Lipoprotein(a): Reloaded
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LIPIDS (JM ORDOVAS, SECTION EDITOR)
Lipoprotein(a): Reloaded Florian Kronenberg & Gerd Utermann
Published online: 26 November 2011 # Springer Science+Business Media, LLC 2011
Abstract Lipoprotein(a) is a macromolecular complex of enigmatic function in human plasma. Concentrations of Lp(a) constitute a quantitative genetic trait. They are primarily determined by the LPA locus on chromosome 6q26-27, which is characterized by a unique type of copy number variation (CNV), the kringle-IV type 2 (K-IV-2) repeats. Meta-analysis of prospective studies as well as old and new genetic evidence have identified Lp(a) as an independent risk factor for atherothrombotic disease. The K-IV-2 CNV in LPA is the strongest known common genetic variation predicting risk for CHD: small isoforms of this CNV are associated with a doubling of risk for CHD. Together with observations that removal of Lp(a) from plasma may be beneficial in individuals with severe CHD, the strong genetic evidence justifies the consideration of Lp(a) in clinical practice.
Keywords Lipoprotein(a) . Lp(a) . Apolipoprotein(a) . Apo (a) . Lipoprotein metabolism . Coronary heart disease . Atherosclerosis . Cardiovascular risk factor . Genetic trait .
F. Kronenberg Division of Genetic Epidemiology; Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Schöpfstr. 41, 6020 Innsbruck, Austria e-mail: [email protected] G. Utermann (*) Division of Human Genetics; Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Schöpfstr. 41, 6020 Innsbruck, Austria e-mail: [email protected]
Copy number variation . Polymorphism . Multiallelic locus . Association study . Causality . Mendelian Randomization . Kidney disease
Introduction Lipoprotein(a) [Lp(a)] was first described as a genetic trait in human plasma by Berg [1] almost 50 years ago. Lp(a) is a macromolecular complex whose characteristics are summarized in Table 1. It consists of a low-density lipoprotein (LDL) to which a high-molecular weight glycoprotein called apolipoprotein(a) [apo(a)] is covalently linked by a single disulfide bridge [2]. Both components are derived from the liver, but it is unclear whether the complex is assembled inside the hepatocyte or outside in plasma (reviewed in detail by Dieplinger and Utermann [3]). It proceeds in two steps, and the first step involves noncovalent docking of apo(a) to LDL followed by formation of the disulfide bridge [4]. Likewise, the mechanism and site of removal of Lp(a) from plasma is unknown. No receptor specific for Lp(a)/apo(a) has been described. Binding of Lp(a) to several receptors, including the LDLreceptor, has been demonstrated but which of these receptors, if any, is involved in Lp(a) clearance in vivo is unclear. The kidney has been implicated in the degradation and clearance of Lp(a)/apo(a) from plasma. Two features make the Lp(a) complex unique: first, concentrations of Lp(a) in plasma constitute a quantitative genetic trait and vary from zero (in
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