Genetic basis and pathophysiological implications of high plasma Lp(a) levels.

Lipoprotein(a) or Lp(a) is a genetic variant of plasma low density lipoproteins (LDL) containing apoB100 covalently linked to apolipoprotein(a) or apo(a), the specific marker of Lp(a). Lp(a) is heterogeneous in size and density, accounting in part for the marked size polymorphism of apo(a), 300 to 800 kDa. The apo(a) size polymorphism is related to the different number of kringle repeats which are structurally similar although not identical to the kringle 4 of plasminogen. Recent studies on a genomic level have indicated that the apo(a) gene contains at least 19 different alleles varying in length between 48 and 190 kb, partially impacting on the plasma levels of Lp(a). High plasma levels of Lp(a) have been found to be associated with an increased prevalence of premature atherosclerotic cardiovascular disease by mechanism(s) yet to be established. Both atherogenic and thrombogenic potentials have been postulated and have been related to the LDL-like and plasminogen-like properties of Lp(a), respectively.     

Lipoprotein(a) as a cardiovascular risk factor

Lipoprotein(a) [Lp(a)] is a class of lipoprotein particles having the lipid composition of plasma low-density lipoprotein (LDL), but with a distinct protein moiety comprised of two proteins linked together by a disulfide bridge. The two proteins are apoB100, the protein moiety of LDL, and apo(a), a heavily glycosylated protein that is specific for Lp(a). Apo(a) has a strong structural similarity to plasminogen and has a wide-size polymorphism that has a genetic origin and is partially responsible for the size and density heterogeneity of Lp(a). High plasma levels of Lp(a) are associated with an increased risk for cardiovascular disease that is related to the atherogenic and thrombogenic potentials of this lipoprotein enhanced by the presence of other risk factors, among which are high plasma levels of LDL or low levels of high-density lipoprotein. The factors determining the plasma levels of Lp(a) have not been clearly identified except for an association with different alleles of the apo(a) gene, which is located in the long arm of chromosome 6. Currently there are no generally accepted ways to normalize the plasma levels of Lp(a) by either dietary and/or pharmacologic means. Until further progress in this area is made, patients with high plasma levels of Lp(a) should be advised to correct modifiable risk factors in order to decrease the cardiovascular pathogenicity of this lipoprotein class.     

Does apolipoprotein(a) heterogeneity influence lipoprotein(a) effects on fibrinolysis?

High plasma levels of lipoprotein(a) [Lp(a)] are considered to be an independent risk factor for premature cardiovascular disease and are inversely associated with apolipoprotein(a) [apo(a)] isoform sizes. The contribution of apo(a) polymorphism to the inhibition of fibrinolysis, a mechanism that may favor thrombus development, was therefore evaluated by measuring the ability of Lp(a) particles of distinct apo(a) isoform content to compete with plasminogen for fibrin binding during plasminogen activation by fibrin-bound tissue-type plasminogen activator. The rate of plasmin generation was most efficiently inhibited by an isoform with a molecular weight (M(r)) of approximately 540 Kd. An isoform with M(r) approximately 590 Kd produced a less pronounced effect, whereas the isoform with M(r) approximately 610 Kd failed to inhibit plasminogen activation. These effects were directly proportional to the amount of Lp(a) bound to the carboxy-terminal lysine residues of degraded fibrin. The relative affinity of the binding (kd range, 16 to 180 nmol/L) reflected the ability of individual Lp(a) isoforms to inhibit the binding of plasminogen (kd, 600 nmol/L). The question of the influence of kringle sequence variability on the binding to fibrin was not addressed by the present work. These data suggest that apo(a) isoform types with high affinity for fibrin may influence the ability of Lp(a) to interfere with fibrinolysis and contribute thereby to the association of elevated levels of Lp(a) with atherosclerotic and thrombotic risks.     

The role of lipoprotein(a) in the pathogenesis of atherosclerotic cardiovascular disease and its utility as predictor of coronary heart disease events

Lipoprotein(a) [Lp(a)], is a highly heterogeneous lipoprotein, due to variations in the size of apolipoprotein(a) [apo(a)], and the density of the apoB100-containing particles to which apo(a) is linked. Although high plasma levels of Lp(a) have been associated with an increased risk for atherosclerotic cardiovascular disease, the mechanism underlying this association is still largely undetermined, as is the potential role played by the particle’s heterogeneity. Lp(a) pathogenicity may also be influenced by the action of environmental factors and post-translational events relating to oxidative processes, and the action of lipolytic and proteolytic enzymes. Complicating the study of Lp(a) are the competing methods for its quantification due to its complex structure, and the lack of standardized methodologies. The recognition that Lp(a) particles may not all be alike in atherogenic potential should encourage studies to identify genetic and nongenetic factors underlying its heterogeneity, in order to reach a better understanding of its actual impact on atherosclerotic cardiovascular disease.     

Lipoprotein(a): a genetically determined lipoprotein containing a glycoprotein of the plasminogen family

Lp(a) represents a genetically transmitted class of plasma LDL having apo B-100 linked by a disulfide bridge to a glycoprotein, apo(a). Lp(a) is heterogeneous in size and density. Apo(a) is also heterogeneous in size (molecular weight between approximately 300,000 and 700,000) due probably to the polymorphism of both polypeptide and carbohydrate chains. Recent studies have shown that apo(a) has a striking amino acid sequence homology with plasminogen, a serine protease zymogen that following activation to plasmin enters the fibrinolytic system. Apo(a) is severalfold larger than plasminogen (molecular weight approximately 90,000) and also differs from it because it fails to be activated to plasmin. This is due to the fact that arginine is replaced by serine at the site of cleavage by streptokinase, urokinase, or tissue plasminogen activator. A single gene locus appears to control the Lp(a) polymorphism as well as the concentration of the Lp(a) phenotypes in the plasma. Patients with high plasma levels of Lp(a) have been shown to have an increased incidence of cardiovascular disease but a causal relationship has not been firmly established. The information that is being rapidly acquired on the structure of Lp(a) should facilitate the understanding of the molecular basis of the polymorphism of this genetic variant and of the role that the various Lp(a) phenotypes play in atherosclerosis and thrombosis. The potential physiologic role of Lp(a) remains open to inquiry.     

The role of lipoprotein[a] in atherosclerosis

Recent studies confirm and extend previous evidence that lipoprotein[a] (Lp[a]) plays a significant role in atherosclerosis and is one of the top five or six risk factors for cardiovascular disease. In Japanese patients, Lp[a] levels and apo[a] phenotypes are significant predictors for myocardial infarction. Lp[a] levels are significantly higher in ischemic stroke patients than in controls. However, plasma concentrations of Lp[a] are not predictive of ischemic cerebral infarction in either men or women. Serum Lp[a] levels are significantly higher in patients with carotid plaques or measurable intima-media thickness than in controls without. Despite these associations, there is no significant relationship between Lp[a] level and arterial endothelial function, smooth muscle response, or carotid wall thickness, even though other lipid risk factors like low-density lipoprotein cholesterol (LDL-C) and LDL-C/high-density lipoprotein cholesterol (HDL-C) ratio are correlated with abnormal arterial function and structure. There is new evidence that the association of Lp[a] with extracellular matrix (ECM) secreted by arterial smooth muscle cells increases two- to threefold the subsequent specific binding of LDL. Alpha-defensins released from activated or senescent neutrophils stimulate the binding of Lp[a] to ECM of endothelial cells. Several factors that affect the accumulation of Lp[a] and oxidized LDL in the arterial intima have been identified. Several recent studies have provided new insights into the physiologic role that Lp[a] might play in compromising fibrinolysis. The interaction of Lp[a] with cells is clearly distinct from that with ECM and with fibrinogen; the regulation sites within Lp[a] and plasminogen for these regulatory molecules are not identical. These recent advances bring us significantly closer to understanding how Lp[a] exerts its atherogenic and thrombogenic properties.     

Major reduction in plasma Lp(a) levels during sepsis and burns

Plasma levels of lipoprotein(a) [Lp(a)], an atherogenic particle, vary widely between individuals and are highly genetically determined. Whether Lp(a) is a positive acute-phase reactant is debated. The present study was designed to evaluate the impact of major inflammatory responses on plasma Lp(a) levels. Plasma levels of C-reactive protein (CRP), low density lipoprotein cholesterol, Lp(a), and apolipoprotein(a) [apo(a)] fragments, as well as urinary apo(a), were measured serially in 9 patients admitted to the intensive care unit for sepsis and 4 patients with extensive burns. Sepsis and burns elicited a major increase in plasma CRP levels. In both conditions, plasma concentrations of Lp(a) declined abruptly and transiently in parallel with plasma low density lipoprotein cholesterol levels and closely mirrored plasma CRP levels. In 5 survivors, the nadir of plasma Lp(a) levels was 5- to 15-fold lower than levels 16 to 18 months after the study period. No change in plasma levels of apo(a) fragments or urinary apo(a) was noticed during the study period. Turnover studies in mice indicated that clearance of Lp(a) was retarded in lipopolysaccharide-treated animals. Taken together, these data demonstrate that Lp(a) behaves as a negative acute-phase reactant during major inflammatory response. Nongenetic factors have a major, acute, and unexpected impact on Lp(a) metabolism in burns and sepsis. Identification of these factors may provide new tools to lower elevated plasma Lp(a) levels.     

Lipoprotein Lp(a) in homozygous familial hypercholesterolemia: density profile, particle heterogeneity and apolipoprotein(a) phenotype.

Homozygous familial hypercholesterolemia (FH) is a genetic disorder featuring a functional defect in cellular LDL receptors, marked elevation in circulating LDL concentrations, and premature atherosclerosis. The potential atherogenic role of apo B-containing lipoproteins other than LDL in this disease is indeterminate. We describe the quantitative and qualitative characteristics of Lp(a) as a function of apo(a) phenotype in a group of eight, unrelated homozygous FH patients. Plasma Lp(a) levels were significantly elevated (2.5-fold; mean 50 +/- 32 mg/dl) as compared to those in healthy subjects. The S2 isoform of apo(a) occurred most frequently (6 of eight patients); the rare B isoform presented in three patients. Plasma Lp(a) levels in homozygous FH did not correspond to those predicted by apo(a) phenotype. Analyses of the density distribution of Lp(a) and of Lp(a) particle size and heterogeneity as a function of density did not reveal any anomalies characteristic of homozygous FH. However, comparison of the hydrated density of Lp(a) particles as a function of apo(a) isoform content revealed a clear influence of isoform on this parameter; thus, in a B/S2 heterozygous patient, the density distribution of Lp(a) fractions containing isoform B alone, B and S2, and S2 alone, demonstrated that the apparent molecular weight of apo(a) plays a determining role in controlling the hydrated density and size of the resulting Lp(a) particle. Indeed, patients expressing the high molecular weight, S2 isoform uniformly displayed a dense form of Lp(a) (hydrated density approximately 1.055 g/ml). In subjects presenting two apo(a) isoforms, each isoform resided on distinct lipoprotein particles; in such cases, the plasma levels of the denser isoform predominated, suggesting differences in rates of formation, or rates of tissular catabolism, or in the plasma stability of the particles, or a combination of these mechanisms. Considered together, our data may be interpreted to suggest that the elevated circulating levels of Lp(a) in homozygous FH patients may reflect either an increased biosynthesis, or diminished catabolism via the cellular LDL receptor pathway, or a combination of both.     

Experimental Animal Models Evaluating the Causal Role of Lipoprotein(a) in Atherosclerosis and Aortic Stenosis

Lipoprotein(a) [Lp(a)], comprised of apolipoprotein(a) [apo(a)] and a low-density lipoprotein-like particle, is a genetically determined, causal risk factor for cardiovascular disease and calcific aortic valve stenosis. Lp(a) is the major plasma lipoprotein carrier of oxidized phospholipids, is pro-inflammatory, inhibits plasminogen activation, and promotes smooth muscle cell proliferation, as defined mostly through in vitro studies. Although Lp(a) is not expressed in commonly studied laboratory animals, mouse and rabbit models transgenic for Lp(a) and apo(a) have been developed to address their pathogenicity in vivo. These models have provided significant insights into the pathophysiology of Lp(a), particularly in understanding the mechanisms of Lp(a) in mediating atherosclerosis. Studies in Lp(a)-transgenic mouse models have demonstrated that apo(a) is retained in atheromas and suggest that it promotes fatty streak formation. Furthermore, rabbit models have shown that Lp(a) promotes atherosclerosis and vascular calcification. However, many of these models have limitations. Mouse models need to be transgenic for both apo(a) and human apolipoprotein B-100 since apo(a) does not covalently associated with mouse apoB to form Lp(a). In established mouse and rabbit models of atherosclerosis, Lp(a) levels are low, generally <20 mg/dL, which is considered to be within the normal range in humans. Furthermore, only one apo(a) isoform can be expressed in a given model whereas over 40 isoforms exist in humans. Mouse models should also ideally be studied in an LDL receptor negative background for atherosclerosis studies, as mice don’t develop sufficiently elevated plasma cholesterol to study atherosclerosis in detail. With recent data that cardiovascular disease and calcific aortic valve stenosis is causally mediated by the LPA gene, development of optimized Lp(a)-transgenic animal models will provide an opportunity to further understand the mechanistic role of Lp(a) in atherosclerosis and aortic stenosis and provide a platform to test novel therapies for cardiovascular disease.     

Factors affecting plasma lipoprotein(a) levels: role of hormones and other nongenetic factors

Lp(a) appears to be one of the most atherogenic lipoproteins. It consists of an low-density lipoprotein core in addition to a covalently bound glycoprotein, apo(a). Apo(a) exists in numerous polymorphic forms. The size of the polymorphism is mediated by the variable number of kringle-4 Type 2 repeats found in apo(a). Plasma Lp(a) levels are determined to more than 90% by genetic factors. Plasma Lp(a) levels in healthy individuals correlate significantly highly with apo(a) biosynthesis, and not with its catabolism. There are several hormones that are known to have a strong effect on Lp(a) metabolism. In certain diseases, such as kidney disease, the Lp(a) catabolism is impaired, leading to elevations that are up to a fivefold increase. Lp(a) levels rise with age but are otherwise only little influenced by diet and lifestyle. There is no safe and efficient way of treating individuals with elevated plasma Lp(a) concentrations. Most of the lipid-lowering drugs have either no significant influence on Lp(a) or exhibit a variable effect in patients with different forms of primary and secondary hyperlipoproteinemia.     

Transgenic rabbits expressing human apolipoprotein (a).

Elevated plasma levels of lipoprotein (a) [Lp(a)] constitutes an independent risk factor for coronary heart disease, stroke, and restenosis. Over the past years, our understanding of the genetics, metabolism and pathophysiology of Lp(a) have increased considerably. However, the precise mechanism(s) by which this atherogenic lipoprotein mediates the development of atherosclerosis remains unclear. This is partly due to the lack of appropriate animal models since apolipoprotein (a) [apo(a)], a distinct component of Lp(a) is found only in primates and humans. Development of transgenic mice expressing human apo(a) has provided an alternative means to investigate many aspects of Lp(a). However, human apo(a) in transgenic mice can not bind to murine apoB to form Lp(a) particles. In this aspect, we generated transgenic rabbits expressing human apo(a). In the plasma of transgenic rabbits, unlike the plasma of transgenic mice, about 80% of the apo(a) was associated with rabbit apo B and was contained in the fractions with density 1.02-1.10 g/ml, indicating the formation of Lp(a). Our study suggests that transgenic rabbits expressing human apo(a) exhibit efficient assembly of Lp(a) and can be used as an animal model for the study of human Lp(a).     

Characterization by yeast artificial chromosome cloning of the linked apolipoprotein(a) and plasminogen genes and identification of the apolipoprotein(a) 5'' flanking region.

The apoprotein(a) [apo(a)] gene encodes a protein component of the circulating lipoprotein(a) [Lp(a)]. The apo(a) gene is highly homologous to the plasminogen gene. It encodes one of the most polymorphic human proteins, due to variability in the number of repetitions of structures called kringles. In addition, Lp(a) levels vary among individuals by more than two orders of magnitude, the high levels being highly correlated with predisposition to early atherosclerotic disease. To better understand the genetics and function of the apo(a) gene, we have cloned in yeast artificial chromosome vectors DNA fragments comprising the linked apo(a) and plasminogen genes and other members of the plasminogen family. By a combination of pulsed-field gel electrophoresis and genome walking experiments, we have identified the 5' portion and flanking regions of the apo(a) gene.     

Apolipoprotein E polymorphism affects plasma levels of lipoprotein(a)

In a group of 303 healthy Caucasian adults of both sexes we studied the influence of the apolipoprotein E (apo E) polymorphism on plasma levels of Lipoprotein(a) (Lp(a)). The APOE^*2 allele was found to decrease the mean plasma Lp(a) level by 24.8%, whereas the APOE^*4 allele increased the mean Lp(a) level by 25.7%. These effects were parallel to the effect of apo E polymorphism on plasma cholesterol and low density lipoprotein (LDL)-cholesterol. For the Lp(a) levels, the genetic variance associated with the APOE locus contributed about 4% to the total phenotypic variance. For plasma cholesterol and LDL-cholesterol this contribution was 4.5 and 6.3%, respectively. We also found a significant positive correlation between LDL-cholesterol and Lp(a) levels. Since the apo E polymorphism effects LDL-receptor activity, we conclude that, at least in healthy normolipidemic individuals, plasma levels of Lp(a) are modulated by the LDL-receptor activity.     

脂蛋白(a)与心血管疾病的关系

脂蛋白(a)[Lp(a)]结构类似于低密度脂蛋白(LDL),高水平Lp(a)是一种公认的心血管疾病危险因子。体内存在氧化型Lp(a)更易于促进动脉粥样硬化的发生发展。Lp(a)中的载脂蛋白(a)[apo(a)]存在异质性,研究显示其危险性可能是由于apo(a)等位基因水平差异引起的,而且apo(a)的多态性影响到Lp(a)水平的临床测定,如何降低apo(a)对结果的影响还需要更多深入研究。目前针对高Lp(a)水平的人群尚无统一的治疗标准,但降脂治疗有益于预防心脑血管疾病的发生。     

Corticotropin-induced reduction of plasma lipoprotein(a) concentrations in healthy individuals and hemodialysis patients: relation to apolipoprotein(a) size polymorphism

Lipoprotein(a) [Lp(a)], a strong independent cardiovascular risk factor, consists of the unique apolipoprotein(a) [apo(a)] covalently linked to a low-density lipoprotein particle. Apo(a) contains a widely differing number of the plasminogen-like kringle IV, a size polymorphism that is codominantly inherited. In addition to powerful genetic control, renal failure is known to influence the plasma Lp(a) concentration. There is still a lot to be learned about the mode and site of catabolism of Lp(a), and there is no readily applicable Lp(a)-lowering treatment available. Therefore, it was of interest to study further the Lp(a)-lowering effect of corticotropin (ACTH) that has been demonstrated in small studies. The main purpose of the present study was to investigate the influence of ACTH on different apo(a) isoforms. Short-term treatment with ACTH decreased the plasma Lp(a) concentration in all 26 study participants. The two study groups (12 healthy individuals and 14 hemodialysis patients) responded similarly, with a median decrease in plasma Lp(a) of 39% and 49%, respectively. In subjects with two clearly separable apo(a) bands, apo(a) phenotyping and densitometric scanning of the bands before and after treatment with ACTH revealed a change in the proportion of apo(a) isoforms, ie, a shift toward the isoform with lower molecular weight. This was observed in seven of nine investigated subjects (four of five healthy individuals and three of four hemodialysis patients).     

Lipoprotein(a): an elusive cardiovascular risk factor

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.     

Lipoprotein (a) is associated with endothelial function in healthy postmenopausal women

BACKGROUND: Lipoprotein (a) (Lp(a)) is an independent risk factor for atherosclerotic cardiovascular disease. The atherogenic potential of Lp(a) may be by impairment of endothelial function. Objectives. We investigated the relation of Lp(a) plasma levels to endothelium dependent and independent dilatation of the brachial artery in healthy postmenopausal women. METHODS: One hundred and five healthy postmenopausal women aged 52-67 years were included in the study. Endothelial function was assessed non-invasively by measuring percent lumen diameter change in the brachial artery after reactive hyperemia and sublingual nitroglycerine spray. RESULTS: Flow mediated dilatation was inversely related to the plasma logLp(a) level. Mean change per unit logLp(a) increase:-2.83% (95% CI: -5.22--0.43). Elevated Lp(a) (>239 mg/l) (upper quartile) was associated with an impaired flow mediated vasodilatation (2.4%+/-1. 2) compared to Lp(a) < or =239 mg/l (5.2%+/-0.7). Adjustment for other cardiovascular risk factors did not change the magnitude of the association. Nitroglycerine-induced vasodilatation was not significantly lower in the high Lp(a) level group, compared to the group with normal levels of Lp(a) (< or =239 mg/l) (8.0+/-1.2 vs. 11.4%+/-0.8). CONCLUSION: Elevated lipoprotein (a) levels are associated with an impaired endothelial function in healthy postmenopausal women, independent of conventional risk factors for cardiovascular disease. Since Lp(a) may be pathogenetically important for early vascular damage, elevated Lp(a) levels might contribute to the increased cardiovascular risk seen in postmenopausal women.     

Urinary excretion of apo(a) fragments in NIDDM patients

Summary Lp(a), one of the most atherogenic lipoproteins, is believed to contribute significantly to vascular diseases in non-insulin-dependent diabetic (NIDDM) patients. Contradictive data have been published on these patients concerning plasma concentrations of Lp(a) and their relation to renal function. Since apo(a) fragments appear in urine, we measured urinary apo(a) in 134 NIDDM patients and 100 matched controls and related urinary apo(a) concentrations to plasma Lp(a) levels and kidney function. Plasma Lp(a) values were found to be significantly higher in NIDDM patients. NIDDM patients also secreted significantly more apo(a) into their urine as compared to control subjects. There was no correlation between creatinine clearance or albumin excretion and urinary apo(a) concentrations. Patients with macroalbuminuria exhibited a twofold higher apparent fractional excretion of apo(a) in comparison to patients with normal renal function. Urinary apo(a) values in both patients and control subjects were highly correlated to plasma Lp(a), yet no correlation was found with HbA_{1 c} or serum lipoproteins. It is concluded that urinary apo(a) excretion is correlated to plasma Lp(a) levels but not to creatinine clearance in patients suffering from NIDDM. [Diabetologia (1997) 40: 1455–1460] Received: 26 May 1997 and in revised form: 21 July 1997     

Lipoprotein(a): genotype-phenotype relationship and impact on atherogenic risk

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).