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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1995;15:1294-1306.)
© 1995 American Heart Association, Inc.

Articles

ApoA-I_Helsinki (Lys₁₀₇0) Associated With Reduced HDL Cholesterol and LpA-I:A-II Deficiency

Marju Tilly-Kiesi; Zhang Qiuping; Sonja Ehnholm; Juhani Kahri; Sanni Lahdenperä; Christian Ehnholm; Marja-Riitta Taskinen

From the Third Department of Medicine (M.T.-K., J.K., S.L., M.-R.T.), University of Helsinki, and the Department of Biochemistry (Z.Q., S.E., C.E.), National Public Health Institute, Helsinki, Finland.

Correspondence to Prof Marja-Riitta Taskinen, MD, Department of Medicine, Helsinki University Central Hospital, Haartmaninkatu 4, FIN-00290 Helsinki, Finland.

Abstract A Finnish kindred with premature coronary heart disease and decreased HDL cholesterol levels was identified as having an apoA-I variant, apoA-I (Lys₁₀₇0), 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 HDL_2b and HDL_2a 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, HDL_2b, HDL_2a, and HDL_3a 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-I_Helsinki mutation (Lys₁₀₇0) 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.

Key Words: apoA-I gene mutation • HDL deficiency • lecithin:cholesterol acyltransferase • CETP • coronary heart disease

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