Genetic and secondary causes of severe HDL deficiency and cardiovascular disease

Area of Science:

• Genetics
• Cardiology
• Biochemistry

Background:

• Severe high-density lipoprotein (HDL) deficiency is a rare condition.
• Understanding its genetic and secondary causes is crucial for managing associated cardiovascular risks.

Purpose of the Study:

• To investigate the secondary and genetic underpinnings of severe HDL deficiency.
• To determine the prevalence of mutations in key lipid-related genes and their association with atherosclerotic cardiovascular disease (ASCVD).

Main Methods:

• A large cohort of 258,252 subjects was screened for severe HDL deficiency (HDL cholesterol <20 mg/dl).
• Subjects with secondary causes or specific conditions were excluded.
• Eligible subjects underwent sequencing of 23 lipid-related genes, including ABCA1, LCAT, APOA1, and LPL.
• Prevalence of ASCVD was compared across genetic mutation groups and a mutation-negative cohort.

Main Results:

• Severe HDL deficiency was identified in 0.33% of men and 0.099% of women.
• Secondary causes accounted for 40.1% of cases.
• Mutations or variants in ABCA1, LCAT, APOA1, or LPL were found in 48.8% of sequenced subjects.
• The highest ASCVD prevalence rates were observed in subjects with ABCA1 (37.0%) and APOA1 (40.0%) mutations.

Conclusions:

• Severe HDL deficiency is uncommon, with a significant proportion attributable to secondary causes.
• Genetic variations in ABCA1, LCAT, APOA1, and LPL play a role in HDL deficiency.
• ABCA1 and APOA1 mutations are strongly associated with increased ASCVD risk in individuals with severe HDL deficiency.