Key result
Heterozygosity for the apoA-IHelsinki mutation was associated with a 36% lower mean serum HDL cholesterol concentration (26.7 mg/dL) compared to unaffected family members (P<0.05).
Why the study?
A Finnish kindred with premature coronary heart disease and decreased HDL cholesterol was identified with an apoA-I variant causing altered HDL composition and levels.
Does the apoA-I (Lys107-->0) mutation reduce HDL cholesterol and alter lipoprotein composition in affected individuals?
Observational
Does the apoA-I (Lys107-->0) mutation reduce HDL cholesterol and alter lipoprotein composition in affected individuals?
The apoA-IHelsinki mutation (Lys107-->0) is associated with decreased HDL cholesterol levels due to reduced LpA-I:A-II particles and smaller HDL particle size.
ApoA-I Lys107 deletion variant associated with low HDL and premature CHD in one kindred; hypothesis-generating for its role in cardiovascular risk.
A Finnish kindred with premature coronary heart disease and decreased HDL cholesterol levels was identified as having an apoA-I variant, apoA-I (Lys107-->0), caused by a 3-bp deletion of nucleotides 1396 through 1398 in exon 4 of the apoA-I gene. These subjects (n = 10) were heterozygous for this mutation. The mean serum HDL cholesterol concentration (26.7 +/- 9.7 mg/dL) of affected family members was 36%, lower than that of unaffected family members (P < .05). Mean serum apoA-I and apoA-II concentrations in heterozygotes were reduced by 18% and 22%, respectively, compared with normal family members (P < .05). In heterozygotes the mean concentration of lipoprotein containing both apoA-I and apoA-II (LpA-I:A-II) was 31% lower than in those with normal apoA-I (P < .001), while the mean level of lipoproteins containing apoA-I without apoA-II was similar in the two groups. HDL density-gradient ultracentrifugation showed a lack of HDL2 and small dense HDL3 in heterozygotes compared with unaffected family members. The HDL particle size distribution, as analyzed by nondenaturing gradient gel electrophoresis of heterozygotes, revealed one major peak at 8.0 to 9.7 nm, a minor peak at 7.8 to 8.5 nm, and an absence of HDL2b and HDL2a peaks. These latter peaks were observed in unaffected family members. Serum levels of LDL cholesterol, triglycerides, VLDL, IDL, and LDL subclasses were similar in the two groups. However, in heterozygotes the cholesterol-to-triglyceride ratios in VLDL2, LDL1, LDL3, HDL2b, HDL2a, and HDL3a were 8% to 54% lower than in unaffected family members (P < .05). Cholesteryl ester transfer protein activity in heterozygotes was reduced by 25% compared with unaffected family members (P < .05), while the plasma lecithin:cholesterol acyltransferase (LCAT) activity did not differ between heterozygotes and unaffected family members. The ability of isolated variant apoA-I to serve as a cofactor for LCAT in vitro did not differ from that of normal apoA-I. Our data are consistent with the concept that a low HDL cholesterol level in subjects heterozygous for the apoA-IHelsinki mutation (Lys107-->0) having normal LCAT activity is a consequence of decreased concentration of LpA-I:A-II particles and of a smaller size and reduced cholesterol content of HDL particles.
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Tilly-Kiesi et al. (1995) conducted an observational in Premature coronary heart disease and decreased HDL cholesterol. apoA-IHelsinki mutation (Lys107->0) vs. Unaffected family members was evaluated on Mean serum HDL cholesterol concentration (36% lower, p=<.05). Heterozygosity for the apoA-IHelsinki mutation was associated with a 36% lower mean serum HDL cholesterol concentration (26.7 mg/dL) compared to unaffected family members (P<0.05).
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