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Biomedical subjects

G Utermann

Publications and source records attributed to G Utermann.

At least 73 records · Page 4Linked to original sources
PubMed1998

Significant impact of the +93 C/T polymorphism in the apolipoprotein(a) gene on Lp(a) concentrations in Africans but not in Caucasians: confounding effect of linkage disequilibrium.

Lipoprotein(a) [Lp(a)] is a quantitative genetic trait in human plasma associated with atherothrombotic disease. The major determinant of Lp(a) concentration is the apolipoprotein(a) [apo(a)] gene locus. Variation in the number of kringle IV repeats (K-IV VNTR) in apo(a) has a direct effect on Lp(a) concentrations but explains only a fraction of the large intra- and inter-population variance in Lp(a) levels. Effects on Lp(a) of other intragenic polymorphisms including a pentanucleotide repeat (PNRP) in the promoter likely reflect allelic associations with as yet unidentified sequence variation in the apo(a) gene. We have studied a candidate C-->T transition in two European and two African populations. This polymorphism in the 5' region of the apo(a) gene creates an ATG start codon thereby reducing apo(a) translation in vitro by 60%. All samples were also analyzed for the K-IV VNTR and the PNRP to stratify for their effects and to consider allelic associations. Consistent with the in vitro effect the C-->T transition was associated with a significant reduction in Lp(a) levels in both African populations ( P < 0.0056). In Caucasians, however, the effect was not significant. This was explained by linkage disequilibrium of the +93 T with apo(a) alleles of intermediate length (K-24-K-34) and with nine PNRs. In Europeans these alleles are associated with low Lp(a) which makes any potential effect of the +93 T undetectable in the total sample. From our results we conclude (i) that the +93 C/T polymorphism is the second known intragenic apo(a) polymorphism which affects Lp(a) levels directly in vivo ; (ii) that allelic associations may mask the effect of a mutation; and (iii) that heterogeneity of an effect of a mutation across populations does not disprove causality.

Alleles↗
PubMed1997

Cloning, structural analysis, and chromosomal localization of the human CSRP2 gene encoding the LIM domain protein CRP2.

The CSRP2 gene encoding the LIM domain protein CRP2 was originally identified in quail based on its strong transcriptional suppression in transformed avian fibroblasts. Here we have isolated a human CSRP2 cDNA clone encoding a 193-amino-acid human CRP2 (hCRP2) protein with 96.4% amino acid sequence identity to the avian homolog. The CSRP2 cDNA clone was used to isolate CSRP2-related clones from gamma EMBL3 and P1 libraries of human genomic DNA. The complete organization of the CSRP2 gene was determined by nucleic acid hybridization, transcriptional mapping, and nucleotide sequence analysis. The gene spans a total of approximately 22 kb and contains six exons. The coding region is confined to exons 2-6 and predicts a hCRP2 protein identical in its amino acid sequence to the protein deduced from the CSRP2 cDNA clone. By fluorescence in situ hybridization using both lambda EMBL3 and P1 library clones as hybridization probes and a new method for computerized signal localization, CSRP2 was mapped to chromosome subband 12q21.1, a region frequently affected by deletion or breakage events in various tumor types. The library screens also led to the isolation of a CSRP2-related pseudogene, CSRP2P, which carried several extensive deletions and nucleotide substitutions but no intervening sequences in comparison to the CSRP2 cDNA sequence. By physical linkage and fluorescence in situ hybridization, CSRP2P was mapped to chromosome subband 3q21.1.

Adaptor Proteins, Signal Transducing↗
PubMed1997

Novel interaction of apolipoprotein(a) with beta-2 glycoprotein I mediated by the kringle IV domain.

Lipoprotein(a) [Lp(a)], which has been shown to interact with fibrin(ogen) and other components of the blood clotting cascade, is a major independent risk factor for atherothrombotic disease in humans. The physiological function(s) of Lp(a), as well as the precise mechanism(s) by which high plasma levels of Lp(a) increase risk are unknown. Identification of further potential apo(a)-protein ligands may be crucial to illuminate apo(a)'s function(s) and pathophysiological properties. We used the repetitive apo(a) kringle IV type 2, which is variable in number in apo(a), to screen a human liver cDNA library by the yeast two-hybrid interaction trap system. Among 11 positive clones that emerged from the screen, eight clones were identified as beta-2 glycoprotein I and one as fibronectin. Coimmunoprecipitation experiments confirmed that beta-2 glycoprotein I and apo(a)/Lp(a) interact in human plasma and in cell culture supernatants of COS-1 cells, which ectopically expressed apo(a). The apo(a)-beta2-glycoprotein I interaction indicates new potential roles for Lp(a) in fibrinolysis and autoimmunity.

Apolipoproteins↗
PubMed1997

Association of serum lipoprotein(a) levels and apolipoprotein(a) size polymorphism with target-organ damage in arterial hypertension.

OBJECTIVE: To investigate the association between lipoprotein(a) [Lp(a)] and other plasma lipids and apolipoproteins and target-organ damage (TOD) in patients with arterial hypertension. DESIGN: Cross-sectional study of a case series. SETTING: University medical center. PARTICIPANTS: Lipoprotein(a) and apolipoproteins were analyzed in 277 untreated patients with mild to moderate essential hypertension and in 102 healthy controls. Apolipoprotein(a) [apo(a)] phenotypes were additionally analyzed in an independent sample set of 106 hypertensive and 105 control subjects. MAIN OUTCOME MEASURES: Staging of TOD obtained according to World Health Organization guidelines by clinical evaluation, and laboratory tests including measurments of creatinine clearance, proteinuria, ophthalmoscopy, electrocardiography, echocardiography, and ultrasound examination of major arteries; levels of lipids, apolipoproteins, Lp(a), fibrinogen, and apo(a) phenotypes. RESULTS: Blood pressure, duration of hypertension, and levels of total cholesterol, low-density lipoprotein cholesterol, apolipoprotein B, Lp(a), and fibrinogen were significantly related to the presence and severity of TOD in univariate analysis. Stepwise multivariate analysis showed Lp(a) levels (P<.001) to be the best discriminator of the presence of TOD, followed by systolic blood pressure (P<.001), duration of hypertension (P=.01), and low-density lipoprotein cholesterol (P=.04). The Lp(a) levels were related to TOD independent of the level of blood pressure. We confirmed this association between Lp(a) concentrations and severity of TOD in a second independent sample set and observed a significantly higher frequency of low-molecular-weight apo(a) isoforms with increasing severity of TOD (P=.02). CONCLUSIONS: Lipoprotein(a) and apo(a) phenotype are sensitive indicators of the severity of TOD in patients with essential hypertension, and their evaluation might permit identification of hypertensive subjects liable to the development of organ damage. The higher frequency of low-molecular-weight apo(a) isoforms in patients with TOD demonstrates a genetically determined risk for the development of TOD in hypertensive patients.

Adult↗
PubMed1997

Sib-pair analysis detects elevated Lp(a) levels and large variation of Lp(a) concentration in subjects with familial defective ApoB.

Whether or not Lp(a) plasma levels are affected by the apoB R3500Q mutation, which causes Familial Defective apoB (FDB), is still a matter of debate. We have analyzed 300 family members of 13 unrelated Dutch index patients for the apoB mutation and the apolipoprotein(a) [apo(a)] genotype. Total cholesterol, LDL-cholesterol, and lipoprotein(a) [Lp(a)] concentrations were determined in 85 FDB heterozygotes and 106 non-FDB relatives. Mean LDL levels were significantly elevated in FDB subjects compared to non-FDB relatives (P < 0.001). Median Lp(a) levels were not different between FDB subjects and their non-FDB relatives. In contrast, sib-pair analysis demonstrated a significant effect of the FDB status on Lp(a) levels. In sib pairs identical by descent for apo(a) alleles but discordant for the FDB mutation (n = 11) each sib with FDB had a higher Lp(a) level than the corresponding non-FDB sib. Further, all possible sib pairs (n = 105) were grouped into three categories according to the absence/presence of the apoB R3500Q mutation in one or both subjects of a sib pair. The variability of differences in Lp(a) levels within the sib pairs increased with the number (0, 1, and 2) of FDB subjects present in the sib pair. This suggests that the FDB status increases Lp(a) level and variability, and that apoB may be a variability gene for Lp(a) levels in plasma.

Adult↗
PubMed1997

Statin therapy in a kindred with both apolipoprotein B and low density lipoprotein receptor gene defects.

We studied an extended family of similar genetic and environmental background to determine whether there is a difference in response to statin therapy in those subjects with heterozygous familial hypercholesterolaemia (FH Afrikaner-1 (FH1) or FH Afrikaner-2 (FH2)) compared to those with familial defective apo B-100 (FDB), or both FH plus FDB. Fasting lipid profiles and Lp(a) levels were done on 18 members of the family and then repeated following 6 weeks of therapy with simvastatin 20 mg daily. Statin therapy reduced LDL-cholesterol (LDL-C) by 31% in those with FH (n = 7); 29.8% in FDB (n = 5) and 25.4% in those with both FDB and FH (n = 5). There was no response to statin therapy in the single subject with both FH1, FH2, as well as FDB. Lp(a) levels did not change significantly either within or between any of the groups following statin therapy (FH from 6.5 (1.2-72.3) to 5.3 (1.2-52.3), FDB from 6.1 (4.70-71) to 8.2 (5.7 79) and FDB plus FH from 4.5 (2.6-17.4) to 3.1 (1.9-24) mg/dl). Statins are equally effective in lowering LDL-C in related subjects with heterozygous FH, FDB or both FDB plus FH. The ability of statins to lower LDL-C in FDB is probably due to increased hepatic uptake of lipoprotein precursors of LDL that can bind via apo E receptors. Lp(a) concentration is not reduced by drugs that stimulate LDL receptor activity implying that LDL receptors do not contribute greatly to normal clearance of Lp(a) in hypercholesterolaemic subjects with defects in receptor-mediated endocytosis of LDL.

Animals↗
PubMed1997

Comparative genomic hybridization reveals a partial de novo trisomy 6q23-qter in an infant with congenital malformations: delineation of the phenotype.

We report the use of comparative genomic hybridization (CGH) to define the origin of a small extra segment (unidentifiable by classical cytogenetics) present in a de novo add(13)q34 chromosome that we found in the karyotype of a newly born boy with congenital heart defects, brain anomalies and dysmorphic signs. Initial investigation with fluorescence in situ hybridization (FISH) and a chromosome-13-specific library revealed that the excess material was not derived from chromosome 13. To uncover the origin of the unknown chromosome material, CGH was carried out on DNA isolated from blood lymphocytes of the patient. By using a conventional fluorescence microscope with no digital imaging devices, a single distinct region with gain of fluorescent intensity was observed on distal chromosome 6q. Confirmation of this finding by FISH with a chromosome-6-specific paint and a subtelomeric yeast artificial chromosome clone from 6q26-q27, in combination with the band morphology of the small extra chromosomal segment, allowed us to diagnose the additional material as being derived from chromosome 6q23-qter. FISH with a telomere 13q probe detected a terminal deletion of 13q34-qter on the derivative chromosome 13, indicating that the der(13) was a result of a translocation event. Genotyping of the hypervariable apolipoprotein (a) gene, which lies within 6q26-q27, showed that the additional chromosome 6 material was inherited from the mother. The karyotype of the proposita is therefore: 46,XY,-13,+der(13)t(6;13)(q23;q34) de novo (mat). Our results confirm the usefulness of CGH as an attractive alternative method for the characterization of constitutional small genetic imbalances and contribute to the delineation of the trisomy 6q23-qter phenotype.

Abnormalities, Multiple↗
PubMed1997

Chromosomal instability in a woman with infertility and two unaffected brothers: a new familial chromosomal breakage syndrome?

Repeated chromosomal analysis of peripheral blood lymphocytes and skin fibroblasts from a woman referred for amenorrhoea, streak gonads, hyperthyroidism, adiposity and elevated alpha-fetoprotein levels but no other manifestations of known chromosomal breakage syndromes demonstrated an increased spontaneous chromosomal breakage rate (ISCBR). Chromatid and chromosomal breaks were more numerous than sporadic rearrangements and dicentric chromosomes. Exposure of the cells to mitomycin C, diepoxybutane, X-rays or UV irradiation induced an increase in chromosomal and chromatid abnormalities over that in controls. A micronucleus assay demonstrated an increase in the incidence of formation of micronuclei and the population doubling time of the fibroblasts of the proposita was delayed. Chromosomal analysis was performed on lymphocytes of the parents and of five sibs of the proposita. Two brothers had chromosomal abnormalities identical to those of the patient and elevated alpha-fetoprotein levels, however, without any clinical abnormalities. The parents were affected by only a moderate ISCBR whereas two brothers and one sister were chromosomally normal. The clinical, chromosomal and biochemical findings in this family represent a novel chromosomal instability syndrome.

Adult↗
PubMed1997

LDL-unbound apolipoprotein(a) and carotid atherosclerosis in hemodialysis patients.

High lipoprotein(a) [Lp(a)] plasma concentrations, which are genetically determined by apo(a) size polymorphism, are directly associated with an increased risk for atherosclerosis. Patients with end-stage renal disease (ESRD), who show an enormous prevalence of cardiovascular disease, have elevated plasma concentrations of Lp(a). In recent studies we were able to show that apo(a) size polymorphism is a better predictor for carotid atherosclerosis and coronary artery disease in hemodialysis patients than concentrations of Lp(a) and other lipoproteins. Less than 5% of apo(a) in plasma exists in a low-density lipoprotein (LDL)-unbound form. This "free" apo(a) consists mainly of disintegrated apo(a) molecules of different molecular weight, ranging from about 125 to 360 kDa. LDL-unbound apo(a) molecules are elevated in patients with ESRD. The aim of this study was therefore to investigate whether the LDL-unbound form of apo(a) contributes to the prediction of carotid atherosclerosis in a group of 153 hemodialysis patients. The absolute amount of LDL-unbound apo(a) showed a trend to increasing values with the degree of carotid atherosclerosis, but the correlation of Lp(a) plasma concentrations with atherosclerosis was more pronounced. In multivariate analysis the two variables were related to neither the presence nor the degree of atherosclerosis. Instead, the apo(a) phenotype took the place of Lp(a) and LDL-unbound apo(a). After adjustment for other variables, the odds ratio for carotid atherosclerosis in patients with a low molecular weight apo(a) phenotype was about 5 (p<0.01). This indicates a strong association between the apo(a) phenotype and the prevalence of carotid atherosclerosis. Finally, multivariate regression analysis revealed age, angina pectoris and the apo(a) phenotype as the only significant predictors of the degree of atherosclerosis in these patients. In summary, it seems that LDL-unbound apo(a) levels do not contribute to the prediction of carotid atherosclerosis in hemodialysis patients. However, this does not mean that "free", mainly disintegrated, apo(a) has no atherogenic potential.

Adult↗
PubMed1997

Detection of a de novo duplication of 1q32-qter by fluorescence in situ hybridisation in a boy with multiple malformations: further delineation of the trisomy 1q syndrome.

We report a dysmorphic boy with a de novo partial trisomy 1q. The boy has microcephaly, bilateral cleft lip and palate, low set and dysmorphic ears, brain anomalies, pulmonary stenosis, duodenal obstruction, dysplastic kidneys, and bifid thumbs. The trisomic segment 1q32-qter is duplicated with an inverted insertion at 1p36.3. The aberration was initially detected at amniocentesis and confirmed and defined by GTG banding, chromosome microdissection, and FISH on postnatal blood samples. The parents had normal karyotypes. De novo partial duplications of chromosome 1q have rarely been reported. Comparison of our patient with other published pure trisomy 1q cases showed similarities which allowed the further delineation of the trisomy 1q syndrome.

Chromosome Aberrations↗
PubMed1997

Renovascular arteriovenous differences in Lp[a] plasma concentrations suggest removal of Lp[a] from the renal circulation.

High plasma concentrations of lipoprotein[a] (Lp[a]) are considered a genetically determined risk factor for atherosclerosis. Lp[a] is produced by the liver. The site(s) and mechanism(s) of catabolism are presently unclear. Lp[a] is elevated secondary to end-stage renal disease which suggests a direct or indirect role of the kidney in the metabolism of Lp[a]. We therefore investigated, by a simple in vivo approach, whether Lp[a] is removed by the human kidney. Lp[a] plasma concentrations were measured simultaneously by various methods in the ascending aorta and renal vein of 100 patients undergoing coronary angiography or coronary angioplasty. Lp[a] levels differed significantly between the two vessels even after correcting for hemoconcentration (20.1 +/- 21.6 mg/dL versus 18.7 +/- 20.3 mg/dL, P < 0.001). This corresponds to a mean arteriovenous difference of -1.4 mg/ dL or -9% of the arterial concentration. No Lp[a] or intact apo[a] could be detected in urine from healthy probands. Although we cannot assign the kidney a regulatory role for Lp[a] plasma levels in humans with normal renal function, we conclude from our data that substantial amounts of this atherogenic lipoprotein are taken up by the kidney. The underlying mechanisms are unknown at the moment. This study therefore demonstrates for the first time that the human kidney plays an active role in the catabolism of Lp[a]. This may explain the elevated Lp[a] concentrations found in patients with chronic renal insufficiency.

Aged↗
PubMed1996

Chromosomal localization of the genes (CLNS1A and CLNS1B) coding for the swelling-dependent chloride channel ICln.

ICln is a cloned chloride channel paramount for regulatory volume decrease. Two different loci that carry the coding region for ICln were identified in the human genome. By PCR strategies an intronless copy of the gene was located on chromosome 6 at position 6p12.1-6q13 (CLNS1B). By fluorescence in situ hybridization a copy carrying introns with a putative length of 19 kb was located at chromosome 11 on position 11q13.5-q14.1 (CLNS1A). The characterization and chromosomal localization of the ICln gene offer the opportunity to study the regulatory sites of this gene in greater detail and could be helpful in establishing linkages between ICln and potential human diseases.

Chloride Channels↗
PubMed1996

The number of identical kringle IV repeats in apolipoprotein(a) affects its processing and secretion by HepG2 cells.

A variable number of 5.6-kilobase kringle IV repeats in the human apolipoprotein(a) (apo(a)) gene results in a size polymorphism of the protein and correlates inversely with the plasma levels of the atherogenic lipoprotein(a) (Lp(a)). In order to analyze whether this association reflects a direct effect of kringle IV repeat number on Lp(a) plasma concentration, we have studied the expression of recombinant apo(a) (r-apo(a)) isoforms in the human hepatocarcinoma cell line HepG2. Following transient transfection of apo(a) cDNA expression plasmids that differed only in the number of kringle IV repeats, we observed a gradual decrease of Lp(a) in the medium of the cells with an increasing number of kringle IV repeats, mimicking the relationship present in humans in vivo. The analysis of apo(a) protein in the lysate and in the medium of cells that were transfected with a plasmid encoding an apo(a) isoform with 22 kringles revealed a predominant intracellular precursor with little secretion of the mature apo(a) protein. In contrast, transfection of a plasmid encoding an isoform with 11 kringles led to effective secretion of the mature peptide into the medium, indicating differential processing rates of apo(a) isoforms in the secretory path way. The intracellular accumulation of an apo(a) precursor in the endoplasmic reticulum was demonstrated by cell fractionation and [35S]Met metabolic labeling/temperature block experiments using HepG2 cells stably transfected with recombinant apo(a). The direct and causal effect of kringle IV repeat number on the expression of recombinant apo(a) in HepG2 cells, and presumably liver cells, provides a novel mechanism for the genetic regulation of the concentration of a protein.

Apolipoproteins A↗
PubMed1996

Role of 7,8-dihydroneopterin in T-cell apoptosis and HTLV-1 transcription in vitro.

Adult T-cell leukemia is associated with high levels of neopterin, released in large amounts from human macrophages upon stimulation with interferon-gamma. Recent data suggested a potential role of neopterin-derivatives in oxygen radical-mediated processes, and evidence accumulates that oxidative stress is involved in the pathogenesis of viral diseases. We now report that increased concentrations of 7,8-dihydroneopterin may lead to enhanced apoptosis and disturbance of the redox-balance of human leukemic Jurkat T cells. Additionally, we demonstrate that 7,8-dihydroneopterin and hydrogen peroxide activate the type 1 human T-cell leukemia virus (HTLV-1) long terminal repeat (LTR). Furthermore, we found that the activity of the HTLV-1 transactivator protein Tax is amplified by an elevated concentration of 7,8-dihydroneopterin. Tax did not significantly augment 7,8-dihydroneopterin mediated apoptosis. Based on our data we propose that 7,8-dihydroneopterin may be involved in the progression to higher stages of HTLV-1 associated disease.

Antioxidants↗
PubMed1996

The relative electrophoretic mobility of apo(a) isoforms depends on the gel system: proposal of a nomenclature for apo(a) phenotypes.

Genetic apo(a) isoforms were originally defined according to their relative mobility in SDS-PAGE compared to apoB-100 and were designated as F, B or S1-S4 isotypes. This widely accepted nomenclature does not accommodate the broad spectrum of apo(a) isoforms (> 30) detected by high resolution SDS-agarose gel electrophoresis. Moreover we here show that the relative mobilities of apo(a) isoforms depend on the SDS-gel system used. Comparison of the SDS-PAGE system originally used for phenotyping with SDS-agarose gel electrophoresis and two commercial SDS-PAGE systems (PhastGel, Pharmacia, Sweden and NOVEX, USA) demonstrated marked differences in resolving power and resulted in very different Rf values for identical isoforms. Hence phenotyping results from laboratories using different systems are not comparable. We therefore propose a nomenclature of apo(a) isoforms which reports the number of kringle IV repeats in the apo(a) allele (e.g. apo(a) K-IV20 would designate an isoform with 20 K-IV repeats). This is achieved by using standards in which the number of kringle IV repeats has been determined by pulsed field gel electrophoresis of genomic DNA. The proposed nomenclature (i) accounts for the increased resolution of apo(a) phenotyping methods: (ii) is flexible to the introduction of smaller or larger isoforms; (iii) allows to report data from systems with lower resolution as 'binned' isoform categories; (iv) allows the comparison of phenotyping results between different investigators; and (v) can be applied on DNA as well as on protein based apo(a) phenotyping.

Apolipoproteins A↗
PubMed1996

Lipoprotein(a) is increased in triglyceride-rich lipoproteins in men with coronary heart disease, but does not change acutely following oral fat ingestion.

Association of apo(a)/Lp(a) with triglyceride-rich lipoproteins (TGR-Lps) is determined by different factors that are poorly understood. Some previous studies suggested that apo(a) in TGR-Lps may affect the atherogenicity of the TGR particles. To study whether there are any peculiarities in postprandial (pp) Lp(a) metabolism, we have determined apo(a) phenotypes and Lp(a) concentrations in 46 subjects with coronary heart disease (CHD) and in six normolipidemic individuals at different time points (4, 6 and 8 h) following an oral fat tolerance test. While mean triglyceride concentration reached its maximum 6 h after a standardized fat meal, no change in total cholesterol and in mean Lp(a) plasma concentration was detected at any time point after the fat load. In 6 normolipidemic probands and in 8 patients with CHD, who were matched for apo(a) phenotype, lipoprotein levels, age and body weight, we followed the distribution of apo(a) in plasma density gradient fractions in the fasting and pp state. In the CHD patients a significant larger percentage of apo(a) reactivity was detected in TGR-Lps in the pre- as well as in the postprandial state, compared to control subjects. The fat intake did not induce a significant change of apo(a) reactivity in the TGR-Lp fractions in both groups. The apo(a) isoform-size and the Lp(a) plasma concentration in the fasting state had no influence on the individual variation of the Lp(a) concentration in pp TGR-Lp fractions. Our results provide evidence that TGR-Lp fractions of CHD patients are enriched in apo(a) reactivity compared to healthy controls, but do not support the hypothesis that Lp(a) acts atherogenically through a pp increase of its plasma concentration.

Adult↗