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. 2024 Mar 1;9(3):263-271.
doi: 10.1001/jamacardio.2023.5366.

Familial Hypercholesterolemia Variant and Cardiovascular Risk in Individuals With Elevated Cholesterol

Yiyi Zhang  1 , Jacqueline S Dron  2   3 , Brandon K Bellows  1 , Amit V Khera  2   4   5 , Junxiu Liu  6 , Pallavi P Balte  1 , Elizabeth C Oelsner  1 , Sami Samir Amr  7   8 , Matthew S Lebo  7   8 , Anna Nagy  8 , Gina M Peloso  9 , Pradeep Natarajan  2   4   10 , Jerome I Rotter  11 , Cristen Willer  12   13   14 , Eric Boerwinkle  15 , Christie M Ballantyne  16 , Pamela L Lutsey  17 , Myriam Fornage  18 , Donald M Lloyd-Jones  19 , Lifang Hou  19 , Bruce M Psaty  20   21   22 , Joshua C Bis  20 , James S Floyd  20   21 , Ramachandran S Vasan  23   24   25 , Nancy L Heard-Costa  26 , April P Carson  27 , Michael E Hall  27 , Stephen S Rich  28 , Xiuqing Guo  11 , Dhruv S Kazi  4   29 , Sarah D de Ferranti  30   31 , Andrew E Moran  1
Affiliations

Familial Hypercholesterolemia Variant and Cardiovascular Risk in Individuals With Elevated Cholesterol

Yiyi Zhang et al. JAMA Cardiol. .

Abstract

Importance: 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.

Objective: 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.

Design, setting, and participants: 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.

Exposures: LDL-C, cumulative past LDL-C, FH variant status.

Main outcomes and measures: 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.

Results: 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.

Conclusions and relevance: 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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Zhang reported grants from the National Heart, Lung, and Blood Institute during the conduct of the study. Dr Khera reported employment and equity at Verve Therapeutics and personal fees from Novartis, Silence Therapeutics, Amgen, Color Health, and Veritas International during the conduct of the study as well as personal fees from Third Rock Ventures and Foresite Labs outside the submitted work. Dr Balte reported grants from the National Institutes of Health during the conduct of the study. Dr Peloso reported grants from the National Heart, Lung, and Blood Institute during the conduct of the study. Dr Natarajan reported grants from Allelica, Apple, Amgen, Boston Scientific, Genentech/Roche, and Novartis; personal fees from Allelica, Apple, AstraZeneca, Blackstone Life Sciences, Creative Education Concepts, CRISPR Therapeutics, Eli Lilly, Foresite Labs, Genentech/Roch, GV Pharma, HeartFlow, Magnet Biomedicine, Novartis, Esperion Therapeutics, and TenSixteen Bio; equity from MyOme, Preciseli, and TenSixteen Bio; and other from Vertex Pharmaceuticals (spousal employment) outside the submitted work. Dr Rotter reported grants from the National Institutes of Health during the conduct of the study. Dr Willer reported employment and stock holdings at Regeneron Pharmaceuticals during the conduct of the study. Dr Boerwinkle reported grants from the National Institutes of Health Atherosclerosis Risk in Communities study during the conduct of the study. Dr Ballantyne reported grant support through his institution from Abbott, Akcea, Amgen, Arrowhead, Esperion, Ionis, Merck, New Amsterdam, Novartis, Novo Nordisk, Regeneron, and Roche and consultant fees from Abbott, Alnylam Pharmaceuticals, Althera, Amarin, Amgen, Arrowhead, AstraZeneca, Denka Seiken, Esperion, Genentech, Gilead, Illumina, Ionis, Matinas BioPharma, Merck, New Amsterdam, Novartis, Novo Nordisk, Pfizer, Regeneron, Roche, and TenSixteen Bio. Dr Lutsey reported grants from the National Institutes of Health to her institution during the conduct of the study. Dr Lloyd-Jones reported grants from the National Institutes of Health during the conduct of the study. Dr Psaty reported grants from the National Institutes of Health during the conduct of the study and serving on the steering committee of the Yale Open Data Access Project funded by Johnson & Johnson. Dr Ramachandran reported grants from the National Institutes of Health during the conduct of the study. Dr Carson reported grants from the National Heart, Lung, and Blood Institute and grants from the National Institute on Minority Health and Health Disparities during the conduct of the study and grants from Amgen outside the submitted work. Dr Kazi reported grants from the National Heart, Lung, and Blood Institute during the conduct of the study. Dr de Ferranti reported grants from the National Institutes of Health during the conduct of the study and personal fees from UpToDate outside the submitted work. Dr Moran reported grants from the National Heart, Lung, and Blood Institute during the conduct of the study. No other disclosures were reported.

Figures

Figure.
Figure.. Low-Density Lipoprotein Cholesterol (LDL-C) Among Individuals With vs Without the Familial Hypercholesterolemia Variant
Individuals with the familial hypercholesterolemia variant were matched 1:5 to those without on age (within 3 years), sex, race, ethnicity, detreated LDL-C levels (within 5 mg/dL), and lipid-lowering medication use at the time of their last LDL-C measurement during age 50 to 60 years. We fitted a linear mixed-effects model of the repeated detreated LDL-C measures against age and familial hypercholesterolemia variant status, with age modeled as restricted cubic splines with random intercept and slope.
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