Inherited disorders of HDL metabolism and atherosclerosis.
OBJECTIVE
Genetic disorders of HDL metabolism are rare and, as a result, the assessment of atherosclerosis risk in individuals suffering from these disorders has been difficult. Ultrasound imaging of carotid arteries has provided a tool to assess the risk in hereditary hypo and hyperalphalipoproteinemia. This review gives a comprehensive summary.


RESULTS
Epidemiological studies have unequivocally shown that HDL cholesterol levels are inversely related to coronary artery disease risk, but the literature concerning genetic disorders of HDL metabolism provides less convincing information. Fortuitously, we were able to directly compare carotid intima media thickness data of substantial numbers of individuals with mutations in either apolipoprotein A-I (apoA-I), ATP binding cassette AI (ABCA1), lecithin: cholesterol acyltransferase (LCAT) or cholesteryl ester transfer protein. These data show that carriers of an apoA-I mutation exhibit the most pronounced accelerated atherosclerosis compared with those carrying mutations in ABCA1 and LCAT. Heterozygosity for a non-sense mutation in cholesteryl ester transfer protein did, by contrast, not distinguish carriers from controls in terms of intima media thickness progression. We will discuss these results in the context of the current literature.


CONCLUSIONS
Intima media thickness studies have provided evidence that hypoalphalipoproteinemia due to mutations in apoA-I, ABCA1, and LCAT is associated with increased progression of atherosclerosis. In contrast, hyperalphalipoproteinemia as a result of loss of cholesteryl ester transfer protein function is associated with unaltered atherosclerosis progression compared with family controls. This insight is of interest, since it can assist in the prioritizing of antiatherogenic therapy by increasing HDL cholesterol levels.
Hovingh
G Kees
GK
Department of Vascular Medicine, Academic Medical Center, AZ Amsterdam, The Netherlands.
de Groot
Eric
E
van der Steeg
Wim
W
Boekholdt
S Matthijs
SM
Hutten
Barbara A
BA
Kuivenhoven
Jan Albert
JA
Kastelein
John J P
JJ
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000328:Adult; D000368:Aged; D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics; D002339:Carotid Arteries / Q000000981:diagnostic imaging; D002352:Carrier Proteins / Q000235:genetics; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL / Q000097:blood* / Q000235:genetics; D003324:Coronary Artery Disease / Q000453:epidemiology / Q000209:etiology / Q000235:genetics*; D005260:Female; D006023:Glycoproteins / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000235:genetics; D013631:Tangier Disease / Q000150:complications / Q000000981:diagnostic imaging / Q000235:genetics*; D017539:Tunica Intima / Q000473:pathology; D014463:Ultrasonography
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; C506642:CETP protein, human; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D006023:Glycoproteins; D007862:Phosphatidylcholine-Sterol O-Acyltransferase