Management and Consequences of Genotype-Positive Familial Hypercholesterolemia

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.