APOA-I-HELSINKI(LYS(107)-]0) ASSOCIATED WITH REDUCED HDL CHOLESTEROL AND LPA-I-A-II DEFICIENCY

A Finnish kindred with premature coronary heart disease and decreased HDL cholesterol levels was identified as having an apoA-I variant, apo A-I (Lys(107)-->0), caused by a 3-bp deletion of nucleotides 1396 thro ugh 1398 in exon 4 of the apoA-I gene. These subjects (n = 10) mere he terozygous for this mutation. The mean serum HDL cholesterol concentra tion (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 apo A-II concentrations in heterozygotes were reduced by 18% and 22%, resp ectively, compared with normal family members (P < .05). Zn heterozygo tes the mean concentration of lipoprotein containing both apoA-I and a poA-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 withou t apoA-II was similar in the two groups. HDL density-gradient ultracen trifugation showed a lack of HDL(2) and small dense HDL(3) in heterozy gotes compared with unaffected family members. The HDL particle size d istribution, as analyzed by nondenaturing gradient gel electrophoresis of heterozygotes, revealed one major peak at 8.0 to 9.7 nn, a minor p eak at 7.8 to 8.5 nn, and an absence of HDL(2b) and HDL(2a) peaks. The se latter peaks were observed in unaffected family members. Serum leve ls of LDL cholesterol, triglycerides, VLDL, IDL, and LDL subclasses we re similar in the two groups. However, in heterozygotes the cholestero l-to-triglyceride ratios in VLDL(2), LDL(1), LDL(3) HDL(2b) HDL(2a) an d 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), whi le the plasma lecithin: cholesterol acyltransferase (LCAT) activity di d 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 consiste nt with the concept that a low HDL cholesterol level in subjects heter ozygous for the apoA-(Helsinki) mutation (Lys(107)-->0) having normal LCAT activity is a consequence of decreased concentration of LpA-I:A-I I particles and of a smaller size and reduced cholesterol content of H DL particles.