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Management and Consequences of Genotype-Positive Familial Hypercholesterolemia
Catherine Spinks1,2,3,4, Margaret Sunitha Selvaraj2,3,5, Christopher Robinson6
1Division of Cardiology, Massachusetts General Hospital, Boston, Massachusetts.
Insights
Familial hypercholesterolemia (FH) affects 0.35% of US adults, increasing atherosclerotic cardiovascular disease (ASCVD) risk. Many with FH do not meet lipid targets, highlighting a need for improved management.
Area of Science:
- Genetics
- Cardiology
- Public Health
Background:
- Familial hypercholesterolemia (FH) is a prevalent genetic disorder causing elevated cholesterol and premature atherosclerotic cardiovascular disease (ASCVD).
- Understanding the prevalence, management, and outcomes of genetically confirmed FH in the US is crucial but limited.
Purpose of the Study:
- To determine the prevalence of genotype-positive FH within a national US cohort.
- To describe the demographic characteristics, ASCVD consequences, and lipid-lowering management strategies in individuals with FH.
Main Methods:
- Analysis of whole-genome sequencing and phenotypic data from the All of Us (AoU) cohort study (n=245,388).
- Identification of FH variants in LDLR, APOB, and PCSK9 genes.
- Assessment of ASCVD events, lipid levels, and lipid-lowering therapy (LLT) use.
Main Results:
- Genotype-positive FH was identified in 0.35% of participants (1 in 287).
- Individuals with FH had significantly higher rates of coronary artery disease, peripheral artery disease, and stroke compared to noncarriers.
- Only 30.1% of FH participants achieved LDL-C <100 mg/dL, and 19.3% met secondary prevention targets (<70 mg/dL).
Conclusions:
- The prevalence of genotype-positive FH in the US All of Us cohort is 0.35%, with variations by state.
- A significant proportion of individuals with FH experience increased ASCVD risk and suboptimal LDL-C management.
- Findings underscore the need for enhanced screening, diagnosis, and treatment strategies for FH to mitigate cardiovascular risk.
Importance:
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.
Objective:
To identify genotype-positive FH in a national US cohort and describe its prevalence, consequences, and lipid-lowering management.
Design, Setting, And Participants:
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.
Exposure:
FH variants (pathogenic or likely pathogenic) in LDLR, APOB, and PCSK9 genes were manually classified with standard criteria.
Main Outcomes And Measures:
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.
Results:
A total of 245 388 participants were included, with mean (SD) age of 56.5 (16.9) years and 145 563 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 (P < .001). Of the total participants with ASCVD and LLT prescription, significantly fewer individuals with FH met the secondary prevention LDL-C target (<70 mg/dL; 19.33% vs 43.12%; P < .001) compared to noncarriers.
Conclusions And Relevance:
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.
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