Genetics
The ApoA-IHelsinki mutation lowers HDL cholesterol and cuts CETP activity by 25% in a Finnish kindred (ATVB 1995)
Original title: ApoA-IHelsinki (Lys107-->0) associated with reduced HDL cholesterol and LpA-I:A-II deficiency
A Finnish kindred with premature coronary heart disease and low HDL cholesterol was found to carry apoA-IHelsinki (Lys107 to 0), a 3-bp deletion in exon 4 of the apoA-I gene, in 10 heterozygous family members. Affected members had 36% lower mean HDL cholesterol (26.7 plus or minus 9.7 mg/dL, P less than .05), 18% lower apoA-I, and 22% lower apoA-II than unaffected relatives, and 31% lower LpA-I:A-II lipoprotein (P less than .001), with HDL2 and small dense HDL3 absent on density-gradient ultracentrifugation. Cholesteryl ester transfer protein activity in heterozygotes was reduced by 25% compared with unaffected family members (P less than .05), while LCAT activity was unchanged and the variant apoA-I functioned normally as an LCAT cofactor in vitro, indicating the low HDL cholesterol arises from reduced LpA-I:A-II particle formation and smaller, cholesterol-poor HDL particles rather than from altered LCAT or CETP activity driving the deficiency itself.
Original abstract
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.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.