Linkage of plasminogen (PLG) and apolipoprotein(a) (LPA) in baboons.

Four allelic forms of serum plasminogen (PLG) were detected in baboons (Papio hamadryas Linneaus 1758) by isoelectric focusing and were determined to be inherited as autosomal codominant traits. Linkage analysis of data from 179 progeny and their parents revealed that PLG is tightly linked (lod score = 30.20) to the gene encoding apolipoprotein(a) (LPA), as in humans. No recombinant individuals were identified. This is the first linkage detected between PLG and LPA in any species other than humans and is the first genetic linkage identified in a nonhuman primate species by family studies.     

Lp(a) lipoprotein level and longevity.

Lp(a) lipoprotein forms a distinct class of serum lipoproteins. Its unique immunochemical properties are caused by the Lp(a) polypeptide chain which is attached to apolipoprotein B (apoB) by a disulfide bridge. The level of Lp(a) lipoprotein is under strict genetic control. It is well established that a high level of Lp(a) lipoprotein is a genetic risk factor for atherosclerotic disease, particularly coronary heart disease (CHD). Since cardiovascular disease is one of the major causes of death there should be a shortage of people with genetic determinants of cardiovascular disease in people who are very old and still have adequate physical and mental capacities. The authors have studied Lp(a) lipoprotein levels in 102 persons who were 83 years or older when blood samples were drawn. This study group was a subpopulation of a series comprising 456 persons who had been 80 years or older at intake in an intervention study of old people living at home. Only those without physical or mental incapacities were included in the present study. There was a striking shortage of persons with an Lp(a) lipoprotein level higher than the 75th percentile of the general population in this series of people who had achieved successful ageing. The highest value observed among the old people corresponds to the 88th percentile of the general population. It is highly unlikely that the present observations reflect chance events or fall in Lp(a) lipoprotein levels in people who had higher levels at a younger age. The most likely explanation of our finding is that a sizeable fraction of people with high Lp(a) lipoprotein levels die before reaching a very high age.(ABSTRACT TRUNCATED AT 250 WORDS)     

Genetics of the quantitative Lp(a) lipoprotein trait

The Lp(a) lipoprotein is a complex particle composed of a low density lipoprotein (LDL)-like lipoprotein and the disulfide bonded Lp(a) glycoprotein. The complex represents a quantitative genetic trait. SDS gel electrophoresis under reducing conditions of sera followed by immunoblotting with affinity-purified polyclonal anti-Lp(a) demonstrated inter- and intra-individual size heterogeneity of the glycoprotein with apparent Mr in the range 400-700kDa. According to their relative mobilities compared to apo B-100 the Lp(a) patterns were categorized into phenotypes F, B, S1, S2, S3 und S4 and into the respective double-band phenotypes. This size heterogeneity seems to be controlled by multiple alleles designated LpF, LpB, LpS1, LpS2, LpS3, LpS4 and a null allele (LpO) at a single locus. Phenotype frequencies observed in 441 unrelated subjects were in good agreement with those expected from the genetic hypothesis. Comparison of Lp(a) lipoprotein concentrations in the different phenotypes revealed a highly significant association of phenotypes B, S1 and S2 with high, and phenotypes S3 und S4 with intermediate Lp(a) concentrations. A third mode is represented by the null phenotype were no Lp(a) band is detected upon immunoblotting and Lp(a) lipoprotein is low or absent. We conclude that the same gene locus is involved in determining Lp(a) glycoprotein phenotype and Lp(a) lipoprotein concentrations in plasma. This major gene seems to be the Lp(a) glycoprotein structural gene locus.     

Genetics of the quantitative Lp(a) lipoprotein trait

Summary Lp(a) glycoprotein exhibits an apparent size polymorphism that is associated with genetically controlled Lp(a) lipoprotein concentrations in plasma (Utermann et al. 1988). We have tested the hypothesis that this polymorphism is genetically controlled by studying 15 matings with a total of 44 offspring. This confirmed our conclusion that Lp(a) types are controlled by a series of codominant alleles Lp^F, Lp^B, Lp^S1, Lp^S2, Lp^S3 and Lp^S4 and by a null allele Lp^o. Together with the data from the accompanying paper this indicates that the structural gene for the Lp(a) protein is the major gene locus determining Lp(a) lipoprotein concentrations in plasma.     

Genetics of the quantitative Lp(a) lipoprotein trait

Summary Apolipoprotein(a) [apo(a)] is a large serum glycoprotein with several genetically determined isoforms differing in their apparent molecular weight. We determined the effects of the apo(a) isoforms on total cholesterol, high-density lipo-protein (HDL)-cholesterol, lipoprotein(a), and triglyceride levels in a sample of 473 unrelated Tyrolean adults. Average lipoprotein(a) and total cholesterol levels were significantly different among apo(a) types. These significant differences were found among the 13 apo(a) isoform patterns observed in this sample and among several logical subsets of the isoform patterns (e.g. considering only the single band types). The data suggest that the effects of apo(a) alleles on Lp(a) levels are additive. The effects of apo(a) on total cholesterol levels cannot be entirely explained by the cholesterol fraction estimated to be contained in the lipoprotein(a) particle. We estimate that the apo(a) glycoprotein polymorphism accounts for 41.9% and 9.6% of the variability in lipoprotein(a) and total cholesterol levels, respectively. This is the strongest effect of a single polymorphic gene on plasma lipid and lipoprotein levels reported so far.     

Radioimmunoassay of human plasma Lp(a) lipoprotein.

A quantitative immunodiffusion assay demonstrated Lp(a) lipoprotein in 91% (911 of 1000) of subjects. In order to quantitate Lp(a) in all plasma, a sensitive and specific double antibody radioimmunoassay was developed. The between-assay coefficient of variation was 8%. Lp(a) levels by radioimmunoassay were highly correlated with those obtained by the less sensitive radial immunodiffusion method (r = 0.98, n = 51). All but one of the 89 Lp(a) "negative" subjects by immunodiffusion had detectable levels of Lp(a) by radioimmunoassay. The one subject without detectable Lp(a) had abetalipoproteinemia (without detectable apolipoprotein B by radioimmunoassay). Furthermore, Lp(a) was detected in all three non-human primates examined: patas monkey, baboon, and pig-tail monkey. Quantitation of Lp(a) levels in 90 male myocardial infarction (MI) survivors and their spouses showed that the distribution of Lp(a) levels of MI survivors was significantly higher above the 50th percentile cut-point (P < 0.02) and exceeded that of the spouses. Furthermore, the Lp(a) distribution at and above the 50th percentile for the MI survivors who had an MI at age <50 (n = 36) was shifted to values higher than those having an MI at age >50. Thus, high levels of Lp(a) may be associated with premature coronary disease. We conclude that Lp(a) is present in all individuals with apolipoprotein B and that apolipoprotein B appears necessary for the plasma transport of the Lp(a) lipoprotein. Consistent with this hypothesis, quantitative immunochemical precipitation of (125)I-Lp(a) indicated that essentially all individual molecules of six purified Lp(a) preparations contain both the Lp(a) antigen and apolipoprotein B.     

Genetic linkage between lipoprotein(a) phenotype and a DNA polymorphism in the plasminogen gene

Coronary heart disease risk correlates directly with plasma concentrations of lipoprotein(a) (Lp(a)), a low-density lipoprotein-like particle distinguished by the presence of the glycoprotein apolipoprotein(a) (apo(a)), which is bound to apolipoprotein B-100 (apoB-100) by disulfide bridges. Size isoforms of apo(a) are inherited as Mendelian codominant traits and are associated with variations in the plasma concentration of lipoprotein(a). Plasminogen and apo(a) show striking protein sequence homology, and their genes both map to chromosome 6q26-27. In a large family with early coronary heart disease and high plasma concentrations of Lp(a), we found tight linkage between apo(a) size isoforms and a DNA polymorphism in the plasminogen gene; plasma concentrations of Lp(a) also appeared to be related to genetic variation at the apo(a) locus. We found free recombination between the same phenotype and alleles of the apoB DNA polymorphism. This suggests that apo(a) size isoforms and plasma lipoprotein(a) concentrations are each determined by genetic variation at the apo(a) locus.     

Studies on the structure of the Lp(a) lipoprotein: Isolation and partial characterization of the Lp(a)-specific antigen

Lp(a), a polymorphic lipoprotein of human serum, has been isolated from strongly positive normal sera. The described procedure utilizes a serum pool of several liters. The purified lipoprotein has been investigated in its intact and totally delipidized form. Protein constituents could be characterized as apolipoprotein-B, apolipoprotein-AIII, and the Lp(a)-specific, dissociable polypeptide. Albumin could only be found in some of the preparations. The Lp(a)-specific polypeptide could be separated and characterized by its amino acid composition.     

Quantitative genetic studies of the human plasma Lp(a) lipoprotein

Lp(a) lipoprotein [Lp(a)] was quantified in 1251 adults, including 300 mother-father-offspring triplets, by a sensitive radial immunodiffusion assay. Lp(a) was not correlated with age, sex, or cholesterol or glyceride concentrations. Significant correlations were found between mother-offspring (r=0.34), father-offspring (r=0.40), and midparent-offspring (r=0.52), whereas no correlation was found between husband-wife pairs (r=0.02). Analysis of triplets separated on the basis of midparent Lp(a) concentrations indicated a resemblance of midparent to offspring regardless of midparent concentration. Bimodality was not detected in any of the offspring distributions. These data are compatible with the hypothesis that the observed quantitative Lp(a) variation is determined by a polygenic model of inheritance. The possibility of major gene effects is not ruled out.     

Protein composition of Lp(a) lipoprotein from human plasma

The apolipoprotein composition of purified human Lp(a) lipoprotein was investigated by SDS--polyacrylamide gel electrophoresis and immunochemically. The lipoprotein contains two different polypeptides. One is identical by its app. Mr of approximately 250 000 and immunologically with apolipoprotein B of LDL (B-100). The other polypeptide has a higher app. Mr (approximately 350 000) and stains strongly with the periodate-Schiff's reagent. This high-Mr glycoprotein contains the specific Lp(a) immunoreactivity but does not react with antibodies against apo B. Apo B and Lp(a)-protein seem to be linked by disulfide bonds in the native lipoprotein. The unreduced detergent delipidized protein moiety from Lp(a) lipoprotein shows a single band of Mr approximately 700 000 in SDS--polyacrylamide gel electrophoresis and the immunoprecipitates formed against anti-Lp(a) and anti-apo B by the unreduced protein show a reaction of immunological identity.     

Linkage between the loci for transferrin and ceruloplasmin in pigs

Summary. Evidence for genetic linkage between the loci for transferrin ( Tf ) and ceruloplasmin ( Cp ) in pigs was presented. The results were based on a study of a single sire family comprising 35 informative offspring. No recombinants were observed. The recombination frequency was estimated to be in the range of 0 to 8%. This indicated that the recombination frequency between Tf and Cp loci in pigs may be much lower than that reported previously between these two loci in cattle and in human.     

Linkage between the loci for transferrin and ceruloplasmin in pigs

Evidence for genetic linkage between the loci for transferrin (Tf) and ceruloplasmin (Cp) in pigs was presented. The results were based on a study of a single sire family comprising 35 informative offspring. No recombinants were observed. The recombination frequency was estimated to be in the range of 0 to 8%. This indicated that the recombination frequency between Tf and Cp loci in pigs may be much lower than that reported previously between these two loci in cattle and in human.     

Linkage between the loci for serum albumin and vitamin D binding protein (GC) in sheep

Evidence for close genetic linkage between the loci for serum albumin (ALB) and vitamin D binding protein (GC) in sheep is presented. No recombinants were found in 28 informative offspring of a single ram family. The recombination frequency between the two loci was estimated to be in the range of 0 to 10%. No sign of linkage was observed between the ALB-GC complex and transferrin.