Subpopulations of high density lipoproteins in homozygous and heterozygousTangier disease

Tangier disease (TD) is characterized by severe high-density lipoproteins ( HDL) deficiency, hypercatabolism of HDL constituents, impaired cellular cho lesterol efflux. and mutations in the gent of ATP-binding cassette 1 (ABC-1 ). In the present determined plasma lipid and apolipoprotein levels. and HD L subpopulations, in 110 subjects from a large TD kindred in which the prob and was homozygous for an A -->C missense mutation at nucleotide 5338 of th e ABC-1 transcript. In the proband HDL-C, apoA-I, and apoA-II concentration s 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 signif icant reductions (P < 0.001) in plasma HDL-C (- 45%,), apoA-I (- 34%). apoA -II (- 59%), apoA-IV (- 40%), Lp(a) (- 62%), and apoB (- 55%) concentration s. 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-I I (- 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 compar ed to unaffected female relatives (n = 41). Large size HDL subpopulations, especially the two LpA-I particles: <alpha>(1) and pre alpha (1) were drama tically reduced in both male and female heterozygotes relative to their una ffected family members. Since apoA-II decreased more than apoA-I in both ma le and female heterozygotes, the ratios of apoA-I/apoA-II were significantl y (P < 0.01) increased. The prevalence of CHD was 60%, higher in the 32 het erozygotes than in the 71 unaffected relatives even though the latter group was on average 7 years older. We conclude that TD homozygotes have only pr e<beta>(1) apoA-I-containing HDL subpopulations. while heterozygotes have H DL that is selectively depleted in the large alpha (1), pre alpha (1), and alpha (2), prec alpha (2) subpopulations, resulting in HDL particles that a re small in size, poor in cholesterol, but relatively enriched in apoA-I co mpared to those of their unaffected relatives. These abnormalities appear t o result in a higher risk of CHD in heterozygotes than in unaffected contro ls. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.