The unique lipoprotein(a): properties and immunochemical measurement

Abstract Lipoprotein (a) [Lp(a)] represents a class of lipoprotein particles defined by the presence of apolipoprotein(a), a unique glycoprotein linked by a disulfide bond to apolipoprotein B-100 to form a single macromolecule. Apolipoprotein(a) is formed by three different structural domains having high amino acid sequence homology with plasminogen. One of the domains, called kringle 4, is present in multiple copies, the number of which varies and is genetically determined. This accounts for the size heterogeneity of apolipoprotein(a) and thus of Lp(a). Because high concentrations of Lp(a) are associated with atherosclerotic cardiovascular and cerebrovascular disease and may inhibit fibrinolysis, interest in measuring Lp(a) has increased considerably, leading to a rapid development of commercially available immunoassays for the measurement of Lp(a) in human plasma. However, the immunochemical measurement of Lp(a) has several peculiar problems in addition to those encountered by the measurements of other apolipoproteins. The major problems that need to be carefully evaluated are (a) the structural complexity and heterogeneity of Lp(a), (b) the homology of apolipoprotein(a) with plasminogen, (c) the lack of standardization of the methods, and (d) the lack of a common means of expressing the Lp(a) values.

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Structural Domains of Apolipoprotein(a) and Its Interaction with Apolipoprotein B-100 in the Lipoprotein(a) Particle

Biochemistry ◽

10.1021/bi00177a026 ◽

1994 ◽

Vol 33 (11) ◽

pp. 3335-3341 ◽

Cited By ~ 15

Author(s):

Thierry Huby ◽

Chantal Doucet ◽

Hans Dieplinger ◽

John Chapman ◽

Joelle Thillet

Keyword(s):

Apolipoprotein B ◽

Structural Domains ◽

Lipoprotein A ◽

Apolipoprotein A

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Effect of the number of apolipoprotein(a) kringle 4 domains on immunochemical measurements of lipoprotein(a)

Clinical Chemistry ◽

10.1093/clinchem/41.2.246 ◽

1995 ◽

Vol 41 (2) ◽

pp. 246-255 ◽

Cited By ~ 197

Author(s):

S M Marcovina ◽

J J Albers ◽

B Gabel ◽

M L Koschinsky ◽

V P Gaur

Keyword(s):

Monoclonal Antibody ◽

Epidemiological Studies ◽

Antibody Specificity ◽

Confounding Effect ◽

Apo B ◽

Lipoprotein A ◽

Apolipoprotein A ◽

Direct Binding ◽

Size Heterogeneity

Abstract Lipoprotein(a) [Lp(a)] has been measured in numerous clinical and epidemiological studies by a variety of immunochemical methods. However, little, if any, consideration has been given to the confounding effect of the size heterogeneity of apolipoprotein(a) [apo(a)] on the measurement of Lp(a). We developed three direct-binding enzyme-linked immunosorbent assays (ELISAs) with detecting antibodies of different specificities to evaluate the effect of apo(a) size on Lp(a) measurement. The three assays used the same monoclonal antibody to capture the apo(a)-containing particles and were calibrated (in nanomoles per liter) with a serum containing apo(a) with 21 kringle 4 domains. Using all three ELISAs, we measured Lp(a) in a group of 723 subjects selected to have a single apo(a) band, as determined by a high-resolution phenotyping system. Essentially identical results were obtained by the two methods that measured Lp(a) by use of either a polyclonal antibody against apo B or a monoclonal antibody against apo(a) that does not recognize the kringle 4 type 2 repeats. In contrast, the ELISA using a monoclonal antibody specific for apo(a) kringle 4 type 2 repeats overestimated Lp(a) concentration in samples containing apo(a) with more than 21 kringle 4 domains and underestimated Lp(a) samples containing apo(a) with fewer than 21 kringle 4 domains. Thus, these differences in Lp(a) values varied as a function of apo(a) size. We conclude that antibody specificity and apo(a) size heterogeneity can significantly affect Lp(a) measurements.

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Early Expression of the Apolipoprotein (a) Gene: Relationships Between Infants' and Their Parents' Serum Apolipoprotein (a) Levels

PEDIATRICS ◽

10.1542/peds.89.3.401 ◽

1992 ◽

Vol 89 (3) ◽

pp. 401-406 ◽

Cited By ~ 1

Author(s):

Xing L. Wang ◽

David E. L. Wilcken ◽

Nicholas P. B. Dudman

Keyword(s):

Positive Family History ◽

Serum Levels ◽

Serum Lipoprotein ◽

Parental Values ◽

Lipoprotein A ◽

Apolipoprotein A ◽

Early Expression ◽

High Concentrations ◽

Family Based ◽

Highly Correlated

The serum concentration of apo(a), the unique apolipoprotein of lipoprotein (a), reflects serum lipoprotein (a) levels. High concentrations are associated with increased cardiovascular risk. Inasmuch as atherogenesis may begin in childhood, the early expression of the apo(a) gene and relationships between serum levels in infants and their parents were explored. Serum apo(a) and lipid profiles were measured in 51 infants when aged 8.5 ± 2 months. They were from among 1032 consecutively born babies in whom apo(a) levels had been measured on day 2 to 5. Levels in 18 infants were in the top 5% of the neonatal apo(a) distribution and in 33 from below the 95th percentile. Parental values were also assessed. Infants' apo(a) levels (n = 51) at the ages of 2 to 5 days and 8.5 ± 2.3 months were highly correlated (r .73, P < .0001) and increased from an initial median value of 48 U/L (range 1 to 462 U/L) to 100 U/L (5 to 969 U/L) at 8.5 months, and they were then not different from parental levels. Measurements at both times were closely correlated with parental levels. Regression coefficients between 8.5-month levels, and the levels of fathers, of mothers, and the average level of both parents were 0.439, 0.521 and 0.93, respectively (P < .0001 for each). It is concluded that the gene for the regulation of apo(a) is fully expressed before the age of 1 year. The apo(a) levels in infants during this time track closely and are predictive of parental values. These results are consistent with apo(a) contributing to that part of coronary risk associated with a positive family history, with implications for both future childhood screening and family-based coronary prevention.

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Report of the National Heart, Lung, and Blood Institute Workshop on Lipoprotein(a) and Cardiovascular Disease: Recent Advances and Future Directions

Clinical Chemistry ◽

10.1373/clinchem.2003.023689 ◽

2003 ◽

Vol 49 (11) ◽

pp. 1785-1796 ◽

Cited By ~ 180

Author(s):

Santica M Marcovina ◽

Marlys L Koschinsky ◽

John J Albers ◽

Sonia Skarlatos

Keyword(s):

Structural Complexity ◽

Lipoprotein A ◽

Blood Institute ◽

Relative Contribution ◽

National Heart ◽

The Us ◽

National Heart Lung ◽

Artery Disease ◽

Underlying Mechanisms ◽

Size Heterogeneity

Abstract It has been estimated that ∼37% of the US population judged to be at high risk for developing coronary artery disease (CAD), based on the National Cholesterol Education Program guidelines, have increased plasma lipoprotein(a) [Lp(a)], whereas Lp(a) is increased in only 14% of those judged to be at low risk. Therefore, the importance of establishing a better understanding of the relative contribution of Lp(a) to the risk burden for CAD and other forms of vascular disease, as well as the underlying mechanisms, is clearly evident. However, the structural complexity and size heterogeneity of Lp(a) have hindered the development of immunoassays to accurately measure Lp(a) concentrations in plasma. The large intermethod variation in Lp(a) values has made it difficult to compare data from different clinical studies and to achieve a uniform interpretation of clinical data. A workshop was recently convened by the National Heart, Lung, and Blood Institute (NHLBI) to evaluate our current understanding of Lp(a) as a risk factor for atherosclerotic disorders; to determine how future studies could be designed to more clearly define the extent to which, and mechanisms by which, Lp(a) participates in these processes; and to present the results of the NHLBI-supported program for the evaluation and standardization of Lp(a) immunoassays. This report includes the most recent data presented by the workshop participants and the resulting practical and research recommendations.

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Increased Serum Lipoprotein(a) Concentrations and Low Molecular Weight Phenotypes of Apolipoprotein(a) Are Associated with Symptomatic Peripheral Arterial Disease

Clinical Chemistry ◽

10.1373/clinchem.2007.088013 ◽

2007 ◽

Vol 53 (7) ◽

pp. 1298-1305 ◽

Cited By ~ 32

Author(s):

Benjamin Dieplinger ◽

Arno Lingenhel ◽

Nadja Baumgartner ◽

Werner Poelz ◽

Hans Dieplinger ◽

...

Keyword(s):

Molecular Weight ◽

Peripheral Arterial Disease ◽

Arterial Disease ◽

Low Molecular Weight ◽

Serum Concentrations ◽

Entire Study ◽

Lipoprotein A ◽

Apolipoprotein A ◽

Peripheral Arterial ◽

Genetically Determined

Abstract Background: Increased concentrations of lipoprotein(a) [Lp(a)] have been considered a genetically determined risk factor for coronary artery and cerebrovascular disease. Only 2 small and conflicting studies have investigated the possibility of an association of peripheral arterial disease (PAD) with high serum Lp(a) concentrations and low molecular weight (LMW) phenotypes of apolipoprotein(a) [apo(a)]. Methods: We measured serum concentrations of Lp(a) and apo(a) phenotypes in 213 patients with symptomatic PAD and 213 controls matched for sex, age (within 2 years), and presence of diabetes. Results: Patients with PAD showed significantly higher median serum concentrations of Lp(a) (76 vs 47 mg/L; P = 0.003) and a higher frequency of LMW apo(a) phenotypes (41% vs 26%; P = 0.002) than controls. After adjustment for several potential confounders, increased Lp(a) concentrations (>195 mg/L, i.e., 75th percentile of the entire study sample) and LMW apo(a) phenotypes were significant predictors of PAD, with odds ratios of 3.73 (95% CI 2.08–6.67; P <0.001) and 2.21 (95% CI 1.33–3.67; P = 0.002), respectively. Conclusions: In this study sample, both increased serum concentrations of Lp(a) and the presence of LMW apo(a) phenotypes were associated with the presence of symptomatic PAD independent of traditional and nontraditional cardiovascular risk factors. Because PAD is considered an indicator of systemic atherosclerotic disease, our results suggest a possible role of Lp(a) as a genetically determined marker for systemic atherosclerosis.

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Quantification of lipoprotein(a) in plasma by assaying cholesterol in lectin-bound plasma fraction

Clinical Chemistry ◽

10.1093/clinchem/40.3.400 ◽

1994 ◽

Vol 40 (3) ◽

pp. 400-403 ◽

Cited By ~ 48

Author(s):

L J Seman ◽

J L Jenner ◽

J R McNamara ◽

E J Schaefer

Keyword(s):

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Cholesterol Content ◽

Lipoprotein A ◽

Apolipoprotein A ◽

Plasma Fraction ◽

Chd Risk ◽

Increased Risk ◽

The Mean ◽

High Concentrations

Abstract Lipoprotein(a) [Lp(a)] is a low-density lipoprotein (LDL)-like particle in which apolipoprotein(a) [apo(a)] is disulfide-linked to apolipoprotein B (apoB). High concentrations of Lp(a) in plasma are associated with an increased risk of coronary heart disease (CHD). Lp(a) has traditionally been measured by immunoassay and expressed as total mass of Lp(a). Measuring Lp(a) by its cholesterol content will provide a way to directly compare Lp(a) with other lipoproteins that are measured by cholesterol. We have developed an assay to quantify Lp(a) by its cholesterol content [Lp(a)-C], using lectin affinity to isolate Lp(a) from other lipoproteins, and then measuring the cholesterol within the isolated fraction. We compared the Lp(a)-C assay with an ELISA for Lp(a) mass in 47 plasma samples from normotriglyceridemic, fasting individuals with high Lp(a) contents (mean +/- SD, 446 +/- 350 mg/L). The mean Lp(a)-C concentration was 110 +/- 89 mg/L and correlated very highly with Lp(a) mass (r = 0.9975). Lp(a)-C measurement is an alternative method to screen for this CHD risk factor.

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Lp(a): der akzeptierte unabhängige Risikofaktor

Dialyse aktuell ◽

10.1055/a-0969-0439 ◽

2019 ◽

Vol 23 (09) ◽

pp. 388-391

Author(s):

Volker Schettler

Keyword(s):

Lipoprotein A ◽

Apolipoprotein A ◽

Apolipoprotein B100

Lipoprotein(a) (Lp(a)) besteht aus einem LDL-Partikel, an dem über das Apolipoprotein B100 des Partikels eine Disulfidbrücke zu einem Apolipoprotein(a) besteht ( Abb. 1 ). Obwohl Lp(a) bereits 1963 von Berg et al. erstmals als „lipoprotein associated antigen“ entdeckt 1 und schon früh ein Zusammenhang mit kardiovaskulären Ereignissen diskutiert wurde 2, konnten diese Annahmen der klinischen Eigenschaften erst deutlich später im Rahmen von epidemiologischen Evaluationen bestätigt werden 3, 4. Ab einer Lp(a)-Konzentration von über 30 mg/dl (> 75 nmol/l) besteht ein nahezu linearer Zusammenhang zwischen dem Anstieg der Lp(a)-Konzentration und kardiovaskulären Ereignissen wie Myokardinfarkt und das Risiko für eine Aortenklappenstenose 3, 4.

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