Lipoprotein(a): resurrected by genetics

Authors

  • F. Kronenberg,

    1. Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Innsbruck, Austria
    Search for more papers by this author
  • G. Utermann

    Corresponding author
    1. Division of Human Genetics, Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Innsbruck, Austria
    • Correspondence: Gerd Utermann MD, Division of Human Genetics, Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Schöpfstr. 41, A-6020 Innsbruck, Austria. (fax: +43 512 9003 73510; e-mail: gerd.utermann@i-med.ac.at)

    Search for more papers by this author

Abstract

Plasma lipoprotein(a) [Lp(a)] is a quantitative genetic trait with a very broad and skewed distribution, which is largely controlled by genetic variants at the LPA locus on chromosome 6q27. Based on genetic evidence provided by studies conducted over the last two decades, Lp(a) is currently considered to be the strongest genetic risk factor for coronary heart disease (CHD). The copy number variation of kringle IV in the LPA gene has been strongly associated with both Lp(a) levels in plasma and risk of CHD, thereby fulfilling the main criterion for causality in a Mendelian randomization approach. Alleles with a low kringle IV copy number that together have a population frequency of 25–35% are associated with a doubling of the relative risk for outcomes, which is exceptional in the field of complex genetic phenotypes. The recently identified binding of oxidized phospholipids to Lp(a) is considered as one of the possible mechanisms that may explain the pathogenicity of Lp(a). Drugs that have been shown to lower Lp(a) have pleiotropic effects on other CHD risk factors, and an improvement of cardiovascular endpoints is up to now lacking. However, it has been established in a proof of principle study that lowering of very high Lp(a) by apheresis in high-risk patients with already maximally reduced low-density lipoprotein cholesterol levels can dramatically reduce major coronary events.

Ancillary