Genetics of Lipoprotein(a) in Relation to Coronary Heart Disease


Lipoprotein(a), Lp(a), a complex between a low‐density lipoprotein‐like lipid moiety containing apolipoprotein (apo) B, and apo(a), a plasminogen‐derived, carbohydrate‐rich, hydrophilic protein, is one of the most genetically regulated cardiovascular risk factors. For any given population, Lp(a) levels are distributed in a skewed fashion and are strongly impacted by polymorphisms of the LPA gene. The quantitatively most impactful polymorphism results in a variable number of kringle 4 (K4) units, a key motif of apo(a) that predicts Lp(a) levels and has been associated with cardiovascular risk. In addition, other LPA genetic variants impact Lp(a) levels and may contribute to interethnic Lp(a) level variability. Further, it has been suggested that genetic variants beyond the LPA gene may affect Lp(a) levels. Recent studies using Mendelian randomisation approaches have documented an association between Lp(a) and cardiovascular disease and are indicative of a causal relationship.

Key Concepts

  • Lp(a) is a type of plasma lipoprotein synthesised in the liver, and consists of a cholesteryl‐ester‐rich lipid core and one molecule each of two different apolipoproteins, apoB‐100 and apo(a).

  • LPA, the gene encoding apo(a) located on chromosome 6, is evolved from the plasminogen gene during primate evolution, and has repeated triloop structures called kringles (K).

  • Lp(a) levels differ significantly between individuals and ethnicities, and are regulated to a major extent by genetics through the LPA gene.

  • A copy number variation (i.e. apo(a) size polymorphism) in the LPA gene plays an important role in Lp(a) regulation, and smaller apo(a) sizes with fewer K repeats, in general, are associated with higher Lp(a) levels.

  • Additionally, some other single‐nucleotide polymorphisms (SNPs) in the LPA gene, as well as in some other non‐LPA genes, have been shown to influence Lp(a) levels.

  • Although the physiological function of Lp(a) is not well understood, its role in the development of atherosclerotic cardiovascular disease is increasingly well documented, and is recognised in clinical guidelines.

  • Lp(a) levels are not appreciably affected by lifestyle improvements (diet, exercise, etc.); however, some nongenetic factors such as hormones, menopausal status, inflammatory burden and immune status have been shown to impact Lp(a) levels.

  • Currently, no drug can specifically and effectively lower high Lp(a) levels, but development of this type of treatment is in progress.

Keywords: LPA gene; polymorphism; apo(a) isoform; kringle; K4 repeats; genetic variants; cardiovascular disease; lipids; risk factors

Figure 1.

Lipoprotein(a) structure. Lp(a) consists of a cholesteryl‐ester‐rich lipid core and one molecule of each apolipoprotein, apoB‐100 and apo(a), which are covalently bound via a disulphide bond. Apo(a) consists of a repeated triloop structure referred to as a kringle (K).There are two different types of kringles, that is, K4 and K5. The K4 domain is further diversified into 10 different subtypes (K41–K410), and of these the K4 type 2 (K42) is present in multiple copies ranging from 3 to more than 40 copies. Abbreviations: Apo, apolipoprotein; n, number and LDL‐R, low‐density lipoprotein receptor.

Figure 2.

Evolution of the LPA gene: Similarities and differences between species. The LPA gene is thought to have evolved from the plasminogen gene during primate evolution. Of the five kringle (K) domains (K1 through K5) present in the plasminogen gene, the human LPA gene contains the K4 and K5 domains, whereas LPA genes of Old World monkeys or the European hedgehog contain only K4‐ or K3‐like repeated structures, respectively. The protease domain of the plasminogen gene is conserved in humans and monkeys, but not in the hedgehog. The similarities in sequence identities between the plasminogen gene and the corresponding apo(a) units within each species are shown as percentage. Abbreviations: Apo, apolipoprotein and Pro, protease domain.

Figure 3.

Frequency distributions of nonexpressed apo(a) alleles across apo(a) size ranges (a) and apo(a) dominance pattern (b) in Caucasians and African Americans. The distributions of nonexpressed apo(a) alleles gradually increase with an increasing number of K4 repeats in Caucasians (CA), whereas a U‐shaped distribution was observed in African Americans (AA) (a). The smaller isoform was dominating in the majority of both Caucasian and African American heterozygotes, whereas the larger isoform was dominating in approximately one‐quarter of all individuals (b). Of note, codominance of both apo(a) isoforms characterised by a similar degree of protein expression level was more common in African Americans than in Caucasians.

Figure 4.

Frequency distribution of apo(a) alleles and isoforms in Caucasians (a) and African Americans (b). Alleles are represented by solid lines and apo(a) protein isoforms by dashed lines (the dashed lines are not shown where they coincide with the solid lines). The isoform distribution was calculated by dividing the total number of protein bands detected by the total number of alleles, separately for each population. Homozygotes (n=15) were excluded as it was not possible to determine if the single apo(a) protein band corresponded to one or two proteins. The African American (AA) distribution had a narrower and taller peak whereas the Caucasian (CA) distribution was wider. Among Caucasians, nonexpressed alleles (the gap between the allele and isoform curves) were most frequent in the midrange, whereas among African Americans they were fairly evenly distributed across apo(a) sizes.

The figure was originally published in the Journal of Lipid Research: Rubin et al. . © The American Society for Biochemistry and Molecular Biology.
Figure 5.

Lipoprotein(a): From genetic level to cardiovascular risk. At the DNA level, Lp(a) levels are primarily regulated by a apo(a) gene size polymorphism, that is, copy number of K4 repeats, as well as other single‐nucleotide polymorphisms (SNPs) in the LPA gene. In addition, SNPs in some other genes have been shown to play roles in Lp(a) regulation. In the majority of individuals, two different populations of Lp(a) particles carrying different‐sized apo(a) contribute to the overall plasma Lp(a) level. The total Lp(a) level thus represents two particle populations and these have been characterised as allele‐specific Lp(a) levels. Furthermore, the individual metabolic, immune and endocrine environment may also have an impact on the plasma Lp(a) level. Finally, individuals with dominating ‘smaller’ apo(a) isoforms in their plasma are at a greater CVD risk compared with individuals with dominating ‘larger’ apo(a) isoforms. Abbreviations: Apo(a), apolipoprotein(a); CNV, copy number variation; K, kringle and Pro, protease domain.



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Further Reading

Anuurad E , Enkhmaa B and Berglund L (2010) Enigmatic role of lipoprotein(a) in cardiovascular disease. Clinical and Translational Science 3(6): 327–332.

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Enkhmaa, Byambaa, Anuurad, Erdembileg, Zhang, Wei, Abbuthalha, Adnan, and Berglund, Lars(Sep 2013) Genetics of Lipoprotein(a) in Relation to Coronary Heart Disease. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0025148]