Other entities represented in this entry:
HGNC Approved Gene Symbol: LPA
Cytogenetic location: 6q25.3-q26 Genomic coordinates (GRCh38) : 6:160,531,482-160,664,275 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6q25.3-q26 | [LPA deficiency, congenital] | 618807 | Autosomal dominant | 3 |
| {Coronary artery disease, susceptibility to} | 618807 | Autosomal dominant | 3 |
Lipoprotein(a) is composed of an LDL-like particle in which apoB (107730) is covalently bound by a single disulfide bond to apolipoprotein(a), the pathognomonic component of Lp(a). Apo(a) evolved over millennia from plasminogen (PLG; 173350). Plasminogen contains 5 kringles (KI to KV) and a protease domain. Apo(a) does not contain KI to KIII of plasminogen, but instead contains 10 subtypes of KIV (with KIV(1) and KIV(3 to 10) present in 1 copy, and KIV(2) present in 1 to over 40 copies), 1 copy of KV, and an inactive protease domain. Unlike apoB, apo(a) does not contain lipid domains or transport lipid, but instead, can bind to denuded and exposed lysine-rich vascular endothelium, similar to and also in competition with plasminogen. Within populations, there is extensive apo(a) protein size heterogeneity, with over 40 different isoforms and thus over 40 different-sized particles. Lp(a) is synthesized almost exclusively in the liver (summary by Tsimikas, 2017).
Berg and Mohr (1963) discovered a new serum protein system, called Lp (for lipoprotein), by the intravenous injection of rabbits with human serum beta-lipoprotein isolated from 1 individual. The resulting antibody distinguishes 2 distinct types of human beta-lipoprotein. Berg and Mohr (1963) demonstrated regular dominant inheritance. The Lp(a) allele has a frequency of 0.19 in Norwegians. The authors concluded that this system is independent of the Ag system of Blumberg (which subsequently proved to be a variation in the APOB gene; see 107730).
McLean et al. (1987) sequenced a human LPA cDNA and found striking similarities to human plasminogen (PLG; 173350).
Studying a large Utah pedigree, Hasstedt et al. (1983) concluded that 'a dominant major gene with polygenic background' determines the quantitative plasma Lp(a) level (618807).
Utermann et al. (1987) studied the Lp(a) glycoprotein directly by sodium dodecyl sulfate-gel electrophoresis. Family studies were compatible with the concept that Lp(a) glycoprotein phenotypes are controlled by a series of autosomal alleles at a single locus. A highly significant association was found between electrophoretic phenotype and concentration of Lp(a) lipoprotein. This suggested that the same gene locus is involved in determining the Lp(a) glycoprotein phenotypes and the Lp(a) lipoprotein concentrations in plasma and was the first indication for structural differences underlying the quantitative genetic Lp(a)-trait. Because in other respects it resembles LDL, the atherogenicity of Lp(a) is probably due to the presence of the apolipoprotein(a) component (apoa).
Apolipoprotein(a) is a very large molecule, larger than plasminogen; it contains duplications of many kringles present in small numbers in plasminogen. Utermann et al. (1988) demonstrated that the size heterogeneity of the Lp(a) glycoprotein is genetically controlled.
Gavish et al. (1989) showed that the variable number of kringle 4-like domains encoded by the LPA gene is the main factor determining the size of the lipoprotein(a) and its plasma concentration.
Kondo and Berg (1990) pointed out that the Lp(a) antigen resides in a polypeptide chain that is attached to apolipoprotein B by a disulfide bridge. They studied a variant 2-kb DNA fragment of the LPA gene detectable after digestion with the restriction enzyme MspI. It was related to the 'kringle 4' region of the LPA gene. A proportion of people appeared to lack (or have an undetectable level of) the 2-kb fragment and there were quantitative differences between samples from persons who had the fragment. Presence and amount of the fragment segregated as a mendelian trait. The variation probably reflects differences between individuals in the number of 'kringle 4' repeats at the LPA locus.
Lipoprotein(a) (Lp(a)) is formed by the disulfide linkage of apolipoprotein B100 (APOB; 107730) of a low-density lipoprotein particle to apolipoprotein(a). Previous studies had suggested that one of the C-terminal cysteine residues of apo-B100 is involved in the disulfide linkage of apo-B100 to apo(a). To identify the apo-B100 cysteine residues involved in the formation of Lp(a), McCormick et al. (1995) constructed a YAC spanning the human APOB gene and used gene-targeting techniques to change cysteine-4326 to glycine. The mutated YAC DNA was used to generate transgenic mice expressing the mutant human APOB (cys4326-to-gly). Unlike the wildtype human APOB, the mutant human APOB completely lacked the ability to bind to apo(a) and form Lp(a). The study succeeded in demonstrating that the cysteine residue was involved in the disulfide linkage and showed that gene targeting in YACs, followed by the generation of transgenic mice, is a useful approach for analyzing the structure of large proteins encoded by large genes.
Scanu (2003) explained the heterogeneity of Lp(a) lipoprotein particles as compared with particles of low density lipoprotein (LDL). Small and large particles of LDL differ mainly in the cholesteryl ester content of the lipid core (the greater the content of cholesteryl ester, the larger the particle), which in the case of both large LDL and small LDL is surrounded by a monolayer of unesterified cholesterol, phospholipids, and apolipoprotein B100. The small and large LDL particles become small and large Lp(a) lipoproteins as a result of the linkage of apolipoprotein(a) to the apolipoprotein B100 ring that surrounds the LDL particle with a single disulfide bond. Apolipoprotein(a) is made of 10 different types of kringles followed by kringle V and a nonfunctional protease domain. Apolipoprotein(a) varies in length as a function of the number of repeats of kringle IV type 2. The length of apolipoprotein(a) is genetically determined; its variability has an effect on the density of Lp(a) lipoprotein.
Ichinose (1995) determined that the LPA gene contains 2 exons.
By a combination of pulsed field gel electrophoresis and genome walking experiments, Malgaretti et al. (1992) cloned in YAC vectors DNA fragments comprising the linked LPA and PLG genes. They identified the 5-prime portion and flanking regions of the LPA gene.
Weitkamp et al. (1988) found close linkage of the LPA locus and the PLG locus on 6q26-q27 in family studies. The locus that determines quantitative variation in Lp(a) lipoprotein was linked to PLG; peak lod score = 12.73. Weitkamp (1988) was suspicious that apparent recombinants may in fact have represented typing problems because of the ambiguities in the Lp(a) system. Indeed, in some of the molecular genetics work determining the assignment of plasminogen, a DNA probe defining the LPA locus, rather than a plasminogen probe, may in fact have been used. Frank et al. (1988) showed that the LPA locus is on chromosome 6 by blot hybridization analysis of DNA from a panel of mouse-human somatic cell hybrids. In situ hybridization yielded a single peak of grain density located at 6q26-q27.
Apolipoprotein(a) has been reported only in Old World primates and in one species of hedgehog; it has not been found in New World primates, rabbits, rats, cattle, mice, or the marsupial Monodelphis domestica. By a linkage study using polymorphisms at the LPA and PLG loci, VandeBerg et al. (1991) demonstrated that the 2 loci are tightly linked in the baboon; the maximum lod score was 30.2 with no recombinants. This was said to be the first genetic linkage identified in a nonhuman primate species by family studies. It would be of interest to determine whether the 2 loci are also tightly linked in hedgehogs. It is possible that LPA arose independently on 2 different occasions during mammalian evolution, by duplication of the PLG locus.
In a large family with early coronary artery disease and high plasma levels of Lp(a), Drayna et al. (1988) found tight linkage between LPA size isoforms and a DNA polymorphism in the plasminogen gene. No linkage was found with alleles of the apoB DNA polymorphism. See review by Scanu (1988).
In studies of three 2-generation families, Lindahl et al. (1989) found no recombination in 18 meioses, indicating very close linkage of LPA and the PLG locus. Berg (1989) demonstrated close linkage between the LPA locus and the SacI restriction site polymorphism at the PLG locus.
Rath and Pauling (1990) hypothesized that Lp(a) is a surrogate for ascorbate in humans and other species that do not synthesize vitamin C (240400) and 'marshaled the evidence bearing on this hypothesis.' They pointed out that the guinea pig, for which vitamin C is essential, develops atherosclerotic deposits in arteries, as does the rabbit and other animals, but these occur on an ascorbate-deficient diet without additional cholesterol. Lp(a) shares with ascorbate the acceleration of wound healing and other cell-repair mechanisms, the strengthening of the extracellular matrix (e.g., in blood vessels), and the prevention of lipid peroxidation. Since apo(a) is associated with low-density lipoprotein by disulfide bridges, and since in vitro N-acetylcysteine (NAC) dissociates this complex, Gavish and Breslow (1991) administered NAC to 2 patients with high Lp(a) levels and found reductions of an order not hitherto achieved by either drugs or diet.
Caplice et al. (2001) showed that Lp(a) binds and inactivates tissue factor pathway inhibitor (TFPI; 152310) in vitro. They found that apo(a) binds to a region spanning the last 37 amino acids of the C terminus of TFPI. In human atherosclerotic plaque, apo(a) and TFPI immunostaining coexisted in smooth muscle cell-rich areas of the intima. These data suggested a novel mechanism whereby Lp(a), through its apo(a) moiety, may promote thrombosis by binding and inactivating TFPI.
Data on gene frequencies of allelic variants were tabulated by Roychoudhury and Nei (1988).
Lipoprotein(a) Quantitative Trait Locus
Berg and Mohr (1963) found that the Lp(a) allele has a frequency of 0.19 in Norwegians.
Kamboh et al. (1991) demonstrated that Lp(a) is a highly polymorphic protein. The average heterozygosity at the LPA structural locus is 94%. Plasma lipoprotein(a) shows wide quantitative variation among individuals. These variations in concentration are heritable and inversely related to the number of kringle 4 repeats in the LPA gene (see LPAQTL, 618807).
Sandholzer et al. (1991) found that the mean level of Lp(a) varied widely in 7 ethnic groups studied: from a mean of 7.2 mg/dl in Chinese to a mean of 45.7 in Sudanese. They found, furthermore, that differences in apo(a) allele frequencies alone did not explain the differences in Lp(a) levels among populations.
Boerwinkle et al. (1992) compared Lp(a) concentrations and LPA genotypes in 48 nuclear Caucasian families. Genotypes were determined by a pulsed field gel electrophoresis method that distinguished 19 genotypes at the LPA locus. They showed that the LPA gene itself accounts for almost all genetic variability in plasma Lp(a) levels. Among 72 sibs who shared both LPA alleles, the correlation coefficient for plasma concentration was 0.95, whereas in 52 sibs who shared no LPA alleles, the correlation coefficient was -0.23. The LPA gene was estimated to be responsible for 91% of the variance of plasma concentration. The number of kringle 4 repeats in the LPA gene accounted for 69% of the variation; yet-to-be defined cis-acting sequences at the LPA locus accounted for the remaining 22% of interindividual variation. During the course of the studies, Boerwinkle et al. (1992) observed the de novo generation of an LPA allele, an event that occurred once in 376 meioses.
Marcovina et al. (1993) identified 34 isoforms of apolipoprotein(a) in a sample of 806 American whites and 701 American blacks, using a high resolution SDS-agarose gel electrophoretic method followed by immunoblotting. The frequency of the various isoforms differed between blacks and whites. Lackner et al. (1993) cloned and characterized the region of the LPA gene responsible for its extraordinary size polymorphism; this glycoprotein varies in size over a range of approximately 500 kD. Lackner et al. (1993) found that the LPA alleles of different lengths contain varying numbers of a subset of a tandemly repeated, 5.5-kb, kringle IV encoding sequence. A total of 34 LPA alleles and corresponding glycoproteins could be distinguished using pulsed field gel electrophoresis and genomic blotting and immunoblotting. Molecular analysis of a newly generated LPA allele of different length suggested that the high degree of length polymorphism is in part due to recombination between sister chromatids.
Knapp et al. (1993) followed up on the observation that Lp(a) levels are approximately twice as high in black adults and children compared with whites by studying the levels in 113 white men (average age = 71 years +/- 6) and 83 black men (average age = 72 years +/- 9). The distribution was skewed in both whites and blacks. The skewed distribution in elderly black men was in contrast to the bell-shaped distribution commonly reported for younger blacks. The data suggested a shift to lower values among elderly as compared to younger men, with the greatest shift occurring among the black men. For black men who had survived to the seventh, eighth, and ninth decades of life, Lp(a) levels approached the lower levels of white men.
Apolipoprotein(a) varies in size over a range of approximately 500 kD due to interallelic differences in the number of tandemly repeated kringle 4 (K4)-encoding 5.5-kb sequences in the LPA gene. Only 1 of the 10 different types of K4 repeats in the LPA gene, the so-called type 2 K4 repeats, vary in number between LPA alleles. Mancini et al. (1995) showed that there is microheterogeneity within the sequence of the type 2 K4 repeat. Digestion with the restriction enzyme DraIII and genomic blotting revealed that a subset of the type 2 K4-encoding sequences contain a DraIII site, which Mancini et al. (1995) referred to as K4-D. The proportion of LPA alleles that had at least one K4-D repeat ranged from 25% in Caucasians to 50% in Chinese. K4-D repeats were clustered at the end(s) of the type 2 K4 tandem array and the number in patterns of the K4-D repeats were in linkage disequilibrium with flanking sequence polymorphisms; these features were remarkably similar to the minisatellite variant repeats (MVRs) found in variable number of tandem repeat sequences (VNTRs). In addition, a DraIII pattern that comprised 9% of the sample was found to be invariably associated with low plasma levels of Lp(a) in Caucasians.
Ichinose (1995) and Ichinose and Kuriyama (1995) demonstrated, by nucleotide sequence analysis of the LPA gene, the presence of polymorphisms in its 5-prime flanking region: G/A at position -773, C/T at position +93, and G/A at position +121, relative to the transcription start site. Since the nucleotide substitutions can be distinguished by the presence or absence of restriction sites for TaqI, MaeII, and HhaI endonucleases, respectively, the LPA alleles among individuals could be classified by restriction digestion analysis into 4 types, A through D. To elucidate whether these polymorphisms affect the expression of the gene, Suzuki et al. (1997) measured plasma Lp(a) concentrations in vivo by ELISA and examined expression of the gene by an in vitro assay using its 5-prime flanking region. Homozygotes of type C had significantly higher Lp(a) levels than those of type D. The relative expression of type C was also about 3 times higher than that of type D, which was consistent with the in vivo results. Deletion analysis revealed that the substitution of C by T at position +93 led to negative regulation in expression of the gene, while a change of G to A at position +121 led to positive regulation. These results indicated that the polymorphisms in the 5-prime flanking region of the LPA gene affect the efficiency of its expression and, in part, play a role in regulating plasma Lp(a) levels. (The 4 alleles, designated A, B, C, and D by Suzuki et al. (1997), showed the following pattern of presence or absence of the restriction site at the 3 positions (-773, +93, +121): A = +/+/+; B = -/+/+; C = -/+/-; D = -/-/+.)
Ogorelkova et al. (2001) identified 14 single-nucleotide polymorphisms (SNPs) in apo(a) K4 types 6, 8, 9, and 10; no sequence variants common to Africans and Caucasians were found. A substitution in K4 type 6 and another in K4 type 8 were associated with Lp(a) levels significantly below average in Africans. In contrast, a substitution in K4 type 9, which occurred with a frequency of 8% in Khoi San Africans, resulted in a significantly increased Lp(a) concentration. The authors concluded that several SNPs in the coding sequence of apo(a) may affect Lp(a) levels.
In an aboriginal African population from Gabon in central Africa consisting of 31 families with 54 children, Schmidt et al. (2006) determined that the correlation of plasma lipoprotein(a) levels associated with LPA alleles resulted in a heritability estimate of 0.801. The authors concluded that LPA is the major quantitative trait locus for plasma lipoprotein(a) in this population.
Chretien et al. (2006) investigated the basis of the 2-fold higher Lp(a) levels in African populations compared with non-African populations by comparing sequence variations in the LPA gene. They studied 534 European Americans and 249 African Americans. Isoform-adjusted Lp(a) level was 2.23-fold higher among African Americans. Three SNPs were independently associated with Lp(a) level in both populations. The Lp(a)-increasing SNP (-21G/A, which increases promoter activity) was more common in African Americans, whereas the Lp(a)-lowering SNPs (T3888P and G+1/inKIV-8A, which inhibit Lp(a) assembly) were more common in European Americans, but all had a frequency of less than 20% in one or both populations. Chretien et al. (2006) concluded that multiple low-prevalence alleles in LPA can account for the large between-population difference in serum Lp(a) levels between European Americans and African Americans.
Lopez et al. (2008) measured Lp(a) levels and performed genomewide linkage analysis in 387 individuals from 21 extended Spanish families and found the strongest evidence of linkage with Lp(a) levels at chromosome 6q25.2-q27, at the locus for the structural LPA gene (lod score, 13.8). The overall heritability of Lp(a) concentration was estimated at 0.79, indicating that approximately 79% of the phenotypic variation in the trait is due to the additive effect of genes.
Lipoprotein(a) Deficiency and Association with Type 2 Diabetes
Ogorelkova et al. (1999) demonstrated that a G-to-A transition at the +1 donor splice site of the K4 type 8 intron of the LPA gene (152200.0003) is associated with congenital deficiency of Lp(a) in plasma and occurs with a high frequency (approximately 6%) in Caucasians but not in Africans. This mutation alone accounts for a quarter of all 'null' LPA alleles in Caucasians. RT-PCR analysis based on LPA illegitimate transcription in lymphoblastoid cells demonstrated that the donor splice site mutation results in alternative splicing of the K4 type 8 intron and encodes a truncated form of apo(a). Expression of the alternatively spliced cDNA analog in cultured HepG2 cells showed that the truncated apo(a) form is secreted but is unable to form the covalent Lp(a) complex. Taken together, the data indicated that a failure in complex formation followed by fast degradation in plasma of the truncated free apo(a) is one mechanism which underlies the null Lp(a) type associated with the donor splice site mutation. Patients with congenital Lp(a) deficiency appeared to be healthy. Ogorelkova et al. (1999) suggested that Lp(a) may exert its normal function only in certain situations, e.g., when challenged by environmental factors such as pathogens. In such situations, low or absent Lp(a) may represent a susceptibility state, and high Lp(a) may be protective. Hence, association of congenital Lp(a) deficiency with a specific clinical phenotype may be difficult to detect and may not or only rarely occur in some ethnic groups or geographic areas. Such a scenario would explain the low Lp(a) levels and the presence of the splice site mutation in Caucasians as opposed to Africans. It appeared that the splice site mutation occurred after the separation of African and non-African populations.
Parson et al. (2004) described a C-to-T transversion at nucleotide 61 in exon 1 of the kringle IV type 2 domain of the LPA gene, predicted to result in an arg21-to-ter (R21X) truncated protein (152200.0004). The allele frequency of this single-nucleotide polymorphism was 0.02. Parson et al. (2004) stated that this mutation represented the second apparent apo(a) null allele in humans (the first being that described by Ogorelkova et al. (1999), 152200.0003).
Elevation of Lipoprotein(a) Levels and Association with Cardiovascular Disease
In 3,145 individuals with coronary artery disease (CAD) and 3,352 controls, Clarke et al. (2009) performed a genomewide association study involving 48,742 SNPs in 2,100 candidate genes and found the strongest association at the LPA locus on chromosome 6q26-q27, with a corrected p of less than 0.05 for 27 SNPs, 16 of which were also significantly associated with Lp(a) level. Clarke et al. (2009) noted that the 2 SNPs most strongly associated with Lp(a) level, rs3798220 and rs10455872, were also the most strongly associated with increased risk of CAD (odds ratio (OR) of 1.92 and 1.70, respectively). In addition, the rare alleles of both rs3798220 and rs10455872 were each correlated with a smaller Lp(a) isoform and a lower copy number. Metaanalysis showed increased risk of CAD for 1 LPA variant allele (OR, 1.51) and 2 or more variant alleles (OR, 2.57).
Association with Aortic Valve Calcification
For discussion of a possible association between variation in the LPA gene and calcification of the aortic valve, see 152200.0008.
Elevated plasma levels of Lp(a) are associated with increased risk for atherosclerosis and its manifestations--myocardial infarction, stroke and restenosis. As the plasma concentration of Lp(a) is strongly influenced by heritable factors and is refractory to most drug and dietary manipulation, the effects of modulating it are difficult to mimic experimentally. In addition, the absence of apolipoprotein(a) from virtually all species other than primates precludes the use of convenient animal models. However, Lawn et al. (1992) demonstrated that transgenic mice expressing human apolipoprotein(a) are more susceptible than control mice to the development of lipid-staining lesions in the aorta, and that apolipoprotein(a) colocalizes with lipid deposition in the artery walls. As an extension of these studies, Grainger et al. (1994) established that the major in vivo action of apolipoprotein(a) is inhibition of conversion of plasminogen to plasmin, resulting in a decreased activation of latent transforming growth factor-beta (TGFB; 190180). TGFBs are negative regulators of smooth muscle cell migration and proliferation, pointing to a possible mechanism for apolipoprotein(a) induction of atherosclerotic lesions.
Lou et al. (1998) crossed apo(a) transgenic mice with fibrinogen knockout mice to generate fibrinogen-deficient apo(a) transgenic mice and control mice. In the vessel wall of apo(a) transgenic mice, fibrinogen deposition was found to be essentially colocalized with focal apo(a) deposition and fatty streak-type atherosclerotic lesions. Fibrinogen deficiency in apo(a) transgenic mice decreased the average accumulation of apo(a) in vessel walls by 78% and the average lesion (fatty streak type) development by 81%. Fibrinogen deficiency in wildtype mice did not significantly reduce lesion development. The results suggested that fibrinogen provides one of the major sites to which apo(a) binds to the vessel wall and participates in the generation of atherosclerosis.
Berg (1967) suggested that at least 4 lipoprotein systems exist: Ag (APOB), Lp, Ld, and Lt. Schultz and Shreffler (1972) espoused a polygenic determination of Lp antigen, whereas Berg (1972) defended his monolocus hypothesis.
Namboodiri et al. (1977) concluded that Lp and esterase D (ESD; 133280) are closely linked; the maximum lod score was 2.32 at a recombination fraction of 0.0. Ott and Falk (1982), however, reanalyzed the data of Namboodiri et al. (1977) in connection with a theoretic consideration of the confounding effects of epistatic association on linkage. Namboodiri et al. (1977) had noted a strong association between the phenotypes a- and a+ at the Lp locus and the phenotypes 2-1 and 1-1 at the ESD locus (no 2-2 persons were found in the pedigree). The reanalysis resulted in a considerable drop in the lod score for linkage. Greger et al. (1988) excluded linkage of LPA not only with ESD but also with the retinoblastoma locus (RB; 180200), which is closely situated on chromosome 13.
Ichinose and Kuriyama (1995) used the designation C for the polymorphism in the 5-prime flanking region of the LPA gene -773A, +93C, +121A. They found that homozygotes of type C had significantly higher Lp(a) levels than those of type D. In vitro studies indicated that the relative expression of type C was also about 3 times higher than that of type D, which was consistent with the in vivo results.
Ichinose and Kuriyama (1995) used the designation D for the LPA allele of the following haplotype: -773G, +93T, +121G. Homozygotes of type D had significantly lower Lp(a) levels than those of type C.
Ogorelkova et al. (1999) identified a G-to-A transition in the donor splice site (position 1) of the 6-kb intron separating the 2 exons of the kringle IV (K4) type 8 repeat of the LPA gene, resulting in deficiency of lipoprotein(a) (Lp(a)); see 618007. The frequency of this splice site mutation was 0.053 in a Tyrolean sample of 113 individuals, and the mutation was not found in 200 Africans. In a sample of 126 Finns, the frequency of the mutation was 0.0635. The alleles of this splice site polymorphism were in Hardy-Weinberg equilibrium in both Tyroleans and Finns. Approximately 11% of Europeans are heterozygous and 0.3% homozygous for this G-to-A splice site mutation. Persons with congenital deficiency of Lp(a) appeared to be clinically healthy.
Gudbjartsson et al. (2019) investigated 143,087 Icelanders with genetic information, including 17,715 with coronary artery disease (CAD) and 8,734 with type 2 diabetes (T2D; see 125853). They identified 2 loss-of-function mutations in the LPA gene in Icelandic patients, including the splice donor variant rs41272114-T (c.4289+1G-A, NM_005577) previously reported by Ogorelkova et al. (1999) (allele frequency = 5.9%) and rs143431368 (152200.0005). Patients with loss-of-function homozygosity were associated with an increased risk of T2D (OR = 1.45; p less than 0.022).
Parson et al. (2004) described a homozygous C-to-T transversion at nucleotide 61 in exon 1 of the kringle IV type 2 domain of the LPA gene, predicted to result in an arg21-to-ter (R21X) truncated protein (GenBank L14005.1). The allele frequency of this single-nucleotide polymorphism was 0.02 and represents the second apparent apo(a) null allele in humans.
Gudbjartsson et al. (2019) investigated 143,087 Icelanders with genetic information, including 17,715 with coronary artery disease (CAD) and 8,734 with type 2 diabetes (T2D). They identified 2 loss-of-function mutations in Icelandic patients, including the rare (allelic frequency of 0.33%) splice acceptor variant rs143431368-C (c.4974A-G, NM_005577) and rs41272114 (152200.0003). Patients with loss-of-function homozygosity were associated with an increased risk of T2D (OR = 1.45; p less than 0.022).
Coassin et al. (2017) described a novel variant in the exonic donor splice site of the second KIV-2 exon of the LPA gene. The authors used the non-standard designation 'G4925A' for the variant because unique position annotation was not possible. To allow context sequence determination, they provided arbitrary HGVS annotation of the variant to the first KIV-2 repeat of the human reference genome as c.853G-A (NM_005577). Coassin et al. (2017) estimated that the variant occurs in only 1 or 2 of all KIV-2 repeats in an individual. In a general European population of 2,892 individuals, the variant had an exceptionally high carrier frequency of 22.1%. Coassin et al. (2017) showed that the variant reduces cardiovascular disease risk in low molecular weight carriers, who are otherwise at high genetic CVD risk.
In a case-control study of 554 white patients with coronary artery disease and 363 controls, Luke et al. (2007) identified an ile4399-to-met (I4399M) substitution in the LPA gene that was associated with severe coronary artery disease. The mutation occurred in the protease-like domain of the protein. Compared with noncarriers, carriers of the 4399M risk allele had an adjusted odds ratio of 3.14 (95% CI, 1.51-6.56).
Clarke et al. (2009) identified the rs3798220-C SNP in the LPA gene with an odds ratio for coronary artery disease of 1.92 (95% CI, 1.48-2.49, p less than 9x10(-7)). The frequency of this variant is about 2%. The rs3798220 SNP correlated with a smaller apolipoprotein(a) isoform as measured by Western blot analysis and a lower copy number as measured with a quantitative PCR assay. The authors noted that this SNP was previously reported to have a strong association with the Lp(a) lipoprotein level, a moderate association with LDL cholesterol level, and a tentative association with the risk of coronary artery disease.
Clarke et al. (2009) identified a SNP, rs10455872-G, that maps to intron 25 in the LPA gene with an odds ratio for coronary disease of 1.70 (95% CI, 1.49-1.95, p less than 3.4x10(-15)). The allele frequency of the high-risk variant is about 7%. The rs10455872 SNP correlated with a smaller apolipoprotein(a) isoform as measured by Western blot analysis and a lower copy number as measured with a quantitative PCR assay.
Thanassoulis et al. (2013) found that rs10455872-G reached genomewide significance for the presence of aortic valve calcification with an odds ratio of 2.05 (p = 9.0x10(-10)). In prospective analyses, the SNP was associated with incident aortic stenosis (hazard ratio = 1.68 per risk allele; 95% CI, 1.32-2.15, p = 3.0x(10-5)) and aortic valve replacement (hazard ratio = 1.54 pre risk allele; 95% CI, 1.05-2.07, p = 0.08).
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