title: Heterozygosity for ABCA1 gene mutations: effects on enzymes, apolipoproteins and lipoprotein particle size.
abstract: A cohort of 13 female and 14 male heterozygotes for ATP binding cassette A1 (ABCA1) gene defects was directly compared with 13 and 14 unaffected female and male family members of almost exact same age. The activities of three proteins that play key roles in HDL metabolism were measured in addition to extensive lipid and (apo) lipoprotein subfraction analysis. Compared to controls, LCAT activity was reduced by 15% in affected subjects (P < 0.001) while PLTP activity was unaffected. Interestingly, CETP activity was elevated by 50% in the heterozygote siblings of one kindred but was unaffected in heterozygotes of the three other families. With respect to lipids, the heterozygotes had normal total cholesterol (TC), and LDL-cholesterol concentrations but presented with a trend towards increased triglyceride levels (13%; P = 0.08). HDL metabolism, by contrast, was severely affected as illustrated by 40% reductions in HDL-cholesterol (P < 0.001) with concomitant reductions in apoAI (25%; P < 0.001) levels and in lipoprotein subfraction LpAI (28%; P < 0.001), LpAI:AII (24%; P=0.014), and LpCIII:nonB (34%; P < 0.001) concentrations. We furthermore observed reduced average HDL particle size (5%; P = 0.004; 16% in female and 3.6% in male) and reduced plasma apoCIII concentration (15%; P = 0.006) while apoAII, apoAIV, apoE and apoB levels were unchanged. In conclusion, heterozygosity for ABCA1 defects was associated with reduced LCAT activity in absence of effects on PLTP activity. Of special interest was our finding that the effects of compromised ABCA1 function on HDL were more pronounced in women than in men.
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. j.a.kuivenhoven@amc.uva.nl
authors.forename: J A
authors.initials: JA
authors.lastname: Kuivenhoven
authors.forename: G K
authors.initials: GK
authors.lastname: Hovingh
authors.forename: A
authors.initials: A
authors.lastname: van Tol
authors.forename: M
authors.initials: M
authors.lastname: Jauhiainen
authors.forename: C
authors.initials: C
authors.lastname: Ehnholm
authors.forename: J C
authors.initials: JC
authors.lastname: Fruchart
authors.forename: E A
authors.initials: EA
authors.lastname: Brinton
authors.forename: J D
authors.initials: JD
authors.lastname: Otvos
authors.forename: A H M
authors.initials: AH
authors.lastname: Smelt
authors.forename: A
authors.initials: A
authors.lastname: Brownlee
authors.forename: A H
authors.initials: AH
authors.lastname: Zwinderman
authors.forename: M R
authors.initials: MR
authors.lastname: Hayden
authors.forename: J J P
authors.initials: JJ
authors.lastname: Kastelein
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000704:Analysis of Variance; D001053:Apolipoproteins / Q000032:analysis / Q000378:metabolism*; D016022:Case-Control Studies; D018389:Codon, Nonsense; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D006579:Heterozygote; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D008074:Lipoproteins / Q000032:analysis / Q000378:metabolism*; D008297:Male; D015999:Multivariate Analysis; D020125:Mutation, Missense; D010316:Particle Size; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000032:analysis / Q000378:metabolism*; D011336:Probability; D012016:Reference Values; D018570:Risk Assessment
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D001053:Apolipoproteins; D018389:Codon, Nonsense; D008074:Lipoproteins; D007862:Phosphatidylcholine-Sterol O-Acyltransferase