Polymorphic forms of human apolipoprotein[a]: inheritance and relationship of their molecular weights to plasma levels of lipoprotein[a].

Abtmt The plasma concentration of human lipoprotein[a], Lp[a], is highly correlated with coronary artery disease. The protein moiety of Lp[a], apoLp[a], consists of two apoproteins, apo[a] and apoB-100, lied by one or more disulfide bonds(s). Apo[a], the protein unique to Lp[a], exists in polymorphic forms that exhibit different apparent molecular weights (M,). Polyacrylamide gel electrophoresis in sodium dodecyl sulfate followed by immunoblotting was used to separate and visualize these different forms and to determine the polymorphic pattern of apo[a] in the plasma samples of 692 individuals. A total of 11 different polymorph bands ranging in M, from 419 kD to 838 kD could be resolved, but only 1 or 2 bands were present per individual. The polymorphic band pattem for an individual was assigned to 1 of the 66 different phenotype designations representing the total number of possible singleand double-band combinations of the 11 detectable bands. All 11 of the possible single-band phenotypes but only 32 of the 55 possible double-band phenotypes were represented. There were 412 plasma samples (59.5%) that contained a single band, 274 (39.6%) contained two bands, and only 6 (0.9%) had no detectable apo[a] band. A highly signrfcant inverse correlation was found between the M, of the band(s) present and the plasma apoLp[a] concentration (r = - 0.461; e = 0.0001). The correlation was better between apoLp[a] and single-band (r = -0.495; e = 0.0001) than double-band (r = - 0.382; = 0.0001) phenotypes. Of the 274 individuals exhibiting double-band phenotypes, the lower M, band was more intense in 141 (51.4%), the two bands were equally intense in 85 (31.0%), while the higher M, band was more intense in 48 (17.5%). Based upon the hypothesis that apo[a] polymorphism is controlled by different alleles at a single locus, the frequency of the 11 alleles determined from the observe phenotypes (low M,+high M,) was: band 1) 419 kD, 0.00875; band 2) 489 kD, 0.00510; band 3) 536 kD, 0.0555; band 4) 553 kD, 0.0758; band 5) 613 kD, 0.135; band 6) 680 kD, 0.0824; band 7) 705 kD, 0.104; band 8) 742 kD, 0.151; band 9) 760 kD, 0.246; band 10) 796 kD, 0.128; band 11) 838 kD, 0.00802. The observed distribution of phenotypes in the population was compared by chi-square analysis to that predicted on the basis of simple Mendelian inheritance, and the hypothesis was rejected (x2 = 921.7; e <0.001). Significantly, the singleband phenotypes are over-represented in the population compand to that predicted.wThe study of a single family pedigree demonstrated high heritability of apo[a] polymorph size, but several deviations from a simple Mendelian pattem of inheritance were obsed. These results suggest that the apparent sizes of apo[a] polymorphs in the plasma compartment are not completely determined by the gene