Biomedical subjects
G Utermann
Publications and source records attributed to G Utermann.
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 32 kb to 189 kb and differed by increments of 5.6 kb, 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.
Plasma apolipoprotein A-IV metabolism in patients with chronic renal disease.
The plasma concentration and distribution of apolipoprotein A-IV were investigated in normotriglyceridaemic patients with end-stage renal disease and compared with those in a sex- and age-matched control group with normal renal function. A three-fold elevated plasma mean concentration of apolipoprotein A-IV was found in patients with end-stage renal disease treated by haemo- or peritoneal dialysis (58.5 +/- 18.9 mg dl-1 or 50.5 +/- 12.2 mg dl-1, respectively) compared with the controls (18.3 +/- 6.4 mg dl-1). The plasma distribution of apolipoprotein A-IV was studied in patients treated by haemodialysis and in controls by gel permeation chromatography. In the haemodialysis group, 40.3% of the apolipoprotein A-IV was found to be associated with the fraction of high density lipoproteins, whereas the rest (59.7%) was not associated with lipoproteins. This distribution was significantly different from that in the control group (24.8% vs. 75.2%, 0.01 less than P less than 0.05). The elevated plasma concentrations of apolipoprotein A-IV in the patients are not related to triglyceride levels and therefore are unlikely to result from an impaired catabolism of triglyceride-rich lipoproteins. The accumulation of apolipoprotein A-IV in high density lipoproteins from patients with end-stage renal disease might reflect the impaired reversed cholesterol transport mechanisms which are believed to be a major cause of the high prevalence of atherosclerotic diseases in these patients.
Apo(a) isoforms predict risk for coronary heart disease. A study in six populations.
Elevated concentrations of lipoprotein(a) (Lp[a]) in plasma are associated with premature coronary heart disease (CHD). Lp(a) levels are largely determined by alleles at the hypervariable apolipoprotein(a) (apo[a]) gene locus, but other genetic and environmental factors as well as diseases also affect plasma Lp(a) concentrations. It is therefore unclear whether Lp(a) is a primary genetic risk factor or whether Lp(a) levels are elevated secondary to disease in CHD patients. We have analyzed apo(a) phenotypes that represent a stable genetic trait in subjects with CHD and control subjects from different populations representing a variety of ethnic groups (Tyrol, Germany, Wales, Israel, Singapore Chinese, and Singapore Indian). Despite differences in sampling design and disease definition in this multipopulation case-control study, those apo(a) isoforms associated with high Lp(a) plasma concentrations (B, S1, and S2) were more frequent in the CHD patients in each ethnic group. These differences were significant in three of the studied populations and highly significant (p < 0.001) in the pooled (total) group. Lp(a) concentrations were also measured in all groups except Germans and were found to be consistently higher in cases than in control subjects in each ethnic group. For all but one population (Israeli) the differences were significant. The effects of the apo(a) size polymorphism on Lp(a) levels were similar in CHD patients and control subjects from different populations. The data demonstrate that alleles at the apo(a) locus determine the risk for CHD through their effects on Lp(a) concentrations across multiple populations with large differences in CHD frequency and risk factor profiles.
Apolipoprotein (a) alleles determine lipoprotein (a) particle density and concentration in plasma.
The distribution of Lp(a) lipoprotein (Lp[a]) and genetic apolipoprotein(a) (apo[a]) isoforms in plasma samples from 29 healthy normolipidemic subjects of known apo(a) phenotype was evaluated by density gradient ultracentrifugation. The density of Lp(a) was directly related to the size of the apo(a) isoform, ranging from 1.043 g/ml for the LpF phenotype to 1.114 g/ml for the LpS4 phenotype. Heterozygotes had two distinct Lp(a) particles, each containing one of the respective isoforms in plasma. In each heterozygote, the concentration of the lighter Lp(a) species was higher than that of the denser Lp(a) population. These data suggest that apo(a) alleles determine the density and the metabolism and thereby also the concentrations of Lp(a) particles in plasma.
Apolipoprotein(a) phenotypes, Lp(a) concentration and plasma lipid levels in relation to coronary heart disease in a Chinese population: evidence for the role of the apo(a) gene in coronary heart disease.
Elevated lipoprotein(a) (Lp[a]) concentrations are associated with premature coronary heart disease (CHD). In the general population, Lp(a) levels are largely determined by alleles at the hypervariable apolipoprotein(a) (apo[a]) gene locus, but other genetic and environmental factors also affect plasma Lp(a) levels. In addition, Lp(a) has been hypothesized to be an acute phase protein. It is therefore unclear whether the association of Lp(a) concentrations with CHD is primary in nature. We have analyzed apo(a) phenotypes, Lp(a) levels, total cholesterol, and HDL-cholesterol in patients with CHD, and in controls from the general population. Both samples were Chinese individuals residing in Singapore. Lp(a) concentrations were significantly higher in the patients than in the population (mean 20.7 +/- 23.9 mg/dl vs 8.9 +/- 12.9 mg/dl). Apo(a) isoforms associated with high Lp(a) levels (B, S1, S2) were significantly more frequent in the CHD patients than in the population sample (15.9% vs 8.5%, P less than 0.01). Higher Lp(a) concentrations in the patients were in part explained by this difference in apo(a) allele frequencies. Results from stepwise logistic regression analysis indicate that apo(a) type was a significant predictor of CHD, independent of total cholesterol and HDL cholesterol, but not independent of Lp(a) levels. The data demonstrate that alleles at the apo(a) locus determine the risk for CHD through their effects on Lp(a) levels, and firmly establish the role of Lp(a) as a primary genetic risk factor for CHD.
Distribution of apolipoprotein(a) in the plasma from patients with lipoprotein lipase deficiency and with type III hyperlipoproteinemia. No evidence for a triglyceride-rich precursor of lipoprotein(a).
Lipoprotein(a) consists of a low-density lipoprotein containing apolipoprotein (apo) B-100 and of the genetically polymorphic apo(a). It is not known where and how lipoprotein(a) is assembled and whether there exists a precursor for lipoprotein(a). We have determined the phenotype, concentration, and distribution of apo(a) in plasma from patients with lipoprotein lipase (LPL) deficiency (type I hyperlipoproteinemia, n = 14), in apo E 2/2 homozygotes with type III hyperlipoproteinemia (n = 12) and in controls (n = 16). In the two genetic conditions, there is grossly impaired catabolic conversion of apo B-100-containing precursor lipoproteins to low-density lipoproteins. Considering apo(a) type, the plasma concentration of apo(a) was normal in type III patients but significantly reduced in LPL deficiency. Despite the defects in the catabolism of other apo B-containing lipoproteins, the distribution of apo(a) was only moderately affected in both metabolic disorders, with 66.7% (type I) and 74.7% (type III) being present as the characteristic lipoprotein(a) in the density range of 1.05-1.125 g/ml (controls 81.6%). The remainder was distributed between the triglyceride-rich lipoproteins (type I 12.4%, type III 8.5%, controls 4.7%) and the lipid-poor bottom fraction (type I 19.3%, type III 15.3%, controls 12.6%). In all conditions most apo(a) (57-88%) dissociated from the triglyceride-rich lipoproteins upon recentrifugation and was recovered as lipoprotein(a). These data suggest that lipoprotein(a) is not generated from a triglyceride-rich precursor. Lipoprotein(a) may be secreted directly into plasma or may be formed by preferential binding of secreted apo(a) to existing low-density lipoprotein.
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.
[Lipoprotein(a) as a risk factor for arteriosclerosis].
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Uniparental paternal disomy in a genetic cancer-predisposing syndrome.
The 11p15.5 region of human chromosome 11 seems to contain a locus or loci involved in congenital overgrowth anomalies as well as in the genesis of many tumours associated with the Beckwith-Wiedemann syndrome (BWS). Given the unusual differential parental allele involvement in the different aetiological forms of BWS and the loss of maternal alleles in associated tumours, we have now used 11p15.5 markers to determine the parental origin of chromosome 11 in eight sporadic cases of BWS. Probands in three informative families had uniparental paternal disomy for region 11p15.5. Further, an overall greatly increased frequency of homozygosity for several 11p15.5 markers in 21 sporadic BWS patients suggests that isodisomy probably accounts for an even higher proportion of BWS sporadic cases. This demonstrates that uniparental paternal disomy can be associated with a genetic cancer-predisposing syndrome.
[Genetically determined risk of coronary heart disease?].
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Effects of the apolipoprotein(a) size polymorphism on the lipoprotein(a) concentration in 7 ethnic groups.
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 (7.0 mg/dl) having the lowest and the Sudanese (46 mg/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 apolipoprotein E polymorphism: a comparison of allele frequencies and effects in nine populations.
Application of uniform methods for measuring the apolipoprotein (apo) E polymorphism and plasma cholesterol levels in nine populations (Tyrolean, Sudanese, Indian, Chinese, Japanese, Hungarian, Icelandic, Finnish, and Malay) revealed significant heterogeneity among them in apo E type frequencies and mean cholesterol levels. The major apo E types in all populations were E3/2 (frequency range from 7.0% in Indians to 16.9% in Malays), E3/3 (frequency range from 39.8% in Sudanese to 72.1% in Japanese), and E3/4 (frequency range from 11.3% in Japanese to 35.9% in Sudanese). Mean cholesterol levels ranged from 144.2 mg/dl in the Sudanese to 228.5 mg/dl in the Icelandics. Two-way analysis of variance of the effect of population and apo E type on cholesterol levels showed no significantly interaction effect, indicating that the effects of apo E type on cholesterol levels do not differ significantly among the populations. The overall average excess for the epsilon 2 allele was -14.12 mg/dl (range -31.63 to -8.82 mg/dl); for the epsilon 3 allele, 0.04 mg/dl (range -1.87 to 1.58 mg/dl; and for the epsilon 4 allele, 8.14 mg/dl (range -1.71 to 13.31 mg/dl). Despite the apparent heterogeneity in these values, especially for the epsilon 4 allele, comparison of the average excesses by a method of repeated sampling with random permutations revealed no significant difference in effects among populations. These data indicate that a given apo E allele acts in a relatively uniform manner in different populations despite differences in genetic background and environmental factors.
[Plasma concentration of lipoprotein(a) and distribution of its subtypes in the healthy population of Hungary].
Authors determined the plasma levels of total cholesterol, HDL-cholesterol, apoprotein B-100 (apo B-100), apoprotein A-I (apo A-I) and lipoprotein(a) in 202 (139 female and 63 male) randomized blood donors. The phenotypes of lipoprotein(a) were detected by SDS-polyacrylamide gelelectrophoresis and Western blotting. The average plasma total cholesterol concentration of this Hungarian population was 5.7 +/- 1.1 mmol/l. The other lipoprotein parameters were HDL-cholesterol: 1.36 +/- 0.04 mmol/l; and the apoprotein B-100 concentration: 70 +/- 17.4 mg/dl. In these parameters no difference between males and females could be found. The average plasma apoprotein A-I in females was 156.3 +/- 23.6 mg/dl and in males 143.8 +/- 26.8 mg/dl and the difference was statistically significant (p less than 0.01). The average lipoprotein(a) concentration of this population was 10.5 +/- 13.5 mg/dl and there was no significant difference between males and females (9.0 +/- 10.7 and 13.9 +/- 17.7 mg/dl, respectively). The distribution of plasma Lp(a) was highly skewed in the direction of low concentration values. In females a moderate bimodial distribution could be demonstrated. Documented by several authors lipoprotein(a) level higher than 30 mg/dl serves as an independent risk factor for atherosclerosis. In this population only 9.4% of subjects had lipoprotein(a) concentrations over this limit (5.9% female and 3.5% male). The relative alle frequency of different phenotypes showed the following distribution: B 0.007, S1 0.015, S2 0.154, S3 0.231, S4 0.230 and null 0.362. In this population the F phenotype could not be detected.
Relation of serum lipoprotein(a) concentration and apolipoprotein(a) phenotype to coronary heart disease in patients with familial hypercholesterolemia.
Familial hypercholesterolemia carries a marked increase in the risk of coronary heart disease (CHD), but there is considerable variation between individuals in susceptibility to CHD. To investigate the possible role of lipoprotein(a) as a risk factor for CHD, we studied the association between serum lipoprotein(a) levels, genetic types of apolipoprotein(a) (which influence lipoprotein(a) levels), and CHD in 115 patients with heterozygous familial hypercholesterolemia. The median lipoprotein(a) level in the 54 patients with CHD was 57 mg per deciliter, which is significantly higher than the corresponding value of 18 mg per deciliter in the 61 patients without CHD. According to discriminant-function analysis, the lipoprotein(a) level was the best discriminator between the two groups (as compared with all other lipid and lipoprotein levels, age, sex, and smoking status). Phenotyping for apolipoprotein(a) was performed in 109 patients. The frequencies of the apolipoprotein(a) phenotypes and alleles differed significantly between the patients with and those without CHD. The allele LpS2, which is associated with high lipoprotein(a) levels, was found more frequently among the patients with CHD (0.33 vs. 0.12). In contrast, the LpS4 allele, which is associated with low lipoprotein(a) levels, was more frequent among those without CHD (0.27 vs. 0.15). We conclude that an elevated level of lipoprotein(a) is a strong risk factor for CHD in patients with familial hypercholesterolemia, and the increase in risk is independent of age, sex, smoking status, and serum levels of total cholesterol, triglyceride, or high-density lipoprotein cholesterol. The higher level of lipoprotein(a) observed in the patients with CHD is the result of genetic influence.
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).
Frequency and effect of human apolipoprotein A-IV polymorphism on lipid and lipoprotein levels in an Icelandic population.
Human apolipoprotein A-IV (apo A-IV) exhibits a genetic polymorphism with two common alleles, A-IV1 and A-IV2, in Caucasian populations. We have investigated this polymorphism in the Icelandic population. The frequencies of the two alleles are significantly different from middel European populations with a higher frequency of the A-IV2 allele (0.117 versus 0.077) occurring in Iceland. The alleles at the apo A-IV locus have significant effects on plasma high density lipoprotein cholesterol (HDL-C) and triglyceride levels. The average effect of the A-IV2 allele is to raise HDL-C by 4.9 mg/dl and to lower triglyceride levels by 19.4 mg/dl. We estimate that the genetic variability at the apo A-IV gene locus accounts for 3.1% of the total variability of HDL-C and for 2.8% of the total variability of triglycerides in the population from Iceland. This confirms and extends our previous observations on apo A-IV allele effects in Tyroleans in an independent population.
Trisomy 18 mosaicism in an adult woman with normal intelligence and history of miscarriage.
We describe a women of short stature but of normal intelligence with 10% trisomy 18 mosaicism. Minor dysmorphic signs including facial asymmetries and a slight length difference of extremities were not suggestive of a chromosomal abnormality.