Lp(a) glycoprotein phenotypes. Inheritance and relation to Lp(a)-lipoprotein concentrations in plasma.

Abstract

The Lp(a) lipoprotein represents a quantitative genetic trait. It contains two different polypeptide chains, the Lp(a) glycoprotein and apo B-100. We have demonstrated the Lp(a) glycoprotein directly in human sera by sodium dodecyl sulfate-gel electrophoresis under reducing conditions after immunoblotting using anti-Lp(a) serum and have observed inter-and intraindividual size heterogeneity of the glycoprotein with apparent molecular weights ranging from 400,000-700,000 D. According to their relative mobilities compared with apo B-100 Lp(a) patterns were categorized into phenotypes F (faster than apo B-100), B (similar to apo B-100), Si, S2, S3, and S4 (all slower than apo B-100), and into the respective double-band phenotypes. Results from neuraminidase treatment of isolated Lp(a) glycoprotein indicate that the phenotypic differences do not reside in the sialic acid moiety of the glycoprotein. Family studies are compatible with the concept that Lp(a) glycoprotein phenotypes are controlled by a series of autosomal alleles (LplaIF, LplajB, Lplar', Lplar2, Lplae, Lpla'4, and Lplar) at a single locus. Comparison of Lp(a) plasma concentrations in different phenotypes revealed a highly significant association of phenotype with concentration.Phenotypes B, Si, and S2 are associated with high and phenotypes S3 and S4 with low Lp(a) concentrations. This suggests that the same gene locus is involved in determining Lp(a) glycoprotein phenotypes and' Lpa) lipoprotein concentrations in plasma and is the first indication for structural differences underlying the quantitative genetic Lp(a)-trait.

Association of elevated lipoprotein(a) levels and coronary heart disease in NIDDM patients. Relationship with apolipoprotein(a) phenotypes

“…Compared to acrylamide gels, the agarose-gel system can detect a larger number of apo(a) isoforms [23]. It was necessary therefore to develop a nomenclature distinct from that of Utermann [6], as the latter discriminates be- tween only six different isoforms. We attributed an arbitrary molecular mass to the four isoforms present in our standard (F, $1, $2 and $3).…”

“…The first group comprised all subjects who displayed a phenotype with at least one small isoform, i.e. ___ 700 kDa, a size which corresponds approximately to the $2 isoform in Utermann's classification; such isoforms are generally associated with high Lp(a) levels in a normal population [6]. The second group included all subjects who exhibited one or two apo(a) isoforms larger than 700 kDa, together with those displaying the null phenotype.…”

“…Apo(a) shows a strong sequence homology with plasminogen [4] and exhibits a genetic size polymorphism which arises from variation in the number of repetitive structures, termed "kringles" [5]. Indeed, the size of apo(a) isoforms is inversely related to plasma concentrations of Lp(a) [6]. Furthermore, the apo(a) phenotype determines at least 40 % of the inter-individual variation in plasma Lp(a) level [7].…”

Factors contributing to variation in lipoprotein (a) in Melbourne Anglo-Celtic population

“…A plasma Lp(a) level of 300 mg=l is the generally accepted threshold for increased risk of atherosclerosis, despite the lack of internationally accepted standards or reference methods. Apo(a) phenotypes were assessed by SDS polyacrylamide gel electrophoresis, using a modification of the method of Huang et al, (1991), based on the original procedure of Utermann et al (1987). After electrophoresis the proteins were transferred by electroblotting to a nitrocellulose membrane.…”

Convergent evolution in primates and an insectivore

“…A most unusual feature of apo(a) is its extremely different levels in humans, varying almost a thousand fold among individuals (between less than 0.1 mg/dl to more than 100 mg/dl). This remarkable concentration polymorphism is mostly associated with the apo(a) locus [1; 2] and is dependent on both the polymorphic structure of apo(a) [3] and on regulatory elements controlling this gene [4; 5].…”