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, the K IV-2 repeat variation at the apo(a) locus, which is inversely correlated with Lp(a) levels and explains from 30 to 70 percent of the variability in Lp(a) levels depending on the population, and sequence variation in regulatory and coding sequences. Among these are a +93 C/T polymorphism that introduces an alternative ATG start codon, a 5' pentanucleotide repeat polymorphism (5'-PNRP) and a splice mutation resulting in a null allele. Mutations in the genes for the LDLR and apo B that cause familial hypercholesterolemia (MIM 143890) or defective apo B (MIM 107730), respectively, may also affect Lp(a) levels.
Numerous epidemiologic studies have shown that high Lp(a) in plasma is a primary genetic risk factor for coronary heart disease (CHD), stroke, and peripheral vascular disease, but the suggested mechanisms are largely speculative. Most in vitro functions attributable to Lp(a) have also been suggested as an explanation for the pathophysiological properties of Lp(a), and may be responsible for the fatal consequences of excessive Lp(a) levels in human subjects. One is the modulation of the balance between clotting and fibrinolysis at the endothelial cell layer of the blood vessel wall, which results in a prothrombic state. The in vitro studies also suggest that a forming fibrin thrombus at a damaged vessel wall has the capacity to bind Lp(a), and an apo(a)/Lp(a) binding site in fibrinogen has been defined. High homocysteine concentrations enhance fibrin binding of Lp(a) and might accelerate thrombus formation. Deposition of apo(a)/apo B complexes in atherosclerotic plaques and coronary vein grafts has been demonstrated. Apo(a)/Lp(a) also induce cellular responses of endothelial cells and smooth muscle cells which are proatherogenic and the identification of ligands for apo(a)/Lp(a) (e.g. 2-glycoprotein I, fibronectin) may result in new insights into the (patho-)physiological functions of Lp(a). Studies in mice that are transgenic for human apo(a), or double transgenics for the human apo(a) and apo B-100 genes, have generated contradictory results.
Lp(a) concentrations may be affected by disease (e.g., end-stage renal disease) and some rare genetic conditions (e.g., familial hypercholesterolemia, MIM 143890) but are only moderately influenced by diet, exercise, or other environmental factors. Most lipid-lowering drugs have no effect on Lp(a) concentration, the only exception being nicotinic acid. Therapeutic plasmapheresis or LDL-/Lp(a)-apheresis may be used in the treatment of severe dyslipidemia with high Lp(a).