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

Abstract

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.