Lipoprotein(a): an elusive cardiovascular risk factor

Abstract

Lipoprotein (a) [Lp(a)], is present only in humans, Old World nonhuman primates, and the European hedgehog. Lp(a) has many properties in common with low-density lipoprotein (LDL) but contains a unique protein, apo(a), which is structurally different from other apolipoproteins. The size of the apo(a) gene is highly variable, resulting in the protein molecular weight ranging from 300 to 800 kDa; this large variation may be caused by neutral evolution in the absence of any selection advantage. Apo(a) influences to a major extent metabolic and physicochemical properties of Lp(a), and the size polymorphism of the apo(a) gene contributes to the pronounced heterogeneity of Lp(a). There is an inverse relationship between apo(a) size and Lp(a) levels; however, this pattern is complex. For a given apo(a) size, there is a considerable variation in Lp(a) levels across individuals, underscoring the importance to assess allele-specific Lp(a) levels. Further, Lp(a) levels differ between populations, and blacks have generally higher levels than Asians and whites, adjusting for apo(a) sizes. In addition to the apo(a) size polymorphism, an upstream pentanucleotide repeat (TTTTA(n)) affects Lp(a) levels. Several meta-analyses have provided support for an association between Lp(a) and coronary artery disease, and the levels of Lp(a) carried in particles with smaller size apo(a) isoforms are associated with cardiovascular disease or with preclinical vascular changes. Further, there is an interaction between Lp(a) and other risk factors for cardiovascular disease. The physiological role of Lp(a) is unknown, although a majority of studies implicate Lp(a) as a risk factor.

Figure 1

Model of Lp(a). The LDL-like moiety consists of a lipid core of cholesteryl esters and triglycerides surrounded by a surface layer of phospholipid and free cholesterol. In addition to lipids, it also contains one molecule of apolipoprotein B, which is linked to apolipoprotein(a) through a single disulfide bond. The putative LDL receptor binding domain of apoB is shown. The apo(a) moiety consists of a single copy of kringles KIV, types 1 and 3 to 10, kringle V, and a protease domain analogous to plasminogen. In addition, it contains multiple copies of kringle IV, type 2.

Figure 2

Two Lp(a) particles with different apo(a) sizes. Symbols as in Figure 1.

Figure 3

Upstream polymorphisms of the apo(a) gene. The PNR polymorphism is indicated by the variable presence (n = 5 to 12) of TTTTA repeats at position −1400, and the C/T polymorphism represent a single nucleotide polymorphism in the promoter region of the apo(a) gene. The variability of KIV type 2 repeats of the apo(a) gene is indicated by the dotted line. Symbols for kringle repeats as in Figure 1.