Prediction of cardiovascular risk by Lp(a) concentrations or genetic variants within the LPA gene region

Florian Kronenberg

doi:10.1007/s11789-019-00093-5

Abstract

In the middle of the 1990s the interest in Lp(a) vanished after a few badly performed studies almost erased Lp(a) from the map of biological targets. However, since roughly 10 years the interest has begun to grow again mainly for two reasons: first, genetic studies using easily accessible and high-throughput techniques for genotyping of single-nucleotide polymorphisms (SNPs) have allowed large studies in patients with cardiovascular disease and controls to be performed. This strengthened the earlier findings on a copy number variation in the LPA gene and its association with cardiovascular outcomes. Second, new therapies are on the horizon raising strong and justified hope that in a few years drugs will become available which tremendously lower Lp(a) concentrations. This review article should provide an introduction to the genetic determination of Lp(a) concentrations and considerations whether Lp(a) concentrations or genetic variants are important for the prediction of cardiovascular risk.

Highlights

The concentrations are under strict genetic control by the LPA gene locus and here especially by a size polymorphism of apo(a) caused by a variable number of so called kringle IV (K-IV) repeats in the LPA gene [1, 4]
Each of these up to more than 40 repeats has a size of 5.6 kB which results in a highly polymorphic and informative copy number variation (CNV)
The K-IV type-2 CNV measured by Quantitative polymerase chain reaction (qPCR) explained only 25% of the variability in Lp(a) levels [11], which is markedly lower than in other studies of European populations using methods such as apo(a) isoforms by western blot or separated alleles by pulsed-field gel electrophoresis

Summary

Introduction

An astonishing characteristic of Lp(a) is the more than 1000-fold range of concentrations between individuals from less than 0.1 mg/dL to more than 300 mg/dL [1]. The concentrations are under strict genetic control by the LPA gene locus and here especially by a size polymorphism of apo(a) caused by a variable number of so called kringle IV (K-IV) repeats in the LPA gene [1, 4]. Each of these up to more than 40 repeats has a size of 5.6 kB which results in a highly polymorphic and informative copy number variation (CNV). The Copenhagen City Heart Study observed for individuals from a general population with concentrations between 30 and 76 mg/dL (corresponding to the 67th–90th percentile) a 1.6-fold increased risk for incident myocardial infarction compared to individuals with Lp(a) concentrations below 5 mg/dL (corresponding to the lower 22% of the population). This risk increased to 1.90 for persons with Lp(a) concentrations between 77 and 117 mg/dL (90th–95th percentile) and to 2.60 for individuals with Lp(a) concentrations above 117 mg/dL

60 Controls CHD

Conclusions

Findings

Compliance with ethical guidelines