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.     

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.     

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.     

A PvuII polymorphism of the low density lipoprotein receptor gene is not associated with plasma concentrations of low density lipoproteins including LP(a)

Lipoprotein(a) [Lp(a)] is a low density lipoprotein (LDL), in which apolipoprotein B-100 (apo B-100) is attached to apolipoprotein(a) [apo(a)], a glycoprotein of variable size. Lp(a) may be as atherogenic as LDL. In normal populations, Lp(a) concentrations in plasma are largely determined by the apo(a) gene locus on chromosome 6, but regulation of synthesis and catabolism of Lp(a) is poorly understood. In some studies, a PvuII restriction fragment length polymorphism (RFLP) in the LDL receptor gene seems to affect concentrations of LDL in plasma, and other studies have indicated that Lp(a) catabolism could be mediated by the LDL receptor. We therefore expected that the PvuII polymorphism in the LDL receptor gene might be associated with Lp(a) levels in 170 Caucasian men aged 40 years, selected to have a high representation of low molecular weight apo(a) phenotypes. However, plasma concentrations of cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides and Lp(a) were all unrelated to the LDL receptor gene PvuII polymorphism both in the group as a whole and when it was subgrouped by apo(a) phenotype. Therefore our data do not support the concept that this particular LDL receptor gene polymorphism is associated with LDL receptor function, and our data therefore neither support nor rule out a role for the LDL receptor in Lp(a) catabolism.     

Evaluation of Lp[a] and other independent risk factors for CHD in Asian Indians and their USA counterparts

Conventional risk factors for coronary heart disease (CHD) do not completely account for the observed increase in premature CHD in people from the Indian subcontinent or for Asian Indians who have immigrated to the USA. The objective of this study was to determine the effect of immigration to the USA on plasma levels of lipoprotein [a] (Lp[a]) and other independent risk factors for CHD in Asian Indians. Three subject groups were studied: group 1, 57 subjects living in India and diagnosed with CHD (CHD patients); group 2, 46 subjects living in India and showing no symptoms of CHD (control subjects); group 3, 206 Asian Indians living in the USA. Fasting blood samples were drawn to determine plasma levels of triglyceride (TG), total cholesterol (TC), low density lipoprotein [LDL cholesterol (LDL-Chol)], high density lipoprotein [HDL cholesterol (HDL-Chol)], apolipoprotein B-100 (apoB-100), and Lp[a]. Apolipoprotein [a] (apo[a]) size polymorphism was determined by immunoblotting. Plasma TG, apoB-100, and Lp[a] concentrations were higher in CHD patients than in control and USA groups. CHD patients had higher levels of TC and LDL-Chol and lower HDL-Chol than control subjects. However, the USA population had higher levels of TC, LDL-Chol, and apoB-100 and lower HDL-Chol than control subjects. Plasma Lp[a] levels were inversely correlated with the relative molecular weight of the more abundant of each subject's two apo[a] isoforms (MAI), and CHD patients showed higher frequencies of lower relative molecular weights among MAI. Our observed changes in lipid profiles suggest that immigrating to the USA may place Asian Indians at increased risk for CHD. This study suggests that elevated plasma Lp[a] confers genetic predisposition to CHD in Asian Indians, and nutritional and environmental factors further increase the risk of CHD. This is the first report implicating MAI size as a predictor for development of premature CHD in Asian Indians. Including plasma Lp[a] concentration and apo[a] phenotype in screening procedures may permit early detection and preventive treatment of CHD in this population.     

Lipoprotein(a): its inheritance and molecular basis of its atherothrombotic role

Lipoprotein(a) or Lp(a), is a member of the plasma lipoproteins with general properties of LDL but with a protein moiety represented by apoB100 disulfide linked to apolipoprotein(a) or apo(a). Apo(a) is polymorphic in size; at present a total of 11 isoforms have been reported, but more are likely to be identified in view of the fact that at least 19 alleles of the apo(a) gene have recently been reported. There are remarkable variations in the plasma Lp(a) levels; but uncertainties still exist about the factors responsible for this variability. High plasma Lp(a) levels have been associated with an increased incidence of cardiovascular disease, mainly based on epidemiological evidence. Both atherogenic and thrombogenic potentials have been suggested; the first attributable to the LDL-like properties of Lp(a) and the other to the plasminogen-like characteristics of apo(a). From the mechanistic viewpoint in vitro studies suggest that the thrombogenic action may occur at the level of the endothelium whereas Lp(a) that localizes in the sub-endothelial intima is expected to undergo complexation with matrix components and favor the formation of the atherosclerotique plaque. How Lp(a) polymorphism relates to the postulated cardiovascular pathogenicity of this lipoprotein remains to be established.     

The Apo(a) gene is the major determinant of variation in plasma Lp(a) levels in African Americans.

The distributions of plasma lipoprotein(a), or Lp(a), levels differ significantly among ethnic groups. Individuals of African descent have a two- to threefold higher mean plasma level of Lp(a) than either Caucasians or Orientals. In Caucasians, variation in the plasma Lp(a) levels has been shown to be largely determined by sequence differences at the apo(a) locus, but little is known about either the genetic architecture of plasma Lp(a) levels in Africans or why they have higher levels of plasma Lp(a). In this paper we analyze the plasma Lp(a) levels of 257 sibling pairs from 49 independent African American families. The plasma Lp(a) levels were much more similar in the sibling pairs who inherited both apo(a) alleles identical by descent (IBD) (r = .85) than in those that shared one (r = .48) or no (r = .22) parental apo(a) alleles in common. On the basis of these findings, it was estimated that 78% of the variation in plasma Lp(a) levels in African Americans is attributable to polymorphism at either the apo(a) locus or sequences closely linked to it. Thus, the apo(a) locus is the major determinant of variation in plasma Lp(a) levels in African Americans, as well as in Caucasians. No molecular evidence was found for a common "high-expressing" apo(a) allele in the African Americans. We propose that the higher plasma levels of Lp(a) in Africans are likely due to a yet-to-be-identified trans-acting factor(s) that causes an increase in the rate of secretion of apo(a) or a decrease in its catabolism.     

Frequent occurrence of familial aggregations of high lipoprotein(a) levels associated with small apolipoprotein(a) isoforms

School-age children with high lipoprotein(a) [Lp(a)] levels were screened and family studies were conducted to examine the relationship between high Lp(a) levels and apolipoprotein(a) [apo(a)] isoforms in families. All the probands from 17 families had one of the A2 to A12 apo(a) isoforms, which are the smaller apo(a) isoforms of the 25 different isoforms thus far detected. The ratio of subjects with high plasma Lp(a) levels was 0.47 among the first-degree relatives. All 15 relatives with high plasma Lp(a) levels shared one of the small apo(a) isoforms with the proband in each family, while 16 of 17 relatives with normal Lp(a) levels did not. These data indicate the frequent occurrence of familial aggregations of high Lp(a) levels associated with one of the small apo(a) isoforms.     

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.     

Genetics of the quantitative Lp(a) lipoprotein trait

The Lp(a) lipoprotein is a complex particle composed of a low density lipoprotein (LDL)-like lipoprotein and the disulfide bonded Lp(a) glycoprotein. The complex represents a quantitative genetic trait. SDS gel electrophoresis under reducing conditions of sera followed by immunoblotting with affinity-purified polyclonal anti-Lp(a) demonstrated inter- and intra-individual size heterogeneity of the glycoprotein with apparent Mr in the range 400-700kDa. According to their relative mobilities compared to apo B-100 the Lp(a) patterns were categorized into phenotypes F, B, S1, S2, S3 und S4 and into the respective double-band phenotypes. This size heterogeneity seems to be controlled by multiple alleles designated LpF, LpB, LpS1, LpS2, LpS3, LpS4 and a null allele (LpO) at a single locus. Phenotype frequencies observed in 441 unrelated subjects were in good agreement with those expected from the genetic hypothesis. Comparison of Lp(a) lipoprotein concentrations in the different phenotypes revealed a highly significant association of phenotypes B, S1 and S2 with high, and phenotypes S3 und S4 with intermediate Lp(a) concentrations. A third mode is represented by the null phenotype were no Lp(a) band is detected upon immunoblotting and Lp(a) lipoprotein is low or absent. We conclude that the same gene locus is involved in determining Lp(a) glycoprotein phenotype and Lp(a) lipoprotein concentrations in plasma. This major gene seems to be the Lp(a) glycoprotein structural gene locus.     

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.     

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.     

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.     

Lipoprotein[a] is the major apoB-containing lipoprotein in the plasma of a hibernator, the hedgehog (Erinaceus europaeus)

We have undertaken studies aimed at elucidating the interrelationships existing between the seasonal modifications in endocrine status (already demonstrated by Saboureau, M., and J. Boissin. 1978. C.R. Acad. Sci. (Paris) 286D: 1479-1482) and plasma lipoprotein metabolism in the male hedgehog. During the course of these studies, we discovered that a lipoprotein comparable to human Lp[a] was a prominent component of the plasma lipoprotein spectrum in the hedgehog. This lipoprotein was present in the 1.040-1.100 g/ml density range (approximately), exhibited pre beta mobility upon agarose gel electrophoresis, and its Stokes diameter was 275 A. Its apolipoprotein moiety consisted of two proteins with molecular weights and amino acid compositions similar to those of human apoB-100 and apo[a], respectively. These two apolipoproteins were present in hedgehog Lp[a] as a complex that could be dissociated using dithiothreitol and whose stoichiometry could be 1:1. Lp[a] polymorphism due to size heterogeneity of apo[a] appeared to be present in the hedgehog as in man. The chemical composition of hedgehog Lp[a], obtained from animals bled during spring and summer, differed from that of its human counterpart in that the proportion of triglycerides was approximately three times higher in the hedgehog particle (13% vs. 4%), to the detriment of cholesteryl esters. Dissociation of the apoB:apo[a] complex has allowed us to obtain Lp[a] devoid of its specific polypeptide (Lp[a-]), a particle that retained the characteristics of Lp[a] as regards its lipid composition but whose Stokes diameter decreased by 30 to 40 A. The plasma concentration of LDL particles, defined as lipoproteins containing apoB-100 as their sole apolipoprotein constituent, was considerably lower than that of Lp[a]. These findings suggest that the hedgehog could be a unique animal model for studies regarding Lp[a] metabolism.     

Abetalipoproteinemia with an ApoB-100-lipoprotein(a) glycoprotein complex in plasma. Indication for an assembly defect

Patients with autosomal recessive abetalipoproteinemia (ABL) lack in their plasma all lipoproteins containing apolipoprotein (apo)B-100 or B-48. Previous studies have suggested that this is due to the complete absence of apoB. We have investigated whether such patients (n = 10) are able to secrete the lipoprotein(a) (Lp(a] glycoprotein (apo(a] which, in normal plasma, exists as a complex with low density lipoproteins containing apoB-100 (Lp(a) lipoprotein). All 10 patients had reduced but detectable apo(a) levels in plasma (mean, 0.49 mg/dl; range, 0.2-2.03 mg/dl) but no Lp(a) lipoprotein. However, we also detected small amounts (0.2-2.8 mg/dl) of apoB in all patients with ABL. The apoB in the ABL patients had the size of apoB-100 and occurred as a lipid-poor complex with the Lp(a) glycoprotein in a fraction of density 1.22 g/ml. This material may represent partially assembled Lp(a) lipoprotein. There was also uncomplexed apo(a) and apoB-100 in the ABL plasma. The distribution and relative concentration of both proteins in the density fraction greater than 1.06 g/ml varied among patients. The data suggest that in ABL, the assembly of apoB-containing lipoproteins is defective and that apoB-100 may be secreted without its full lipid complement when complexed with apo(a).     

Lipoprotein(a) levels, apo(a) isoform size, and coronary heart disease risk in the Framingham Offspring Study

The aim of this study was to assess the independent contributions of plasma levels of lipoprotein(a) (Lp(a)), Lp(a) cholesterol, and of apo(a) isoform size to prospective coronary heart disease (CHD) risk. Plasma Lp(a) and Lp(a) cholesterol levels, and apo(a) isoform size were measured at examination cycle 5 in subjects participating in the Framingham Offspring Study who were free of CHD. After a mean follow-up of 12.3 years, 98 men and 47 women developed new CHD events. In multivariate analysis, the hazard ratio of CHD was approximately two-fold greater in men in the upper tertile of plasma Lp(a) levels, relative to those in the bottom tertile (P < 0.002). The apo(a) isoform size contributed only modestly to the association between Lp(a) and CHD and was not an independent predictor of CHD. In multivariate analysis, Lp(a) cholesterol was not significantly associated with CHD risk in men. In women, no association between Lp(a) and CHD risk was observed. Elevated plasma Lp(a) levels are a significant and independent predictor of CHD risk in men. The assessment of apo(a) isoform size in this cohort does not add significant information about CHD risk. In addition, the cholesterol content in Lp(a) is not a significant predictor of CHD risk.     

Lipoprotein(a) binds to fibronectin and has serine proteinase activity capable of cleaving it.

The plasma concentration of human lipoprotein(a) [Lp(a)] is correlated with the risk of heart disease. A distinct feature of the Lp(a) particle is the apolipoprotein (a) [apo(a)], which is associated with apoB-100, the main protein component of low-density lipoprotein. We now report that apo(a), which has extensive homology to plasminogen, binds to immobilized fibronectin. The binding of Lp(a) was localized to the C-terminal heparin-binding domain of fibronectin. Incubation of Lp(a) with fibronectin resulted in fragmentation of fibronectin. The cleavage pattern, as visualized by gel electrophoresis and immunoblotting, was reproducibly obtained with Lp(a) purified from five different individuals and was distinct from that obtained upon proteolysis of fibronectin by plasmin or kallikrein. The use of synthetic peptide substrates demonstrated that the amino acid specificity for Lp(a) was arginine rather than lysine. The proteolytic activity of Lp(a) was localized to apo(a) and experiments with inhibitors indicated that the proteolytic activity was of serine proteinase-type.     

Differences in apolipoprotein(a) polymorphism in West Greenland Eskimos and Caucasian Danes

Summary Previous studies in Greenland suggest that death rates from ischemic heart disease [IHD] are lower in Eskimos than in Danes and other Caucasian populations. This has been explained by a high intake of n-3 polyunsaturated fatty acids with beneficial effects on blood lipids and hemostasis. In other populations, lipoprotein(a) [Lp(a)] is associated with IHD, plasma concentrations of Lp(a) being genetically determined to a major extent. We have compared Lp(a) concentrations and apo(a) phenotypes in 120 Greenlandic Eskimos with those in 466 Danish men. The median Lp(a) concentration in Eskimos (8.7mg/dl;[95% CI 6.5–10.7]) was not significantly different from that in Danes (6.3mg/dl; [95% CI 5.2–7.0]), whereas the 90th percentile was significantly higher among Danes: 46.36mg/dl; [95% Cl 43.0–54.3] vs. 27.6mg/dl [95% CI 20.7–36.9]. In 20% of the Danes, but in only 8% of the Eskimos (P = 0.009), the concentration of Lp(a) exceeded 30mg/dl. The difference is probably explained by a low frequency of the low molecular weight apo(a) phenotypes among Eskimos, since the apo(a) isoforms F and B were absent, and the S1 and S2 types were present in only 3.3% of Eskimos. In contrast, these apo(a) isoforms were present in 26.6% of the Danes in either single-band or double-band phenotypes. The pattern of apo(a) polymorphism found in this study could provide part of a genetic explanation for the putative low rates of IHD in Eskimo populations.     

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.