Genetics and metabolism of lipoprotein(a) and their clinical implications (Part 1)

The human plasma lipoprotein Lp(a) has gained considerable clinical interes t as a genetically determined risk factor for atherosclerotic vascular dise ases. Numerous (including prospective) studies have described a correlation between elevated Lp(a) plasma levels and coronary heart disease, stroke an d peripheral atherosclerosis. Lp(a) consists of a large LDL-like particle to which the specific glycoprot ein apo(a) is covalently linked. The apo(a) gene is located on chromosome 6 and belongs to a gene family including the highly homologous plasminogen. Lp(a) plasma concentrations are controled to a large extent by the extremel y polymorphic apo(a) gene. More than 30 alleles at this locus determine a s ize polymorphism. The size of the apo(a) isoform is inversely correlated wi th Lp(a) plasma concentrations, which are nonnormally distributed in most p opulations. To a minor extent, apo(a) gene-independent effects also influen ce Lp(a) concentrations. These include diet, hormonal status and diseases l ike renal disease and familial hypercholesterolemia. The standardisation of Lp(a) quantification is still an unresolved problem due to the enormous particle heterogeneity of Lp(a) and homologies to other members of the gene family. Stability problems of Lp(a) as well as statist ical pitfalls in studies with small group sizes have created conflicting re sults. The apo(a)/Lp(a) secretion from hepatocytes is regulated at various levels including postranslationally by apo(a) isoform-dependent prolonged retentio n in the endoplasmic reticulum. This mechanism can partly explain the inver se correlation between apo(a) size and plasma concentrations. According to numerous investigations, Lp(a) is assembled extracellularly from separately secreted apo(a) and LDL. The sites and mechanisms of Lp(a) removal from pl asma are only poorly understood. The human kidney seems to represent a majo r catabolic organ for Lp(a) uptake. The underlying mechanism is rather uncl ear; several candidate receptors from the LDL-receptor gene family do not o r poorly bind Lp(a) in vitro. Lp(a) plasma levels are elevated over controls in patients with renal disea ses like nephrotic syndrome and end-stage renal disease. Following renal tr ansplantation, Lp(a) concentrations decrease to values observed in controls matched for apo(a) type. Controversial data on Lp(a) in diabetes mellitus mainly result from insufficient sample sizes in numerous studies. Large stu dies and those including apo(a) phenotype analysis have come to the conclus ion that Lp(a) levels are not or only moderately elevated in insulin-depend ent patients. In non-insulin-dependent diabetics Lp(a) is not elevated. Sev eral rare disorders, such as LCAT and LPL deficiency, as well as liver dise ases and abetalipoproteinemia are associated with low plasma levels or lack of Lp(a).