Lipoprotein(a): Genotype–Phenotype Relationship and Impact on Atherogenic Risk

Abstract

In 2010, more than 45 years after the initial discovery of lipoprotein(a) [Lp(a)] by Kare Berg, an European Atherosclerosis Society Consensus Panel recommended screening for elevated Lp(a) in people at moderate to high risk of atherosclerotic cardiovascular disease (CVD). This recommendation was based on extensive epidemiological findings demonstrating a significant association between elevated plasma Lp(a) levels and coronary heart disease, myocardial infarction, and stroke. In addition to those patients considered to be at moderate to high risk of heart disease, statin-treated patients with recurrent heart disease were also identified as targeted for screening of elevated Lp(a) levels. Taken together, recent findings have significantly strengthened the notion of Lp(a) as a causal risk factor for CVD. It is well established that Lp(a) levels are largely determined by the size of the apolipoprotein a [apo(a)] gene; however, recent studies have identified several other LPA gene polymorphisms that have significant associations with an elevated Lp(a) level and a reduced copy number of K4 repeats. In addition, the contribution of other genes in regulating Lp(a) levels has been described. Besides the strong genetic regulation, new evidence has emerged regarding the impact of inflammation as a modulator of Lp(a) risk factor properties. Thus, oxidized phospholipids that possess a strong proinflammatory potential are preferentially carried on Lp(a) particles. Collectively, these findings point to the importance of both phenotypic and genotypic factors in influencing apo(a) proatherogenic properties. Therefore, studies taking both of these factors into account determining the amount of Lp(a) associated with each individual apo(a) size allele are valuable tools when assessing a risk factor role of Lp(a). Apo(a) Gene Size Polymorphism and Lp(a)T he plasma lipoprotein(a)[Lp(a)] level is one of the most heritable quantitative traits in humans, and the high heritability of this trait has been attributed to variations at LPA locus.

LDL as a Cause of Atherosclerosis

“…Both SNPs were associated with coronary disease and, after adjustment for the plasma Lp(a) lipoprotein level, the association between LPA genotypes and CAD are abolished. The mechanism whereby Lp(a) may be particularly atherogenic is through its binding and transportation of phospholipids [28]. However, due to the particle homology with plasminogen a pro-enzyme related to fibrinolysis [29,30].…”

Wine Lees Polyphenols as a Novel Functional Bioactive Compound in the Protection against Oxidative Stress and Hyperlipidemia

“…CVD is currently the preeminent health issue worldwide and signifi cant risk factors include hyperlipidaemia, high serum low-density lipoprotein (LDL) cholesterol and lipoprotein(a) levels, with low high-density (HDL) cholesterol (10)(11)(12). In 2013, the results of a large prospective randomised trial on stroke risks showed the benefi ts of a Mediterranean diet with moderate wine consumption in comparison with a low-fat diet.…”

Evidence-based assessment of lipoprotein(a) as a risk biomarker for cardiovascular diseases – Some answers and still many questions

“…First, a meta-analysis which included population-based observational studies has examined the relationship between apo(a) and cardio-and cerebrovascular disease risk 40 . Apo(a) is a heritable modulator of Lp (a) effects and smaller apo(a) isoforms have been convincingly shown to be associated with higher Lp(a) levels 15,[17][18][19][20][21][22] . A significant association between smaller apo(a) isoforms and CHD events compared with larger apo(a) isoforms was described by Erqou et al (RR, 2.08; 95% CI, 1.67 to 8 2.58) 40 .…”

“…Intriguingly, a large part of the circulating Lp(a) level is heritable, with its genetic components located in the LPA gene responsible for the encoding of apo(a) [17][18][19][20][21][22] . However, Lp (a) concentrations are also dependent on the rate of hepatic apo (a) and apoB 100 secretion 23 .…”