Lipoprotein (a) measurements for clinical application

Santica M Marcovina,John J Albers

doi:10.1194/jlr.r061648

Abstract

The high degree of size heterogeneity of apo(a), the distinct protein component of lipoprotein (a) [Lp(a)], renders the development and selection of specific antibodies directed to apo(a) more difficult and poses significant challenges to the development of immunoassays to measure its concentration in plasma or serum samples. Apo(a) is extremely variable in size not only between but also within individuals because of the presence of two different, genetically determined apo(a) isoform sizes. Therefore, the antigenic determinants per particle available to interact with the antibodies will vary in the samples and the calibrators, thus contributing to apo(a) size-dependent inaccuracy of different methods. The lack of rigorous validation of the immunoassays and common means of expressing Lp(a) concentrations hinder the harmonization of results obtained by different studies and contribute to the lack of common cut points for identification of individuals at risk for coronary artery disease or for interventions aimed at reducing Lp(a) levels. The aim of our review is to present and critically evaluate the issues surrounding the measurements of Lp(a), their impact on the clinical interpretation of the data, and the obstacles we need to overcome to achieve the standardization of Lp(a) measurements.

Highlights

The high degree of size heterogeneity of apo(a), the distinct protein component of lipoprotein (a) [Lp(a)], renders the development and selection of specific antibodies directed to apo(a) more difficult and poses significant challenges to the development of immunoassays to measure its concentration in plasma or serum samples
Apo(a), shares a high amino acid sequence homology to several regions of the serine protease zymogen plasminogen, including the protease domain, and the so-called kringle 4 (K4) and 5 domains, which are tri-loop polypeptides stabilized by three internal disulfide bridges
We have demonstrated that Lp(a) contains 1 mol of apo(a) and 1 mol of apoB [13], and we determined by amino acid analysis the protein concentration of an Lp(a) preparation isolated from human plasma containing an apo(a) with 21 K4 motifs

Summary

Introduction

The high degree of size heterogeneity of apo(a), the distinct protein component of lipoprotein (a) [Lp(a)], renders the development and selection of specific antibodies directed to apo(a) more difficult and poses significant challenges to the development of immunoassays to measure its concentration in plasma or serum samples. The antigenic determinants per particle available to interact with the antibodies will vary in the samples and the calibrators, contributing to apo(a) size-dependent inaccuracy of different methods. Lp(a) particles have been reported to associate noncovalently with triglyceride-rich lipoproteins in hypertriglyceridemic individuals or after a fatty meal [4]. This association may result in overestimation of Lp(a) measured by ELISA methods based on the apo(a) capture/apoB detection approach. This article is available online at http://www.jlr.org that join individual kringles [8], contributing to the size heterogeneity of Lp(a)

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Conclusion