Familial hypobetalipoproteinemia is not associated with low levels of lipoprotein(a).

To assess whether very low concentrations of LDL affected lipoprotein(a) [Lp(a)] concentrations and apo(a) associations with lipoproteins, we studied Lp(a) levels and associations in heterozygous subjects with familial hypobeta-lipoproteinemia FHBL) associated with several truncated forms of apoB-100, ranging from apoB-31 to apoB-89. Distributions of apo(a) isotypes were assessed by a combined electrophoresis-immunoblotting procedure that detects 34 isoforms. Lp(a) concentrations were quantified by two ELISAs, one detecting total apo(a) and the other apoB-bound apo(a) in plasma. Associations of apo(a) with plasma lipoproteins were evaluated by gel permeation chromatography (FPLC) and DGUC followed by analyses of elution and gradient fractions by apo(a) ELISA. In addition, associations were examined by nondenaturing electrophoresis or immunoprecipitation of whole plasma and examination of contents by immunoblotting. Finally, interactions between r-apo(a) and LDLs were evaluated in reconstitution experiments. The distributions of apo(a) isotypes did not differ between FHBL-affected and unaffected members of the same kindreds, and concentrations of Lp(a) were similar even when subjects were matched for isotypes both within and across kindreds. In subjects heterozygous for apo(a) isoforms, the smaller isoforms were inversely related to Lp(a) concentrations, the larger isoforms were not. The regression lines between Lp(a) concentrations and the smaller apo(a) isoforms were significant and negative in slope for both FHBL-affected and unaffected subjects, but the slopes of the lines did not differ. In multiple regression analyses, only the sizes of the smaller apo(a) isoforms contributed to the prediction of Lp(a) concentrations. ApoB-size made no difference. In simple apoB-100/apoB-truncation heterozygotes, virtually all apo(a) was complexed with apoB-100-containing particles but not apoB-truncation particles, and r-apo(a) recombined with apoB-100-containing LDLs but not with apoB-89-containing LDLs. Thus, (1) low apoB levels do not affect the plasma concentrations of Lp(a), (2) apo(a) binds apoB-100 to form Lp(a) particles of usual sizes and densities, and (3) apoB truncations even as large as apoB-89 do not form covalent bands with apo(a), although noncovalent associations with apoB-89 may be present in plasma.