Common ABCA1 variants, HDL levels, and cellular cholesterol efflux in subjects with familial low HDL

Area of Science:

• Cardiovascular Science
• Molecular Biology
• Genetics

Background:

• High-density lipoprotein (HDL) facilitates cholesterol removal from peripheral cells through apolipoprotein A-I (apoA-I) and ABCA1.
• Familial low HDL cholesterol is associated with an elevated risk of early atherosclerosis.
• The early steps of reverse cholesterol transport (RCT) and their relation to familial low HDL require further investigation.

Purpose of the Study:

• To investigate whether the early stages of RCT are compromised in individuals with familial low HDL.
• To explore the role of ABCA1 gene variants and expression in cholesterol efflux in familial low HDL.

Main Methods:

• Cholesterol efflux capacity was measured in monocyte-derived macrophages from familial low HDL patients and healthy controls.
• ABCA1 and ABCG1 mRNA expression levels were quantified in cholesterol-loaded macrophages.
• Single-nucleotide polymorphism (SNP) haplotypes were used to define ABCA1 alleles.

Main Results:

• Cholesterol efflux to apoA-I was similar between groups, but normalized for ABCA1 mRNA expression, it was significantly lower in the familial low HDL group.
• Macrophages from familial low HDL subjects exhibited increased ABCA1 mRNA levels but not ABCG1 mRNA.
• Familial low HDL patients were more frequently carriers of rare ABCA1 alleles (L158, R219K).

Conclusions:

• Defective ABCA1 function in macrophages may contribute to impaired RCT in familial low HDL.
• This functional defect is a potential factor underlying the increased coronary heart disease risk observed in familial low HDL individuals.
• ABCA1 gene variants and altered mRNA expression play a role in the pathogenesis of familial low HDL.