>\n \n FH variants (pathogenic or likely pathogenic) in\n LDLR, APOB,<\/jats:italic>\n and\n PCSK9<\/jats:italic>\n genes were manually classified with standard criteria.\n <\/jats:p>\n <\/jats:sec>\n \n Main Outcomes and Measures<\/jats:title>\n The primary outcomes were demographic characteristics, lipid measurements, ASCVD, and prevalence of FH and noncarriers in AoU. Lipid management was then characterized among individuals with FH through lipid-lowering therapy (LLT) documentation and guideline-based low-density lipoprotein cholesterol (LDL-C) targets.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n A total of 245\u202f388 participants were included, with mean (SD) age of 56.5 (16.9) years and 145\u202f563 female participants (59.3%). Genotype-positive FH was identified in 865 participants (prevalence, 0.35%; 95% CI, 0.33%-0.38%; 1 in 287 participants). Among individuals with genotype-positive FH, 349 (40%) were prescribed statins, and 332 (38.4%) had LDL-C measured. Coronary artery disease, peripheral artery disease, and transient ischemic attack or stroke were significantly more common in genotype-positive FH carriers compared to noncarriers (coronary artery disease: odds ratio [OR], 2.91; 95% CI, 2.34-3.58; peripheral artery disease: OR, 1.51; 95% CI, 1.16-1.96; and transient ischemic attack or stroke: OR, 1.54; 95% CI, 1.11-2.09). Only 30.1% of participants positive for FH variants had LDL-C less than 100 mg\/dL at their most recent result compared to 48.2% of noncarriers (\n P<\/jats:italic>\n \u2009&amp;lt;\u2009.001). Of the total participants with ASCVD and LLT prescription, significantly fewer individuals with FH met the secondary prevention LDL-C target (&amp;lt;70 mg\/dL; 19.33% vs 43.12%;\n P<\/jats:italic>\n \u2009&amp;lt;\u2009.001) compared to noncarriers.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n This cohort study finds a prevalence of genotype-positive FH in All of Us participants of 0.35% (95% CI, 0.33%-0.38%), with state-level variation. A minority of individuals with genotype-positive FH met guideline-recommended LDL-C targets and had increased rates of ASCVD.<\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jamacardio.2026.0006","type":"journal-article","created":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T16:30:38Z","timestamp":1772641838000},"page":"378","source":"Crossref","is-referenced-by-count":4,"title":["Management and Consequences of Genotype-Positive Familial Hypercholesterolemia"],"prefix":"10.1001","volume":"11","author":[{"given":"Catherine","family":"Spinks","sequence":"first","affiliation":[{"name":"Division of Cardiology, Massachusetts General Hospital, Boston, Massachusetts"},{"name":"Program of Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts"},{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts"},{"name":"Garvan Institute of Medical Research, UNSW School of Clinical Medicine, Faculty of Medicine and Health, The University of New South Wales Sydney, Sydney, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret Sunitha","family":"Selvaraj","sequence":"additional","affiliation":[{"name":"Program of Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts"},{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts"},{"name":"Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Robinson","sequence":"additional","affiliation":[{"name":"Department of Medicine, Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gina M.","family":"Peloso","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Courtney","family":"Gwynne","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Massachusetts General Hospital, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Urbut","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Massachusetts General Hospital, Boston, Massachusetts"},{"name":"Program of Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts"},{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Buu","family":"Truong","sequence":"additional","affiliation":[{"name":"Program of Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts"},{"name":"Program in Genetic Epidemiology and Statistical Genetics, Harvard T. 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Chan School of Public Health, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaavya","family":"Paruchuri","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Massachusetts General Hospital, Boston, Massachusetts"},{"name":"Program of Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts"},{"name":"Department of Medicine, Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Whitney","family":"Hornsby","sequence":"additional","affiliation":[{"name":"Program of Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts"},{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pradeep","family":"Natarajan","sequence":"additional","affiliation":[{"name":"Program of Medical and Population Genetics, 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