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Lipoprotein, Lp(a)

The LPA gene encodes a plasminogene-like lipoprotein, Lp(a), which is bound to apolipoprotein B. Height plasma concentrations of that lipoprotein are associated with accelerated cardiovascular disease. Genetically, plasma concentration of Lp(a) is associated with the number of kringle IV-2 repeats such that shorter proteins result higher Lp(a) levels. An association is also found between the number of kringles and two polymorphisms (rs10455872 and rs3798220).

Gene Structure

The LPA gene and the plasminogen gene (PLG) show great sequence homology. Both genes are located in a head-to-head position on chromosome 6 (6q26). It is hypothesized that the LPA gene arose from the PLG gene by duplication and subsequent deletion and copy number variation. However, as calculations of the time of divergence yield different results when calculated for the 3'UTR (PLG distant region) and 5'UTR (PLG-near region), 40 and 7 million years, respectively, the LPA gene may have evolved in two steps.

While the domain structure of the PLG gene consists of signal peptide, tail, kringles 1-5, and protease, the LPA gene lacks the tail and kringles 1-3. In addition it has a variable number of kringle 4 (10-51). 10 types of kringle 4 showing subtle sequnece differences can be distinguished. Only with kringle 4-2 copy number variations (1-42 are observed). Kringle 4-2 consists of two exons (161 bp and 181 bp), an intra-kringle intron between these exons of about 4kb, and an inter-kringle intron to the next kringle (1.2kb).

The protease of the LPA gene significantly differs from that of plasminogen, so it is not clear whether it acts as a protease at all.

Interpretation

The minor allele frequency of the two SNPs (rs10455872 and rs3798220) is 7% and 2%, respectively. 15% of the normal population carries at least one such minor allele. Among carriers of the large lipoprotein (a) [Lp(a)] phenotype only 2% carry one of the two minoralleles while among patient with the short phenotype the percentage is 53%.

Genetests:

Clinic Method Carrier testing
Turnaround 5 days
Specimen type genomic DNA
Clinic Method Massive parallel sequencing
Turnaround 25 days
Specimen type genomic DNA
Clinic Method Genomic sequencing of the entire coding region
Turnaround 25 days
Specimen type genomic DNA
Clinic Method Target mutation analysis
Turnaround 25 days
Specimen type genomic DNA

Related Diseases:

Arteriosclerosis
APOB
APOE
HABP2
LDLR
LPA
MTHFR
PON1
SLC3A1
Lp(a) hyperlipoproteinemia
LPA

References:

1.

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2.

Drayna DT et al. (1988) Genetic linkage between lipoprotein(a) phenotype and a DNA polymorphism in the plasminogen gene.

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3.

Greger V et al. (1988) No evidence for linkage between lipoprotein(a) (LPA) and esterase D (ESD).

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4.

Frank SL et al. (1988) The apolipoprotein(a) gene resides on human chromosome 6q26-27, in close proximity to the homologous gene for plasminogen.

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5.

McLean JW et al. () cDNA sequence of human apolipoprotein(a) is homologous to plasminogen.

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6.

Hasstedt SJ et al. (1983) The genetics of quantitative plasma Lp(a): analysis of a large pedigree.

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None (2013) Causes and consequences of lipoprotein(a) abnormalities in kidney disease.

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26.

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35.

Dahlén G et al. (1976) Further evidence for the existence of genetically determined metabolic differences between Lp(a+) and Lp(a-) individuals.

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36.

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37.

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38.

Malgaretti N et al. (1992) Characterization by yeast artificial chromosome cloning of the linked apolipoprotein(a) and plasminogen genes and identification of the apolipoprotein(a) 5' flanking region.

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39.

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40.

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41.

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42.

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43.

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44.

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45.

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46.

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47.

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48.

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49.

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50.

Gavish D et al. (1989) Plasma Ip(a) concentration is inversely correlated with the ratio of Kringle IV/Kringle V encoding domains in the apo(a) gene.

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51.

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52.

Lindahl G et al. (1989) The gene for the Lp(a)-specific glycoprotein is closely linked to the gene for plasminogen on chromosome 6.

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53.

Berg K et al. (1979) Lp(a) phenotypes, other lipoprotein parameters, and a family history of coronary heart disease in middle-aged males.

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54.

Rath M et al. (1990) Hypothesis: lipoprotein(a) is a surrogate for ascorbate.

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55.

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56.

Clarke R et al. (2009) Genetic variants associated with Lp(a) lipoprotein level and coronary disease.

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57.

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58.

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59.

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60.

OMIM.ORG article

Omim 152200 external link
61.

NCBI article

NCBI 4018 external link
62.

Wikipedia article

Wikipedia EN (Lipoprotein(a)) external link
Update: Aug. 14, 2020
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