{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T04:11:49Z","timestamp":1791864709724,"version":"4.3.4"},"reference-count":31,"publisher":"American Medical Association (AMA)","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Cardiol"],"published-print":{"date-parts":[[2024,3,1]]},"abstract":"\n Importance<\/jats:title>\n Familial hypercholesterolemia (FH) is a genetic disorder that often results in severely high low-density lipoprotein cholesterol (LDL-C) and high risk of premature coronary heart disease (CHD). However, the impact of FH variants on CHD risk among individuals with moderately elevated LDL-C is not well quantified.<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n To assess CHD risk associated with FH variants among individuals with moderately (130-189 mg\/dL) and severely (\u2265190 mg\/dL) elevated LDL-C and to quantify excess CHD deaths attributable to FH variants in US adults.<\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n A total of 21\u202f426 individuals without preexisting CHD from 6 US cohort studies (Atherosclerosis Risk in Communities study, Coronary Artery Risk Development in Young Adults study, Cardiovascular Health Study, Framingham Heart Study Offspring cohort, Jackson Heart Study, and Multi-Ethnic Study of Atherosclerosis) were included, 63 of whom had an FH variant. Data were collected from 1971 to 2018, and the median (IQR) follow-up was 18 (13-28) years. Data were analyzed from March to May 2023.<\/jats:p>\n <\/jats:sec>\n \n Exposures<\/jats:title>\n LDL-C, cumulative past LDL-C, FH variant status.<\/jats:p>\n <\/jats:sec>\n \n Main Outcomes and Measures<\/jats:title>\n Cox proportional hazards models estimated associations between FH variants and incident CHD. The Cardiovascular Disease Policy Model projected excess CHD deaths associated with FH variants in US adults.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n Of the 21\u202f426 individuals without preexisting CHD (mean [SD] age 52.1 [15.5] years; 12\u202f041 [56.2%] female), an FH variant was found in 22 individuals with moderately elevated LDL-C (0.3%) and in 33 individuals with severely elevated LDL-C (2.5%). The adjusted hazard ratios for incident CHD comparing those with and without FH variants were 2.9 (95% CI, 1.4-6.0) and 2.6 (95% CI, 1.4-4.9) among individuals with moderately and severely elevated LDL-C, respectively. The association between FH variants and CHD was slightly attenuated when further adjusting for baseline LDL-C level, whereas the association was no longer statistically significant after adjusting for cumulative past LDL-C exposure. Among US adults 20 years and older with no history of CHD and LDL-C 130 mg\/dL or higher, more than 417\u202f000 carry an FH variant and were projected to experience more than 12\u202f000 excess CHD deaths in those with moderately elevated LDL-C and 15\u202f000 in those with severely elevated LDL-C compared with individuals without an FH variant.<\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n In this pooled cohort study, the presence of FH variants was associated with a 2-fold higher CHD risk, even when LDL-C was only moderately elevated. The increased CHD risk appeared to be largely explained by the higher cumulative LDL-C exposure in individuals with an FH variant compared to those without. Further research is needed to assess the value of adding genetic testing to traditional phenotypic FH screening.<\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jamacardio.2023.5366","type":"journal-article","created":{"date-parts":[[2024,1,31]],"date-time":"2024-01-31T11:33:16Z","timestamp":1706700796000},"page":"263","source":"Crossref","is-referenced-by-count":31,"title":["Familial Hypercholesterolemia Variant and Cardiovascular Risk in Individuals With Elevated Cholesterol"],"prefix":"10.1001","volume":"9","author":[{"given":"Yiyi","family":"Zhang","sequence":"first","affiliation":[{"name":"Division of General Medicine, Columbia University, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline S.","family":"Dron","sequence":"additional","affiliation":[{"name":"Cardiovascular Disease Initiative, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge"},{"name":"Center for Genomic Medicine, Massachusetts General Hospital, 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