Lipoprotein(a) and Genetics
- Genetic studies have demonstrated a causal role of blood levels of lipoprotein(a) (Lp(a)) in CAD (coronary artery disease).1 Lp(a) levels are estimated to be greater than 90% genetically determined and elevated levels are associated with increased risk of coronary and carotid atherosclerosis (plaque build-up) as well as heart attack and stroke.2-5
- Lp(a) levels vary more than 1000-fold (from <0.1 to >300 mg/dL) in individuals and 7-fold in populations unlike most other lipoproteins where normal levels may vary by 3- to 5-fold.6
- Blood levels of Lp(a) are primarily determined by the LPA gene located on chromosome 6q26-27 and are only minimally affected by environmental factors.7 The LPA gene encodes apolipoprotein(a) (apo(a)), the specific apolipoprotein of Lp(a) particle.
- The apo(a) has repeating subunits called kringles and includes 10 unique copies of kringle-4 (KIV), which additionally includes variable numbers of identical KIV-type 2 repeats (from 3 to >40), and a protease-like domain that is catalytically inactive. LPA gene determines the number of KIV-type 2 repeats and hence the size of apo(a).8 Lp(a) levels are generally inversely associated with apo(a) size.9
- Most subjects have 2 distinct apo(a) alleles, which vary in size due to kringle copy number, resulting in a marked size heterogeneity of the expressed apo(a) protein. Although the size heterogeneity of the KIV-2 repeats is a direct mediator of Lp(a) levels, it explains 50%-70% of the variability Lp(a) levels and additional genetic differences may play a role.9-11 This explains the 1,000-fold range of plasma Lp(a) levels among individuals.
- In addition to variations in KIV-type 2 repeats,9, 10 several SNPs (single nucleotide polymorphisms) explain an additional 35% of the variability in blood Lp(a) levels. In particular, SNPs rs3798220 and rs10455872 have been associated with both increased Lp(a) levels and an increased risk for CAD.9-11 There are also other SNPs that have been previously identified that can result in increased Lp(a) levels.7
- The linear dose-response relationship of the LPA variants with both level and the risk of CAD provides compelling support for the causal role of elevated plasma level of Lp(a) in the risk of CAD.9
- Apolipoprotein(a) is synthesized primarily in the liver, where it is subsequently covalently linked to apoB-100 to form the Lp(a) lipoprotein.12, 13 Small apo(a) isoforms, which are more rapidly synthesized, are associated with higher Lp(a) particle number in blood and therefore higher blood Lp(a) levels. In contrast, larger apo(a) isoforms take longer to synthesize in the hepatocyte, and therefore, their production rates are lower, generally leading to lower blood levels.13
- In patients with elevated triglyceride levels, up to 5% of the apo(a) can be associated with large very-low density lipoprotein particles. Humans generally have no free apo(a) circulating in blood, as blood apoB-100 synthesis is in excess of synthesis of apo(a).13
- The clearance of Lp(a) is not well understood, although it does not appear to involve the LDL receptor and is not dependent on kringle copy number. Murine studies have suggested the existence of a yet to be identified apo(a) receptor in the liver.13
- Apo(a) is characterized by a high genetic polymorphism with at least 34 isoforms in plasma. Recent studies have shown that in atherothrombosis apo(a) polymorphism could play a role independent of Lp(a) levels.
- Despite having been discovered nearly 50 years ago, a physiological function for Lp(a) has not been identified
1. Hopewell JC, Clarke R, Parish S, et al. Lipoprotein(a) genetic variants associated with coronary and peripheral vascular disease but not with stroke risk in the Heart Protection Study. Circ Cardiovasc Genet. Feb 1 2011;4(1):68-73.
2. Boerwinkle E, Leffert CC, Lin J, Lackner C, Chiesa G, Hobbs HH. Apolipoprotein(a) gene accounts for greater than 90% of the variation in plasma lipoprotein(a) concentrations. J Clin Invest. 1992;90(1):52-60.
3. Berg K, Dahlen G, Borresen AL. Lp(a) phenotypes, other lipoprotein parameters, and a family history of coronary heart disease in middle-aged males. Clin Genet. Nov 1979;16(5):347-352.
4. Kronenberg F, Kronenberg MF, Kiechl S, et al. Role of lipoprotein(a) and apolipoprotein(a) phenotype in atherogenesis: prospective results from the Bruneck study. Circulation. 1999;100(11):1154-1160.
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7. Utermann G. Genetic architecture and evolution of the lipoprotein(a) trait. Curr Opin Lipidol. Apr 1999;10(2):133-141.
8. Uterman G, ed Genetics of the Lp(a) lipoprotein: Academic Press; 1990. AM S, ed. Lipoprotein (a).
9. Clarke R, Peden JF, Hopewell JC, et al. Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N Engl J Med. Dec 24 2009;361(26):2518-2528.
10. Luke M M, Kane JP, Liu DM, et al. A polymorphism in the protease-like domain of apolipoprotein(a) is associated with severe coronary artery disease. Arterioscler Thromb Vasc Biol. Sep 2007;27(9):2030-2036.
11. Chasman DI, Shiffman D, Zee RY, et al. Polymorphism in the apolipoprotein(a) gene, plasma lipoprotein(a), cardiovascular disease, and low-dose aspirin therapy. Atherosclerosis. Apr 2009;203(2):371-376.
12. Gazzaruso C, Garzaniti A, Geroldi D, Finardi G. Genetics and cardiovascular risk: a role for apolipoprotein(a) polymorphism. Cardiologia. 1999;44(4):347-354.
13. Nordestgaard BG, Chapman MJ, Ray K, et al. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J. Oct 21 2010.