Subpopulations of high density lipoproteins in homozygous and heterozygous Tangier disease

Tangier disease (TD) is characterized by severe high-density lipoproteins (HDL) deficiency, hypercatabolism of HDL constituents, impaired cellular cholesterol efflux. and mutations in the gent of ATP-binding cassette 1 (ABC-1). In the present determined plasma lipid and apolipoprotein levels. and HDL subpopulations, in 110 subjects from a large TD kindred in which the proband was homozygous for an A -->C missense mutation at nucleotide 5338 of the ABC-1 transcript. In the proband HDL-C, apoA-I, and apoA-II concentrations were 2, 1, and 2 mg/dl. respectively. apoA-I was present only in pre beta (1), while apoA-II was found free of apoA-I in two distinct alpha mobility subpopulations with different sizes. The smaller size particles contained only apoA-II while the larger one contained apoA-II and apo(a). Relative to unaffected male relatives (n = 30), male heterozygotes (n = 21) had significant reductions (P < 0.001) in plasma HDL-C (- 45%,), apoA-I (- 34%). apoA-II (- 59%), apoA-IV (- 40%), Lp(a) (- 62%), and apoB (- 55%) concentrations. and a significant increase (P < 0.05. + 33%,) in plasma apoC-III levels. Female heterozygotes (n = 11) similarly had significant reductions (P < 0.001) in the concentrations of plasma HDL-C (- 42%,), apoA-I (- 27%), apoA-II (- 52%), Lp(a) (- 27%), and (P < 0.01) apoA-IV (- 28%), apoB (- 13%). and a significant increase (P < 0.05) in plasma apoE levels ( + 29%) as compared to unaffected female relatives (n = 41). Large size HDL subpopulations, especially the two LpA-I particles: (1) and pre alpha (1) were dramatically reduced in both male and female heterozygotes relative to their unaffected family members. Since apoA-II decreased more than apoA-I in both male and female heterozygotes, the ratios of apoA-I/apoA-II were significantly (P < 0.01) increased. The prevalence of CHD was 60%, higher in the 32 heterozygotes than in the 71 unaffected relatives even though the latter group was on average 7 years older. We conclude that TD homozygotes have only pre(1) apoA-I-containing HDL subpopulations. while heterozygotes have HDL that is selectively depleted in the large alpha (1), pre alpha (1), and alpha (2), prec alpha (2) subpopulations, resulting in HDL particles that are small in size, poor in cholesterol, but relatively enriched in apoA-I compared to those of their unaffected relatives. These abnormalities appear to result in a higher risk of CHD in heterozygotes than in unaffected controls. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.