Human Genetics and the Causal Role of Lipoprotein(a) for Various Diseases

Abstract

Lipoprotein(a) [Lp(a)] is a highly atherogenic lipoprotein that is under strong genetic control by the LPA gene locus. Genetic variants including a highly polymorphic copy number variation of the so called kringle IV repeats at this locus have a pronounced influence on Lp(a) concentrations. High concentrations of Lp(a) as well as genetic variants which are associated with high Lp(a) concentrations are both associated with cardiovascular disease which very strongly supports causality between Lp(a) concetrations and cardiovascular disease. This method of using a genetic variant that has a pronounced influence on a biomarker to support causality with an outcome is called Mendelian randomization approach and was applied for the first time two decades ago with data from Lp(a) and cardiovascular disease. This approach was also used to demonstrate a causal association between high Lp(a) concentrations and aortic valve stenosis, between low concentrations and type-2 diabetes mellitus and to exclude a causal association between Lp(a) concentrations and venous thrombosis. Considering the high frequency of these genetic variants in the population makes Lp(a) the strongest genetic risk factor for cardiovascular disease identified so far. Promising drugs that lower Lp(a) are on the horizon but their efficacy in terms of reducing clinical outcomes still has to be shown.

Keywords: Apolipoprotein(a); Association study; Cardiovascular disease; Copy number variation; Mendelian randomization; lipoprotein(a).

Fig. 1

Panel a, distribution of Lp(a) concentration in 6218 individuals from the two population-based studies KORA F3 and F4. Panel b, median Lp(a) concentrations in various groups of subjects stratified by the number of KIV repeats and genotypes of SNP rs10455872; 11–22 KIV repeats are considered as low molecular weight (LMW) or small apo(a) isoforms and those with >22 KIV repeats are considered as high molecular weight (HMW) or large apo(a) isoforms. Figure adapted and reprinted with permission of reference [107]

Fig. 2

Overview on the most important genetic and non-genetic factors that have an influence on Lp(a) concentrations. The graphical illustration of the Lp(a) particle has been taken with permission from Hansi Weissensteiner (Medical University of Innsbruck)

Fig. 3

Mendelian Randomization approach to demonstrate a causal association between Lp(a) concentrations and coronary heart disease (CHD). Panel a shows the association between elevated Lp(a) concentrations and cardiovascular disease (CVD) as shown in the Copenhagen City Heart Study [53]. Panel b shows the association between the number of K-IV repeats in the LPA gene and Lp(a) concentrations: individuals with small apo(a) isoform have markedly higher median Lp(a) concentrations than individuals with large apo(a) isoforms. Data are derived from [107]. Panel c shows the preponderance of small apo(a) isoforms in patients with CVD when compared to controls. Data are taken from a case–control study in multiple populations [56]. Since a low number of KIV copies (11–22 copies) is associated with high Lp(a) levels and high Lp(a) levels are associated with CHD, it follows that a low number of KIV copies has to be associated with CVD if the association of Lp(a) with CVD is causal

Fig. 4

Simplified illustration how Mendelian segregation of small and large apo(a) isoforms and thereby the transmission of high or low Lp(a) concentrations and risk for CVD, respectively, works. It is randomly determined at the time of conception which of the two alleles from the father and which of the two alleles from the mother are transmitted to the offspring. The height of the bars represents the size of the isoforms. The three boxes illustrate the most common situations where both parents carry at least one small apo(a) isoform each (left box), where at least on parent carries one small apo(a) isoform (middle box) or where both parents carry only large apo(a) isoforms (right box). Underneath the typically observed Lp(a) concentrations (high or low) and the associated risk for CVD (high or low) are given. It should be pointed out that exceptions from the rules can occur since also other variants than the KIV repeat polymorphism have an influence on Lp(a) concentrations

Fig. 5

Study design and summary of the results of the study by Jaeger et al. [89] that investigated the effect of Lp(a)-lowering by lipid apheresis in very high-risk patients. “True LDL-C” is considered to be LDL-cholesterol without the cholesterol from the Lp(a) particles. The Lp(a)-derived cholesterol is not accessible for therapeutic interventions with statins and is about 45 % of the Lp(a) concentration. For extended explanation, see text. Figure taken with permission from reference [1]