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ABSTRACT

  • Lipoprotein-a (Lp-a) is a complex particle in human plasma. It combines elements of the lipid transport and the blood-clotting system in its structure. It is assembled from one LDL which carries all the lipid, and one glycoprotein called apolipoprotein-a (apo-a). Apo(a) has a high degree of homology to plasminogen (PLG) and a high degree of internal repeat structure due to the presence of multiple repeats of plasminogen-like kringle IV modules. In the Lp(a) particle, LDL and apo(a) are linked by a single disulfide bridge between apo B-100 from LDL and one of the repeated kringle IV structures (K IV-9).

  • Plasma apo(a) is secreted exclusively by the liver. Assembly of Lp(a) from LDL and apo(a) occurs in plasma or at the hepatocyte plasma membrane surface. Plasma Lp(a) concentrations are primarily determined by the rate of synthesis rather than by catabolism. The mechanism and sites of Lp(a) catabolism are unknown. The LDL-receptor (LDLR) pathway seems to play only a minor role, if any, but members of the LDLR gene family (including megalin/GP 330) have been implicated in Lp(a)/apo(a) degradation, and some data indicate that the kidney may be involved in Lp(a)/apo(a) catabolism. Apo(a) fragments have been demonstrated in plasma and urine, but their significance is unclear.

  • Lp(a) is a quantitative genetic trait. The distribution of Lp(a) concentrations in most populations is highly positively skewed and very broad varying over one thousandfold (from less than 0.2 to more than 200 mg/dl) among subjects. There exist striking but unexplained differences in the concentration and distribution of Lp(a) concentrations across populations. African populations have severalfold-higher average Lp(a) levels than do Caucasian and most Asian populations.

  • The human apo(a) gene is closely linked to the gene for plasminogen on chromosome 6q27 from which it evolved during primate evolution by duplication, deletion, gene conversion, and mutation. Most striking is the enormous expansion of the plasminogen-like kringle IV modules in the gene. Ten types of kringle IV repeats (K IV-1 to K IV-10), which vary in sequence, exist in apo(a), one of which (K IV-2) occurs in variable number (K IV-2 VNTR). Apo(a)/Lp(a) evolved twice independently during vertebrate evolution. An apo(a) gene that has evolved from a PLG K III and contains a variable number of K III repeats is present in the hedgehog. Insectivore apo(a) also forms a disulfide-linked complex with LDL.

  • The number of K IV-2 repeats in apo(a) may vary from 2 to >40, resulting in a genetic size polymorphism of the apo(a) DNA, mRNA, and protein. Determination of the numbers, frequencies, sequence variations, and effects of apo(a) alleles on Lp(a) levels has resulted into some insights into the genetic architecture of the Lp(a) trait, which differs between Africans and Caucasians. Sib-pair linkage and family analyses demonstrated that from 70 percent to >90 percent of the within-population variance in Lp(a) levels is explained by variation at the apo(a) gene locus, but that transacting factors may exist in Africans. The apo(a) effect has been dissected into two components, ...

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