Defective ABCA1 increases coronary risk in familial low high-density lipoprotein (HDL) cholesterol

HDL Forum Editor Professor Kerry-Anne Rye discusses a study investigating the relationship between familial low high-density lipoprotein (HDL) cholesterol, coronary risk and ABCA1, reported by A Soro-Paavonen and co-workers in the Journal of Lipid Research.

Soro-Paavonen A, Naukkarinen J, Lee-Rueckert M et al. Common ABCA1 variants, HDL levels, and cellular cholesterol efflux in subjects with familial low HDL. J Lipid Res 2007 48: 1409-16.

The association of familial low HDL cholesterol with increased coronary risk is a topic of ongoing interest and investigation. There is no doubt that mutations in the gene coding for ATPbinding cassette transporter A1 (ABCA1), a cell membrane transporter that facilitates the delivery of cholesterol from cells to lipid-poor apolipoprotein A-I in the extracellular space, play a key role in the aetiology of low HDL states. However, it is becoming increasingly apparent that other factors may also play important roles.

This study investigates the relationship between low HDL cholesterol levels and the presence of rare alleles in the ABCA1 gene. Researchers at the Helsinki University Central Hospital analysed the efficiency of cholesterol efflux using a model of monocyte-derived macrophages obtained from Finnish subjects with familial low HDL cholesterol and at increased risk for premature coronary heart disease. The researchers studied macrophages from 22 subjects with familial low HDL cholesterol and 21 healthy controls. ABCA1-dependent cholesterol efflux was assessed in a foam cell model that measured cholesterol loading of macrophages isolated from the study participants and unloading of macrophage-derived foam cells by incubation with lipid-free apolipoprotein A-I (apoA-I) as a primary cholesterol acceptor.

At the functional level, individuals with low HDL cholesterol levels were shown to have a small, but statistically significant, reduction in the amount of cholesterol exported from macrophages. While it could be argued that this reduction in cholesterol export is associated with increased coronary risk because it decreases reverse cholesterol transport (the process whereby excess cholesterol is removed from cells and transported to the liver by HDL), macrophages are known to be only minor contributors to this process. Furthermore, as this reduction in cholesterol export was associated with a somewhat counter-intuitive increase in ABCA1 mRNA levels, it becomes difficult to determine precisely how this outcome is likely to effect coronary risk.

Of possibly more interest was the additional observation showing that the subjects in the low HDL cholesterol arm of the study had a greater than expected frequency of three unusual ABCA1 single nucleotide polymorphisms (SNPs), and that these polymorphisms were associated with altered HDL cholesterol levels and reduced cholesterol efflux.