Apolipoprotein [a] genotype influences isoform dominance pattern differently in African Americans and Caucasians

Plasma lipoprotein [a] (Lp[a]) concentrations are inversely associated with, and largely determined by, apolipoprotein [a] (apo[a]) gene size, a highly polymorphic trait. We studied if, within an individual, the smaller apo[a] isoform always dominated, whether there was interaction between the two alleles, and whether these features differed between Caucasians and African Americans. We determined apo[a] gene sizes, apo[a] protein sizes and relative amounts, and plasma Lp[a] levels in 430 individuals (263 Caucasians and 167 African Americans). Of the 397 heterozygotes with at least one detectable apo[a] isoform (238 Caucasians and 159 African Americans), the larger allele dominated in 28% of Caucasians and 23% of African Americans, while the smaller allele dominated in 56% of Caucasians and 45% of African Americans. In Caucasians, dominance of the smaller allele increased with Lp[a] levels, from 44% at Lp[a] < or = 30 nM to 81% at Lp[a] >100 nM (P < 0.0001). Dominance by the smaller allele increased with increasing size of the larger allele in both groups but with the smaller allele only in African Americans. There was no interaction between apo[a] alleles within genotypes; one apo[a] isoform level was not associated with the other isoform level, and isoform levels were not affected by the difference in size. More of the dominance pattern was explained by Lp[a] level and apo[a] genotype in African Americans than in Caucasians (29% vs. 13%). Thus, genotype influences isoform-specific Lp[a] levels and dominance patterns differently in African Americans and in Caucasians.     

ApoE genotype affects allele-specific apo[a] levels for large apo[a] sizes in African Americans: the Harlem-Basset Study

The genetic variability of apolipoprotein E (apoE) influences plasma lipoprotein levels, and allele frequencies differ between African Americans and Caucasians. As African Americans have higher lipoprotein [a] (Lp[a]) levels than Caucasians, we investigated the effects of the apoE gene on allele-specific apolipoprotein [a] (apo[a]) levels across ethnicity. We determined apo[a] sizes, allele-specific apo[a] levels (i.e., levels associated with alleles defined by size), and the apoE gene polymorphism in 231 African Americans and 336 Caucasians. African Americans, but not Caucasians, with the apo E2 genotype had lower levels of Lp[a] compared with those with the apo E4 genotype (9.6 vs. 11.2 nmol/l; P = 0.034, expressed as square root levels). Distribution of apo[a] alleles across apoE genotypes were similar between African Americans and Caucasians. Among African Americans with large apo[a], the allele-specific apo[a] level was significantly lower among epsilon2 carriers compared with epsilon3 or epsilon4 carriers (5.4 vs. 6.6 and 7.4 nmol/l, respectively; P < 0.005, expressed as square root levels). In contrast, there was no significant difference in allele-specific apo[a] levels across apoE genotypes among Caucasians. For large apo[a] sizes, apoE genotype contributed to the observed African American-Caucasian differences in allele-specific apo[a] levels.     

The apolipoprotein (a) gene: a transcribed hypervariable locus controlling plasma lipoprotein (a) concentration

Lipoprotein(a) [Lp(a)] is a quantitative trait in human plasma. Lp(a) consists of a low-density lipoprotein and the plasminogen-related apolipoprotein(a) [apo(a)]. The apo(a) gene determines a size polymorphism of the protein, which is related to Lp(a) levels in plasma. In an attempt to gain a deeper insight into the genetic architecture of this risk factor for coronary heart disease, we have investigated the basis of the apo(a) size polymorphism by pulsed field gel electrophoresis of genomic DNA employing various restriction enzymes (SwaI, KpnI, KspI, SfiI, NotI) and an apo(a) kringle-IV-specific probe. All enzymes detected the same size polymorphism in the kringle IV repeat domain of apo(a). With KpnI, 26 different alleles were identified among 156 unrelated subjects; these alleles ranged in size from 32kb to 189kb and differed by increments of 5.6kb, corresponding to one kringle IV unit. There was a perfect match between the size of the apo(a) DNA phenotypes and the size of apo(a) isoforms in plasma. The apo(a) DNA polymorphism was further used to estimate the magnitude of the apo(a) gene effect on Lp(a) levels by a sib-pair comparison approach based on 253 sib-pairs from 64 families. Intra-class correlation of log-transformed Lp(a) levels was high in sib-pairs sharing both parental alleles (r = 0.91), significant in those with one common allele (r = 0.31), and absent in those with no parental allele in common (r = 0.12). The data show that the intra-individual variability in Lp(a) levels is almost entirely explained by variation at the apo(a) locus but that only a fraction (46%) is explained by the DNA size polymorphism. This suggests further heterogeneity relating to Lp(a) levels in the apo(a) gene.     

Genetic linkage between lipoprotein(a) phenotype and a DNA polymorphism in the plasminogen gene

Coronary heart disease risk correlates directly with plasma concentrations of lipoprotein(a) (Lp(a)), a low-density lipoprotein-like particle distinguished by the presence of the glycoprotein apolipoprotein(a) (apo(a)), which is bound to apolipoprotein B-100 (apoB-100) by disulfide bridges. Size isoforms of apo(a) are inherited as Mendelian codominant traits and are associated with variations in the plasma concentration of lipoprotein(a). Plasminogen and apo(a) show striking protein sequence homology, and their genes both map to chromosome 6q26-27. In a large family with early coronary heart disease and high plasma concentrations of Lp(a), we found tight linkage between apo(a) size isoforms and a DNA polymorphism in the plasminogen gene; plasma concentrations of Lp(a) also appeared to be related to genetic variation at the apo(a) locus. We found free recombination between the same phenotype and alleles of the apoB DNA polymorphism. This suggests that apo(a) size isoforms and plasma lipoprotein(a) concentrations are each determined by genetic variation at the apo(a) locus.     

High degree of genetic polymorphism in apolipoprotein(a) associated with plasma lipoprotein(a) levels in Japanese and Chinese populations

We have developed a sensitve, high-resolution method for the analysis of the apolipoprotein(a) [apo(a)] isoforms using sodium dodecyl sulfate (SDS)-agarose/ gradient polyacrylamide gel electrophoresis. In an analysis of the genetic polymorphism of apo(a) isoforms and their relationship with plasma lipoprotein(a) [Lp(a)] levels in Japanese and Chinese, this method identified 25 different apo(a) isoforms and detected one or two apo(a) isoforms in more than 99.5% of the individuals tested. The apparent molecular weights of the apo(a) isoforms ranged from 370 kDa to 950 kDa, and 22 of the 25 different apo(a) isoforns had a higher molecular weight than of apo B-100. Studies on Japanese families confirmed the autosomal codominant segregation of apo(a) isoforms and the existence of a null allele at the apo(a) locus. The observed frequency distribution of apo(a) isoform phenotypes fit the expectations of the Hardy-Weinberg equilibrium in both the Japanese and Chinese populations. Our data indicate the existence of at least 26 alleles, including a null allele, at the apo(a) locus. The frequency distribution patterns of the apo(a) isoform alleles in Japanese and Chinese were similar to each other and also similar to that of apo(a) gene sizes reported in Caucasian American individuals. The average heterozygosity at the apo(a) locus was 92% in Japanese and 93% in Chinese. A highly significant inverse correlation was observed between plasma Lp(a) levels and the size of apo(a) isoforms in both the Japanese (r=-0.677, P=0.0001) and the Chinese (r=-0.703, P=0.0001). A highly skewed distribution of Lp(a) concentrations towards lower levels in the Japanese population may be explained by high frequencies of alleles encoding large apo(a) isoforms and the null allele.     

Lipoprotein(a) in women twins: heritability and relationship to apolipoprotein(a) phenotypes.

Lp(a) is a unique lipoprotein consisting of an LDL-like particle and a characteristic protein, apo(a). Increased levels of Lp(a) constitute a risk factor for coronary heart disease. Variation in the size of the apo(a) protein is a phenotype controlled by the apo(a) gene on chromosome 6 and is related to Lp(a) plasma levels. Based on 169 MZ and 125 DZ adult female twin pairs, this study's purpose was to estimate the proportion of the variation in Lp(a) levels that is due to genetic influences and to determine the extent to which the apo(a) locus explains this heritability. Lp(a) levels were significantly more similar in MZ twins than in DZ twins: mean co-twin differences were 3.9 +/- 5.7 mg/dl and 16.0 +/- 19.9 mg/dl (P less than .001), respectively. Intraclass correlations were .94 in MZ twins and .32 in DZ twins, resulting in a heritability estimate of .94 (P less than .001). Heritability was then calculated using only co-twins with the same apo(a) phenotype: the heritability estimate decreased to .45 but was still highly significant (P less than .001). Therefore, on the basis of heritability analysis of women twins, Lp(a) levels are almost entirely genetically controlled. Variation at the apo(a) locus contributes to this heritability, although other genetic factors could be involved.     

Single-nucleotide polymorphisms in LPA explain most of the ancestry-specific variation in Lp(a) levels in African Americans

Lipoprotein(a) (Lp(a)) is an important causal cardiovascular risk factor, with serum Lp(a) levels predicting atherosclerotic heart disease and genetic determinants of Lp(a) levels showing association with myocardial infarction. Lp(a) levels vary widely between populations, with African-derived populations having nearly 2-fold higher Lp(a) levels than European Americans. We investigated the genetic basis of this difference in 4464 African Americans from the Jackson Heart Study (JHS) using a panel of up to 1447 ancestry informative markers, allowing us to accurately estimate the African ancestry proportion of each individual at each position in the genome. In an unbiased genome-wide admixture scan for frequency-differentiated genetic determinants of Lp(a) level, we found a convincing peak (LOD = 13.6) at 6q25.3, which spans the LPA locus. Dense fine-mapping of the LPA locus identified a number of strongly associated, common biallelic SNPs, a subset of which can account for up to 7% of the variation in Lp(a) level, as well as >70% of the African-European population differences in Lp(a) level. We replicated the association of the most strongly associated SNP, rs9457951 (p = 6 × 10(-22), 27% change in Lp(a) per allele, ～5% of Lp(a) variance explained in JHS), in 1,726 African Americans from the Dallas Heart Study and found an even stronger association after adjustment for the kringle(IV) repeat copy number. Despite the strong association with Lp(a) levels, we find no association of any LPA SNP with incident coronary heart disease in 3,225 African Americans from the Atherosclerosis Risk in Communities Study.     

Genetic variation in lipoprotein (a) levels in families enriched for coronary artery disease is determined almost entirely by the apolipoprotein (a) gene locus.

Lipoprotein (a) (Lp[a]) is a cholesterol-rich lipoprotein resembling LDL but also containing a large polypeptide designated apolipoprotein (a) (apo[a]). Its levels are highly variable among individuals and, in a number of studies, are strongly correlated with the risk of coronary artery disease (CAD). In an effort to determine which genes control Lp(a) levels, we have studied 25 multiplex families (comprising 298 members) enriched for CAD. The apo(a) gene was genotyped among the families, using a highly informative pulse-field gel electrophoresis procedure. In addition, polymorphisms of the gene for the other major protein of Lp(a), apolipoprotein B (apoB), were examined. Quantitative sib-pair linkage analysis indicates that apo(a) is the major gene controlling Lp(a) levels in this CAD population (P = .001; 99 sib pairs), whereas the apoB gene demonstrated no significant quantitative linkage effect. We estimate that the apo(a) locus accounts for < or = 98% of variance of Lp(a) serum levels. Approximately 43% of this variation is explained by size polymorphisms within the apo(a) gene. These results indicate that the apo(a) gene is the major determinant of Lp(a) serum levels not only in the general population but also in a high-risk CAD population.     

The effect of apolipoprotein(a)-, apolipoprotein E-, and apolipoprotein A4- polymorphisms on quantitative lipoprotein(a) concentrations.

The effects of apolipoprotein (a), apolipoprotein-E, and apolipoprotein-A4 isoforms on quantitative lipoprotein(a) [Lp(a)] levels were assessed in a sample of 142 Dutch families consisting of two parents and their adolescent twin offspring. A total heritability of 95% was estimated for plasma Lp(a) concentrations. The largest part of this heritability was due to the apo(a) locus which explained 61% of the total variance in Lp(a) levels. The pattern of familial correlations for the residual part of the Lp(a) variance that could not be attributed to the apo(a) isoforms, suggested genetic influences on the residual variance. We addressed the question whether this residual genetic variance could be ascribed to the apoE or the apoA4 locus. A simultaneous analysis of all three loci showed that both the apoE and the apoA4 polymorphism did not contribute significantly to Lp(a) variation.     

Variation in Lp(a) levels and apo(a) isoform frequencies in five baboon subspecies

Elevated levels of lipoprotein (a) [Lp(a)] are positively correlated with risk of cardiovascular disease and are thought to be a function of allelic variation in apo(a), the unique protein component of Lp(a). In this article we examine subspecies variation in Lp(a) levels and apo(a) isoforms in the baboon. Breeding populations of the five subspecies (Papio hamadryas hamadryas, P.h. cynocephalus, P.h. ursinus, P.h. papio, and P.h. anubis) of common long-tailed baboons are maintained at the Southwest Foundation for Biomedical Research. Serum samples were obtained from at least 20 unrelated animals of each subspecies. Twelve different size isoforms (including the null) of apo(a) were identified across the five subspecies. These isoforms act as alleles; a maximum likelihood method was used to obtain the allele frequencies. Significant differences in apo(a) isoform frequencies were found between subspecies (chi 2(44) = 163.10, p less than 0.0001). Quantitative levels of Lp(a) also differed among subspecies. We evaluated the correlation between genetic distances calculated using the quantitative Lp(a) levels and the apo(a) isoform data. Observed genetic relationships among the subspecies are consistent with the present-day geographic distribution and information from other marker protein systems. The findings indicate that the marker apo(a) may have great utility in both evolutionary and biomedical studies.     

Genetic effect of two APOA repeat polymorphisms (kringle 4 and pentanucleotide repeats) on plasma Lp(a) levels in American Samoans

Elevated plasma lipoprotein(a) [Lp(a)] level has been established as an independent risk factor for atherosclerosis and coronary heart disease. Considerable ethnic group differences in the distribution of plasma Lp(a) levels have raised public health concerns. Recently, we have reported that Samoans have the lowest plasma Lp(a) levels of any population group. In the present investigation, we report the contribution of two apolipoprotein(a) (APOA) polymorphisms, the kringle 4 type 2 (K4) repeat and the pentanucleotide repeat (PNR), in affecting plasma Lp(a) levels in an American Samoan sample (n = 309). The K4 repeats ranged in size from 15 to 40. The common alleles contained repeats ranging from 26 to 36 with allele frequencies between 5.5% to 9.7%, and these accounted for 82% of all alleles. An inverse relationship between K4 repeat number and plasma Lp(a) level was observed for single-banded (r = -0.59, p = 0.0001) and double-banded phenotypes (r = -0.50, p = 0.0001). This polymorphism explained 60% of the variation in plasma Lp(a) level in American Samoans. For the PNR polymorphism, five different repeat alleles and eight different genotypes were identified; the most common allele was eight repeats. The *8 PNR allele was associated with a wide range of K4 repeats, the *9 PNR allele with larger K4 repeats (25-40), and the *10 PNR with smaller K4 repeats (15-24). Analysis of variance (ANOVA) revealed that the PNR polymorphism accounts for 2.1% of the variability in plasma Lp(a) levels in this sample, when the K4 repeat polymorphism was taken into account. Our data show that common polymorphisms in the APOA gene are major determinants of plasma Lp(a) variation in American Samoans.     

Apo[a] size and PNR explain African American-Caucasian differences in allele-specific apo[a] levels for small but not large apo[a

Apolipoprotein [a] (apo[a]) gene size is a major predictor of lipoprotein [a] level. To determine genetic predictors of allele-specific apo[a] levels beyond gene size, we evaluated the upstream C/T and pentanucleotide repeat (PNR) polymorphisms. We determined apo[a] sizes, allele-specific apo[a] levels, and C/T and PNR in 215 Caucasians and 139 African Americans. For Caucasians, apo[a] size affected allele-specific levels substantially greater in subjects with apo[a] < 24 K4; for African Americans, the size effect was smaller than in Caucasians, <24 K4, but did not decrease at higher repeats. In both groups, the level decreased with increasing size of the other allele. Controlling for apo[a] sizes, PNR decreased allele-specific apo[a] levels in Caucasians with increasing PNR > 8. In a multiple regression model, apo[a] allele size and size and expression of the other apo[a] allele (and PNR > 8 for Caucasians) significantly predicted allele-specific apo[a] levels. For a common PNR 8 allele, predicted values were similar in the two ethnicities for small size apo[a]. Allele-specific apo[a] levels were influenced by the other allele size and expression. Observed differences between Caucasians and African Americans in allele-specific apo[a] levels were explained for small apo[a] sizes by the other allele size and PNR; the ethnicity differences remain unexplained for larger sizes.     

Effects of the apolipoprotein(a) size polymorphism on the lipoprotein(a) concentration in 7 ethnic groups

Summary Apolipoprotein(a) [apo(a)] exhibits a genetic size polymorphism explaining about 40% of the variability in lipoprotein(a) [Lp(a)] concentration in Tyroleans. Lp(a) concentrations and apo(a) phenotypes were determined in 7 ethnic groups (Tyrolean, Icelandic, Hungarian, Malay, Chinese, Indian, Black Sudanese) and the effects of the apo(a) size polymorphism on Lp(a) levels were estimated in each group. Average Lp(a) concentrations were highly significantly different among these populations, with the Chinese (7.0mg/dl) having the lowest and the Sudanese (46mg/dl) the highest levels. Apo(a) phenotype and derived apo(a) allele frequencies were also significantly different among the populations. Apo(a) isoform effects on Lp(a) levels were not significantly different among populations. Lp(a) levels were however roughly twice as high in the same phenotypes in the Indians, and several times as high in the Sudanese, compared with Caucasians. The size variation of apo(a) explains from 0.77 (Malays) to only 0.19 (Sudanese) of the total variability in Lp(a) levels. Together these data show (I) that there is considerable heterogeneity of the Lp(a) polymorphism among populations, (II) that differences in apo(a) allele frequencies alone do not explain the differences in Lp(a) levels among populations and (III) that in some populations, e.g. Sudanese Blacks, Lp(a) levels are mainly determined by factors that are different from the apo(a) size polymorphism.     

The relationship among apolipoprotein(a) polymorphisms, the low-density lipoprotein receptor-related protein, and the very low density lipoprotein receptor genes, and plasma lipoprotein(A) concentration in the Czech population

Increased plasma concentration of lipoprotein(a) [Lp(a)] is an established independent risk factor for coronary artery disease (CAD), which is strongly genetically determined. This study was designed to investigate the relationship between the K-IV and (TTTTA)n apolipoprotein(a) [apo(a), protein; APOA, gene] polymorphisms, as well as the C766T low-density lipoprotein receptor-related protein (LRP) and the (CGG)n very low density lipoprotein receptor (VLDLR) polymorphisms on the one hand, and plasma Lp(a) levels in Czech subjects who underwent coronary angiography on the other hand. The lengths of the alleles of the APOA K-IV and (TTTTA)n polymorphisms were strongly inversely correlated with plasma Lp(a) levels in univariate analysis (r = -0.41, p < 10(-4) and r = -0.20, p < 0.01, respectively). Multivariate analysis revealed significant associations between the APOA polymorphisms studied and plasma Lp(a) levels in subjects expressing only one APOA K-IV allele (p < 10(-6) for K-IV and p < 0.001 for TTTTA). In subjects expressing both APOA K-IV alleles, the multivariate analysis revealed that only the APOA K-IV alleles were inversely correlated with plasma Lp(a) levels (p < 0.001). Associations between both the LRP and VLDLR gene polymorphisms and plasma Lp(a) levels were only of borderline significance (p < 0.06 and p < 0.07, respectively) and were not confirmed in multivariate analysis. In conclusion, both APOA length polymorphisms significantly influenced plasma Lp(a) concentration in the Czech population studied, and this circumstance could explain the association in this population observed earlier between APOA (TTTTA)n polymorphism and CAD (Benes et al. 2000). Only a minor role in the regulation of plasma Lp(a) levels is suggested for the C766T LRP and the (CGG)n VLDLR polymorphisms.     

Lipoprotein(a) accelerates atherosclerosis in uremic mice

Uremic patients have increased plasma lipoprotein(a) [Lp(a)] levels and elevated risk of cardiovascular disease. Lp(a) is a subfraction of LDL, where apolipoprotein(a) [apo(a)] is disulfide bound to apolipoprotein B-100 (apoB). Lp(a) binds oxidized phospholipids (OxPL), and uremia increases lipoprotein-associated OxPL. Thus, Lp(a) may be particularly atherogenic in a uremic setting. We therefore investigated whether transgenic (Tg) expression of human Lp(a) increases atherosclerosis in uremic mice. Moderate uremia was induced by 5/6 nephrectomy (NX) in Tg mice with expression of human apo(a) (n = 19), human apoB-100 (n = 20), or human apo(a) + human apoB [Lp(a)] (n = 15), and in wild-type (WT) controls (n = 21). The uremic mice received a high-fat diet, and aortic atherosclerosis was examined 35 weeks later. LDL-cholesterol was increased in apoB-Tg and Lp(a)-Tg mice, but it was normal in apo(a)-Tg and WT mice. Uremia did not result in increased plasma apo(a) or Lp(a). Mean atherosclerotic plaque area in the aortic root was increased 1.8-fold in apo(a)-Tg (P = 0.025) and 3.3-fold (P = 0.0001) in Lp(a)-Tg mice compared with WT mice. Plasma OxPL, as detected with the E06 antibody, was associated with both apo(a) and Lp(a). In conclusion, expression of apo(a) or Lp(a) increased uremia-induced atherosclerosis. Binding of OxPL on apo(a) and Lp(a) may contribute to the atherogenicity of Lp(a) in uremia.     

IL-6 and lipoprotein(a) [LP(a)] concentrations are related only in patients with high APO(a) isoforms in monoclonal gammopathy

We have investigated the influence of apo(a) genetics on the relationship between interleukin (IL)-6, and lipoprotein (a) [Lp(a)] levels in 154 patients with monoclonal gammopathy and 189 healthy subjects. No significant differences in Lp(a) levels and distribution of subjects with different sizes of apo(a) isoforms were found between patients and healthy controls. Relationship between IL-6 and Lp(a) levels was strongly dependent on the size of apo(a) isoforms. In patients with high-size apo(a) isoforms Lp(a) levels positively correlated (r=0.475, P=0.0007) to IL-6 concentrations, whereas no correlation was found in patients with low apo(a) isoforms. Our present finding may provide a plausible explanation for the contradictory findings about the acute phase protein nature of Lp(a).     

Lack of genetic linkage evidence for a trans-acting factor having a large effect on plasma lipoprotein[a] levels in African Americans

The distribution of plasma lipoprotein[a] (Lp[a]) concentrations, a risk factor for cardiovascular disease, varies greatly among racial groups, with African Americans having values that are shifted toward higher levels than those of whites. The underlying cause of this heterogeneity is unknown, but a role for "trans-acting" factors has been hypothesized. This study used genetic linkage analysis to localize genetic factors influencing Lp[a] levels in African Americans that were absent in other populations; linkage results were analyzed separately in non-Hispanic whites, Hispanic whites, and African Americans. As expected, all three samples showed highly significant linkage at the approximate location of the lysophosphatidic acid locus. The white populations also independently had regions of significant linkage on chromosome 19 (LOD 3.80) and suggestive linkage on chromosomes 12 (LOD 1.60), 14 (LOD 2.56), and 19 (LOD 2.52).No linkage evidence was found to support the hypothesis of another single gene with large effects specifically segregating in African Americans that may account for their elevated Lp[a] levels.     

Apolipoprotein A polymorphisms and plasma lipoprotein(a) concentrations in non-Hispanic Whites and Hispanics

Elevated levels of plasma lipoprotein(a) [Lp(a)] are thought to be a risk factor for atherosclerosis and coronary heart disease. Plasma levels of Lp(a) are highly variable between individuals, ranging from 0.1 mg/dL to > 100 mg/dL These levels are under strict genetic control, and genetic variation in the apolipoprotein A (APOA) gene accounts for almost all variation in Lp(a) levels. In this study, we investigated the relationship between two APOA polymorphisms (kringle 4 and 5' pentanucleotide repeat) and plasma Lp(a) levels in normoglycemic non-Hispanic Whites (NHWs) (n = 390) and Hispanics (n = 214) from the San Luis Valley, Colorado. Mean (+/- SD) and median Lp(a) levels were 9.6 +/- 12.5 mg/dL and 3.8 mg/dL, respectively, in NHWs and 12.1 +/- 15.6 mg/dL and 4.9 mg/dL, respectively, in Hispanics. The number of observed kringle 4 repeats ranged from 11 to 38 in NHWs and from 10 to 41 in Hispanics. Spearman rank correlation revealed an inverse relationship between the size of the kringle 4 repeat and plasma Lp(a) levels in both populations (r = -0.38; p < 0.0001 in NHWs and r = -0.64; p < 0.0001 in Hispanics). About 30% and 48% of the variation in plasma Lp(a) was explained by this polymorphism in NHWs and Hispanics, respectively. This study confirms that the kringle 4 polymorphism in the APOA gene is a significant determinant of Lp(a) levels in both study groups. A pentanucleotide repeat polymorphism in the 5' promoter region of the APOA gene did not show significant impact on plasma Lp(a) levels in either NHWs or Hispanics.     

Effect of tranexamic acid and delta-aminovaleric acid on lipoprotein(a) metabolism in transgenic mice

The assembly of lipoprotein(a) (Lp(a)) is a two-step process which involves the interaction of kringle-4 (K-IV) domains in apolipoprotein(a) (apo(a)) with Lys groups in apoB-100. Lys analogues such as tranexamic acid (TXA) or delta-aminovaleric acid (delta-AVA) proved to prevent the Lp(a) assembly in vitro. In order to study the in vivo effect of Lys analogues, transgenic apo(a) or Lp(a) mice were treated with TXA or delta-AVA and plasma levels of free and low density lipoprotein bound apo(a) were measured. In parallel experiments, McA-RH 7777 cells, stably transfected with apo(a), were also treated with these substances and apo(a) secretion was followed. Treatment of transgenic mice with Lys analogues caused a doubling of plasma Lp(a) levels, while the ratio of free:apoB-100 bound apo(a) remained unchanged. In transgenic apo(a) mice a 1. 5-fold increase in plasma apo(a) levels was noticed. TXA significantly increased Lp(a) half-life from 6 h to 8 h. Incubation of McA-RH 7777 cells with Lys analogues resulted in an up to 1. 4-fold increase in apo(a) in the medium. The amount of intracellular low molecular weight apo(a) precursor remained unchanged. We hypothesize that Lys analogues increase plasma Lp(a) levels by increasing the dissociation of cell bound apo(a) in combination with reducing Lp(a) catabolism.