Full Citation
Title: Familial Hypercholesterolemia Variant and Cardiovascular Risk in Individuals With Elevated Cholesterol
Citation Type: Journal Article
Publication Year: 2024
ISBN:
ISSN: 2380-6583
DOI: 10.1001/JAMACARDIO.2023.5366
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Abstract: <h3>Importance</h3><p>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.</p><h3>Objective</h3><p>To assess CHD risk associated with FH variants among individuals with moderately (130-189 mg/dL) and severely (≥190 mg/dL) elevated LDL-C and to quantify excess CHD deaths attributable to FH variants in US adults.</p><h3>Design, Setting, and Participants</h3><p>A total of 21 426 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.</p><h3>Exposures</h3><p>LDL-C, cumulative past LDL-C, FH variant status.</p><h3>Main Outcomes and Measures</h3><p>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.</p><h3>Results</h3><p>Of the 21 426 individuals without preexisting CHD (mean [SD] age 52.1 [15.5] years; 12 041 [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 417 000 carry an FH variant and were projected to experience more than 12 000 excess CHD deaths in those with moderately elevated LDL-C and 15 000 in those with severely elevated LDL-C compared with individuals without an FH variant.</p><h3>Conclusions and Relevance</h3><p>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.</p>
Url: https://jamanetwork.com/journals/jamacardiology/fullarticle/2814372
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Authors: Zhang, Yiyi; Dron, Jacqueline S; Bellows, Brandon K; Khera, Amit V; Liu, Junxiu; Balte, Pallavi P; Oelsner, Elizabeth C; Sami, ;; Amr, Samir; Lebo, Matthew S; Nagy, Anna; Peloso, Gina M; Natarajan, Pradeep; Rotter, Jerome I; Willer, Cristen; Boerwinkle, Eric; Ballantyne, Christie M; Lutsey, Pamela L; Fornage, Myriam; Donald, ;; Lloyd-Jones, M; Lifang Hou, Scm ;; Psaty, Bruce M; Bis, Joshua C; Floyd, James S; Ramachandran, ;; Vasan, S; Heard-Costa, Nancy L; Carson, April P; Hall, Michael E; Rich, Stephen S; Guo, Xiuqing; Dhruv, ;; Kazi, S; De Ferranti, Sarah D; Moran, Andrew E
Periodical (Full): JAMA Cardiology
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