Cellular cholesterol efflux in heterozygotes for Tangier disease is markedly reduced and correlates with high density lipoprotein cholesterol concentration and particle size

Tangier disease (TD), caused by mutations in the ATP-binding cassette 1 (AB C-1) gene, is a rare genetic disorder characterized by severe deficiency of high density lipoproteins (HDL) in the plasma, hypercatabolism of HDL, and defective apolipoprotein (apo)-mediated cellular cholesterol efflux. In th e present study, we assessed plasma lipid concentrations, HDL particle size and subspecies, and cellular cholesterol efflux in 9 TD heterozygotes from a kindred in which the proband was homozygous for an A-->C missense mutati on at nucleotide 5338 of the ABC-1 transcript. Relative to age- and gender- matched controls from the Framing-ham Offspring Study (FOS), TD heterozygot es had significant reductions (P < 0.000) in HDL-C (-54% female; -40% male) and apoA-I (-33% female; -37% male) concentrations, as well as significant ly less cholesterol (-68% female; -58% male) distributed in the largest HDL subclasses, H5 and H4. Consequently, HDL particle size (mm) was significan tly smaller (P < 0.000) in TD heterozygotes (8.6 +/- 0.6 female; 8.7 +/- 0. 1 male) relative to FOS controls (9.4 +/- 0.4 female; 9.0 +/- 0.3 male). Fu rther studies demonstrated that apoA-I-mediated cellular cholesterol efflux in TD heterozygotes was essentially half that of controls (11 +/- 2 vs. 20 +/- 3% of total [H-3]cholesterol, P < 0.001), with strong correlations obs erved between cholesterol efflux and both HDL- C level (r = 0.600) and part icle size (r = 0.680). In summary, our data demonstrate that apolipoprotein -mediated cholesterol efflux is aberrant in TD heterozygotes, as it is in h omozygotes. This finding, along with the associations observed between HDL- C concentration, HDL particle size, and cholesterol efflux, supports the co ncept that plasma HDL-C levels are regulated, in part, by cholesterol efflu x, which in turn influences HDL particle size and, ultimately, HDL apoA-I c atabolism.