Search PubMed⌕ Search

Biomedical subjects

H J Menzel

Publications and source records attributed to H J Menzel.

At least 19 recordsLinked to original sources
PubMed1995

Apolipoprotein A-IV polymorphism in the Hungarian population: gene frequencies, effect on lipid levels, and sequence of two new variants.

The genetic polymorphism of human apolipoprotein A-IV was investigated in Hungarian blood donors (n = 202) by isoelectric focusing (IEF) of plasma samples followed by immunoblotting. The frequency of apo A-IV alleles was f(A-IV1) = 0.95, f(A-IV2) = 0.039 and f(A-IV3) = 0.002. This frequency distribution is significantly different from other Caucasian populations (P < 0.05). The association of apo A-IV phenotypes with HDL-cholesterol concentration which was previously described for two other European populations was only of borderline significance (P = 0.08). Three previously undescribed apo A-IV variants, designated Budapest-1, Budapest-2 and Budapest-3, were detected by IEF. The mutant proteins are not associated with alterations in the lipid/lipoprotein concentrations in heterozygotes. DNA-sequencing revealed two point mutations (Arg285-->Cys and Thr347-->Ser) in exon 3 of apo A-IV-Budapest-1 and a Glu-->Lys substitution at position 24 in exon 2 of apo A-IV-Budapest-2.

Adult↗
PubMed1995

Allele-specific competitive blocker PCR: a one-step method with applicability to pool screening.

We have developed a novel one-step pool screening PCR procedure which is based on the principles of amplification refractory mutation system (ARMS) and competitive oligonuleotide priming (COP) PCR. In addition to the usual primers, this approach uses two allele-specific competitive oligonucleotides, one of which is 3'-end labeled with a dideoxynucleotide and blocks amplification of the wild-type allele. An allele-specific product is generated only in the presence of the mutation. The introduction of an allele-specific competitive blocker oligonucleotide improves the specificity and robustness of ARMS-PCR. Further its sensitivity is dramatically increased, which allows detection of one mutant allele in a large excess of wild-type-bearing genomic DNA by electrophoresis in an ethidium bromide-stained agarose gel (up to 1 in 10(4) alleles). This makes the method ideal for nonradioactive pool screening. The successful application of the method has been demonstrated for four different point mutations, two in the apolipoprotein B gene (R3500Q, R3531C) which result in familial defective apolipoprotein B-100, one in the CFTR gene (R1162X), and one in the gene for lipoprotein lipase (G188E).

Alleles↗
PubMed1995

Apo(a) phenotypes and Lp(a) concentrations in offspring of men with and without myocardial infarction. The EARS Study. European Atherosclerosis Research Study.

In the European Atherosclerosis Research Study, genetic and environmental markers of risk of premature coronary heart disease were compared in offspring of men with and without myocardial infarction before the age of 55 years. Cases were 682 students with a paternal history of myocardial infarction, and control subjects were 1312 students without such a history. The students were enrolled in 14 universities in five European regions (Finland, Great Britain, and northern, middle, and southern Europe). Lipoprotein(a) [Lp(a)] concentrations were skewed towards lower concentrations in both cases (median, 7.3 mg/dL; 95% confidence interval, 6.3 to 8.1 mg/dL) and control subjects (median, 6.6 mg/dL; 95% confidence interval, 6.1 to 7.2 mg/dL) (P = .37). Significantly more northern European male cases than control subjects had Lp(a) levels exceeding 30 mg/dL (P = .040), but this did not pertain to females (P = .29), and overall, there was no difference between cases (16.5%) and control subjects (15.5%) in the frequency of Lp(a) concentrations above 30 mg/dL (P = .63). As expected, there was a significant (P < .01) inverse relationship between apo(a) molecular size and Lp(a) concentration. In Great Britain there was a significant difference in phenotype distribution between cases and control subjects (P = .035), due mainly to a high frequency of the apo(a) S2 isoform in cases. A similar but statistically insignificant tendency was seen in northern Europeans. In the three other regions, however, the distribution of apo(a) phenotypes among cases and controls was similar, and in the study population overall, the distribution of apo(a) phenotypes did not differ significantly (P = .74) between cases and control subjects.

Adult↗
PubMed1994

Genetic polymorphism of apolipoprotein A-IV in five different regions of Europe. Relations to plasma lipoproteins and to history of myocardial infarction: the EARS study. European Atherosclerosis Research Study.

As a part of the EARS study we assessed the role of the common apo A-IV polymorphism in determining the hereditary predisposition to cardiovascular disease. The study population consisted of 1261 controls and 629 cases (students whose father had MI before 55 years) from five different European regions. The apo A-IV 1-1 phenotype accounted for 85% of the individuals. One per cent of subjects were homozygous for the apo A-IV2 allele. There was significant regional variation in the apo A-IV allele frequencies from North to South in Europe, with the lowest A-IV2 frequency in Finland. The distribution of the apo A-IV phenotypes was similar in cases and controls, as was the regional variation. The apo A-IV polymorphism did not affect HDL cholesterol. There was no correlation between apo A-IV alleles and the plasma concentration of apo A-IV. The plasma concentration of apo A-IV was lower in females than in males; furthermore, there was a significant difference in apo A-IV concentrations between oral contraceptive users and nonusers: users had the lowest values. As no strongly significant genetic difference could be demonstrated between plasma lipid concentration in cases and controls, and as the apo A-IV polymorphism did not significantly influence plasma lipid concentration, we conclude that the apo A-IV gene is not a major determinant of the risk for MI and/or CHD.

Adolescent↗
PubMed1994

ApoE polymorphism and predisposition to coronary heart disease in youths of different European populations. The EARS Study. European Atherosclerosis Research Study.

The European Atherosclerosis Research Study was based on the comparison of offspring having a paternal history of premature myocardial infarction with age- and sex-matched control subjects. Case (n = 635) and control (n = 1259) subjects aged 18 through 26 years were recruited from 14 universities of 11 European countries. The allele distributions of apolipoprotein (apo) E polymorphism differed between populations, with a clear-cut gradient for allele epsilon 4 frequency decreasing from 0.18 in Finland to 0.11 in the south of Europe, following the gradient of coronary heart disease mortality rates. The association of apoE polymorphism with plasma total cholesterol, low-density lipoprotein cholesterol, apoB, and apoE levels was consistent with the now well-identified effects of epsilon 2 and epsilon 4 alleles on these traits. Both epsilon 2 and epsilon 4 alleles equally increased the level of triglycerides, and epsilon 2 had a lowering effect on lipoprotein(a) concentration. There were also weak effects of epsilon 2 and epsilon 4 on high-density lipoprotein cholesterol, apoA-I, and apoA-I-containing lipoprotein levels that paralleled those on apoE levels. The main finding of this study was the significant association of the apoE polymorphism with a paternal history of myocardial infarction. The association was consistent across regions, except in the south. When excluding this region, the population-adjusted odds ratios by reference to phenotype E3/3 were estimated as 0.23, 0.61, 0.78, 1.16, and 1.33 for E2/2, E3/2, E4/2, E4/3, and E4/4, respectively. The apoE locus largely explained the case/control difference of apoB level.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1992

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.

Alleles↗
PubMed1992

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.

Alleles↗
PubMed1991

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.

Alleles↗
PubMed1990

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).

Abetalipoproteinemia↗
PubMed1990

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.

Alleles↗
PubMed1990

Variation in the size of human apolipoprotein(a) is due to a hypervariable region in the gene.

We have investigated whether the size heterogeneity of the human apolipoprotein(a) [apo(a)] is due to differences in the number of plasminogen kringle 4-like repeat units present in the different alleles. Using the Southern blot hybridization technique and a DNA probe for the kringle 4 domain of plasminogen, we have observed that in 31 different individuals a 5.8-kb PvuII restriction fragment band varies widely in intensity relative to other bands. A strong correlation (r = 0.76, P less than 0.001) was found between apo(a) protein size and the variation in intensity of the detected restriction fragment band. We confirmed this correlation in a large family where the parents are heterozygous for the apo(a) protein size isoforms. The specificity of the 5.8-kb band was established by using an apo(a)-specific oligonucleotide. These correlations strongly suggest that the observed size heterogeneity in apo(a) protein is due to different numbers of copies of the kringle 4 sequence in the apo(a) glycoprotein gene.

Alleles↗
PubMed1989

Genetics of the quantitative Lp(a) lipoprotein trait. III. Contribution of Lp(a) glycoprotein phenotypes to normal lipid variation.

Apolipoprotein(a) [apo(a)] is a large serum glycoprotein with several genetically determined isoforms differing in their apparent molecular weight. We determined the effects of the apo(a) isoforms on total cholesterol, high-density lipoprotein (HDL)-cholesterol, lipoprotein(a), and triglyceride levels in a sample of 473 unrelated Tyrolean adults. Average lipoprotein(a) and total cholesterol levels were significantly different among apo(a) types. These significant differences were found among the 13 apo(a) isoform patterns observed in this sample and among several logical subsets of the isoform patterns (e.g. considering only the single band types). The data suggest that the effects of apo(a) alleles on Lp(a) levels are additive. The effects of apo(a) on total cholesterol levels cannot be entirely explained by the cholesterol fraction estimated to be contained in the lipoprotein(a) particle. We estimate that the apo(a) glycoprotein polymorphism accounts for 41.9% and 9.6% of the variability in lipoprotein(a) and total cholesterol levels, respectively. This is the strongest effect of a single polymorphic gene on plasma lipid and lipoprotein levels reported so far.

Cholesterol↗
PubMed1989

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

We have studied the segregation of the Lp(a) glycoprotein phenotypes and of the plasminogen (PLG) polymorphism in three two-generation families. The inheritance of the Lp(a) gene was followed using the Lp(a) glycoprotein size polymorphism and that of the plasminogen gene, using protein and DNA polymorphisms. In the three families studied, no recombination was observed in 18 meioses. The lod score for linkage between the Lp(a) glycoprotein locus and the plasminogen locus in these families is greater than 5.0 at a recombination fraction of theta = 0. Our results show that the structural gene for the Lp(a) glycoprotein is closely linked to the gene for plasminogen on chromosome 6.

Chromosomes, Human, Pair 6↗
PubMed1989

Changes of genetic apolipoprotein phenotypes caused by liver transplantation. Implications for apolipoprotein synthesis.

Liver transplantation provides a unique opportunity to investigate the contribution in vivo of the liver to the synthesis and degradation of genetically polymorphic plasma proteins. We have determined the genetic polymorphisms plasma proteins. We have determined the genetic polymorphisms of apo A-IV, apo E, and of the Lp(a) glycoprotein (apo (a] in the plasma of subjects undergoing liver transplantation and in respective organ donors. The results show that in humans, greater than 90% of the plasma apo E and virtually all apo (a) are liver derived, whereas this organ does not significantly contribute to plasma apo A-IV levels.

Adolescent↗
PubMed1988

Human apolipoprotein A-IV polymorphism: frequency and effect on lipid and lipoprotein levels.

Human apolipoprotein (apo) A-IV is genetically polymorphic, the apo A-IV polymorphism being controlled by two common alleles, A-IV1 and A-IV2. We have developed a method for typing the apo A-IV polymorphism by Western blotting using polyclonal rabbit antiapo A-IV as the first and gold-labeled antirabbit IgG as the second antibody. Apolipoprotein phenotypes were determined in plasma samples from 473 tiroleans. The frequencies of the apo A-IV alleles in this sample were f(A-IV1) = 0.919, f(A-IV2) = 0.077, and f(A-IV3) = 0.004. Although average triglyceride levels were lower in apo A-IV 2-1 heterozygotes, average total serum cholesterol and triglyceride levels were not significantly different among apo A-IV types. High density lipoprotein (HDL) cholesterol was significantly increased in individuals with the A-IV 2-1 phenotype. We estimate that genetic variation at the apo A-IV gene locus accounts for 11% of the total variability in HDL-cholesterol levels in Tiroleans. The effects of the apo A-IV polymorphism described here are consistant with, and may serve to enrich, our limited knowledge of the role of apo A-IV in lipid metabolism.

Apolipoproteins A↗
PubMed1988

Genetics of the quantitative Lp(a) lipoprotein trait. I. Relation of LP(a) glycoprotein phenotypes to Lp(a) lipoprotein concentrations in plasma.

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.

Alleles↗
PubMed1988

Genetics of the quantitative Lp(a) lipoprotein trait. II. Inheritance of Lp(a) glycoprotein phenotypes.

Lp(a) glycoprotein exhibits an apparent size polymorphism that is associated with genetically controlled Lp(a) lipoprotein concentrations in plasma (Utermann et al. 1988). We have tested the hypothesis that this polymorphism is genetically controlled by studying 15 matings with a total of 44 offspring. This confirmed our conclusion that Lp(a) types are controlled by a series of codominant alleles LpF, LpB, LpS1, LpS2, LpS3 and LpS4 and by a null allele LpO. Together with the data from the accompanying paper this indicates that the structural gene for the Lp(a) protein is the major gene locus determining Lp(a) lipoprotein concentrations in plasma.

Electrophoresis, Polyacrylamide Gel↗