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Wien Klin Wochenschr. 1999 Jan 15;111(1):5-20.

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

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Institute of Medical Biology and Human Genetics, University of Innsbruck, Austria.


The human plasma lipoprotein Lp(a) has gained considerable clinical interest as a genetically determined risk factor for atherosclerotic vascular diseases. Numerous (including prospective) studies have described a correlation between elevated Lp(a) plasma levels and coronary heart disease, stroke and peripheral atherosclerosis. Lp(a) consists of a large LDL-like particle to which the specific glycoprotein 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 controlled to a large extent by the extremely polymorphic apo(a) gene. More than 30 alleles at this locus determine a size polymorphism. The size of the apo(a) isoform is inversely correlated with Lp(a) plasma concentrations, which are non-normally distributed in most populations. To a minor extent, apo(a) gene-independent effects also influence Lp(a) concentrations. These include diet, hormonal status and diseases like 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 of other members of the gene family. Stability problems of Lp(a) as well as statistical pitfalls in studies with small group sizes have created conflicting results. The apo(a)/Lp(a) secretion from hepatocytes is regulated at various levels including postranslationally by apo(a) isoform-dependent prolonged retention in the endoplasmic reticulum. This mechanism can partly explain the inverse 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 plasma are only poorly understood. The human kidney seems to represent a major catabolic organ for Lp(a) uptake. The underlying mechanism is rather unclear; several candidate receptors from the LDL-receptor gene family do not or poorly bind Lp(a) in vitro. Lp(a) plasma levels are elevated over controls in patients with renal diseases like nephrotic syndrome and end-stage renal disease. Following renal transplantation, 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 studies and those including apo(a) phenotype analysis have come to the conclusion that Lp(a) levels are not or only moderately elevated in insulin-dependent patients. In non-insulin-dependent diabetics Lp(a) is not elevated. Several rare disorders, such as LCAT and LPL deficiency, as well as liver diseases and abetalipoproteinemia are associated with low plasma levels or lack of Lp(a).

[Indexed for MEDLINE]

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