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Biomedical subjects

H Schuster

Publications and source records attributed to H Schuster.

At least 55 records · Page 3Linked to original sources
PubMed1998

Approaches to the genetics of cardiovascular disease through genetic field work.

Successful molecular genetic studies of complex disease require exact, careful phenotypization, which is more difficult than that performed for monogenic diseases. We have developed a family-oriented field working approach, which relies on index patients, their primary care physicians, and a minimum number of field working staff. The patients are responsible for recruiting their family members. Packets containing an explanatory pamphlet, an informed consent statement, a questionnaire, and blood cuvettes are provided. Data are transferred from questionnaire and from the laboratory into a computer program that facilitates construction of the family tree. We have applied this genetic field working approach primarily to patients with lipid disorders. Coupling results from genetic field working with modern DNA diagnostic tests such as the oligonucleotide ligation assay, has enabled us to effectively identify patients with familial hypercholesterolemia in the German population. We are now extending genetic field working to hypertension. Hypertension is much more difficult to study, because the phenotype is more difficult to discern and document. Both complex diseases have the disadvantage that the parents of the index patients are likely to already be dead. Nevertheless, we concentrate on the recruitment of large pedigrees, sibling pairs with parents whenever possible, and trios consisting of index patient and both parents or index patient, parent and sibling. With these constellations we can conduct association studies, linkage analysis, and novel combinations of both approaches.

Automation↗
PubMed1998

Absence of hypertensive retinopathy in a Turkish kindred with autosomal dominant hypertension and brachydactyly.

BACKGROUND: A 60 member Turkish kindred with autosomal dominant hypertension, which cosegregates completely with brachydactyly and short stature, was studied. Affected people have severe hypertension and generally die of stroke by the age of 50. The hypertension closely resembles essential hypertension and, accordingly, the mechanisms of blood pressure elevation are unknown. The gene responsible was mapped to chromosome 12p. METHODS: All 29 affected family members underwent a basic physical examination and funduscopy. Other than markedly elevated blood pressures and the residua of stroke in a few subjects, the apparent lack of end organ damage was striking, including the normal appearing fundi. Five affected individuals were studied in a clinical research unit study. All underwent a complete ophthalmological examination. Fluorescein angiograms were obtained in three subjects. RESULTS: Systolic blood pressures ranged from 170 to 250 mm Hg, while diastolic blood pressures ranged from 100 to 150 mm Hg in affected individuals. In all affected subjects, the fundi were only minimally altered or clinically normal. All three fluorescein angiograms were normal. Despite severe hypertension since childhood the patients showed no signs of hypertensive retinopathy. CONCLUSIONS: The absence of hypertensive retinopathy in this novel form of inherited hypertension is due to an altered structure of retinal arteriolar walls or some other protective mechanism. Since evidence of end organ damage is scarce in other organs as well, the protective mechanism appears to be generalised.

Adolescent↗
PubMed1998

Detection of the low density lipoprotein receptor gene PvuII intron 15 polymorphism using the polymerase chain reaction: association with plasma lipid traits in healthy men and women.

We have used anchored PCR to amplify and sequence 1400 bp of the 15th intron of the Low Density Lipoprotein (LDL) receptor gene, and have determined oligonucleotides and conditions for the genotyping of the previously reported PvuII polymorphism. The cutting site (CAGCTG) is created by the transition of a CpG to a TpG within the sequence CAGCCG at a position roughly 600 bp 5' from the splice acceptor site of exon 16. Genotype was determined in three population-based samples of healthy individuals. In a group of 318 men and women from Iceland the frequencies of the Intron-15 T (cutting) allele was 0.23 (95% CI, 0.19-0.28) and was similar in men and women. In two groups of men from England (n = 385) and Scotland (n = 320), the frequency was similar, being 0.23 (0.19-0.27) and 0.25 (0.22-0.28) respectively. Individuals who were homozygous for the T allele had lower levels of total-cholesterol triglycerides and apolipoprotein B, than those with other genotypes, and in the combined group of UK men this effect reached statistical significance; compared to the C/C group, the T/T group had 6% lower cholesterol (p = 0.02) and 15% lower triglycerides (p = 0.03). The lowering effect associated with the T/T genotype was greater in men who were in the lowest tertile of body mass index (< 25 kg/m2) and for the trait of apoB levels, this genotype x obesity interaction was statistically significant (p = 0.01). We thus confirm the association between this allele and lower levels of plasma lipid levels previously reported. The availability of a PCR-based method to detect this polymorphism will facilitate further investigation of the impact of LDL-receptor gene variation in determining lipid levels.

Alleles↗
PubMed1998

Evaluation of the angiotensinogen locus in human essential hypertension: a European study.

Different family and case-control studies support genetic linkage and association at the human angiotensinogen (AGT) locus with essential hypertension. To extend these previous observations, a European collaborative study of nine centers was set up to create a large resource of affected sibling pairs. The AGT locus was studied using a highly polymorphic dinucleotide repeat in the 3'-flanking region of the gene in 350 European families, comprising 630 affected sibling pairs. Statistical analyses using two different methods did not show any evidence for linkage either in the whole panel or in family subsets selected for severity or early onset of disease. Although several arguments from association studies suggest a role of the AGT gene in essential hypertension, this large family study did not replicate the initial linkage reported in smaller studies. Our results highlight the difficulty of identifying susceptibility genes by linkage analysis in complex diseases.

Adult↗
PubMed1997

Phenotyping and genotyping patients with cardiovascular risk factors.

Complex diseases require precise phenotyping if their genetic basis is to be properly understood. This process is more complex than the analysis used for monogenic diseases. Collecting family phenotypic data is costly and time consuming, making such studies difficult. We have developed a family-oriented, field working approach that relies on index patients, their primary-care physicians, and a minimum number of field working staff. The index patients recruit family members by distributing packs containing the materials necessary for participation. Computer analysis of the data returned enables construction of the medical family tree. We have extended this genetic field working approach to patients with lipid disorders, arterial hypertension, non-insulin-dependent diabetes mellitus, and the 'Metabolic Syndrome'. Data from these groups can be used to identify susceptibility genes for premature arteriosclerosis. We describe a cost-effective methodology that can be used in the primary-care setting to identify 'at-risk' patients and facilitate effective targeting of limited health-care resources.

Cardiovascular Diseases↗
PubMed1997

Primary neuroendocrine (merkel cell) carcinoma of the anterior skull base.

A case of a primary neuroendocrine (Merkel cell) carcinoma arising in the anterior skull base involving the dura, both frontal lobes, and the paranasal sinuses is presented. The tumor was completely removed by an enlarged bifrontal transbasal approach. The neuropathological, immunohistological, and electron microscopical investigation revealed all characteristics of a Merkel cell carcinoma, normally presenting as a skin carcinoma of the head and neck. The history, treatment, neuropathology, and possible explanation for this rare manifestation are discussed.

Case Reports↗
PubMed1997

Heritability analysis of lipids and three gene loci in twins link the macrophage scavenger receptor to HDL cholesterol concentrations.

We studied 100 healthy monozygotic and 72 dizygotic twin pairs (mean age, 34 +/- 14 years) to test for genetic influences on blood lipids and to examine relevant gene loci. Total cholesterol (TC), LDL cholesterol (LDL-C), HDL cholesterol (HDL-C), and triglyceride (TG) levels were determined after a 12-hour fast. Zygosity was determined with the use of microsatellite markers. Heritability estimates were conducted by using the lisrel 8 program; a sib-pair analysis was conducted by using the sibpal program. Linear regression analyses were carried out between identical-by-descent status and squared within-pair differences of TC, LDL-C, HDL-C, and TG values. Heritability estimates of the lipid serum concentrations ranged from .58 to .66. A significant linkage relationship was found for HDL-C (P = .008) and TGs (P = .05) with D8S261 on chromosome 8p. However, no linkage was found between any of the lipid variables and the lipoprotein lipase gene locus (LPL GZ14/15 and D8S282). Because D8S261 is located approximately halfway between the LPL and macrophage scavenger receptor genes, we examined the nearby markers D8S549 and D8S1731. Linkage was found for HDL-C and D8S549 (P = .001) and for HDL-C and D8S1731 (P = .04). On the other hand, we found no linkage between the LDL receptor gene locus and LDL-C serum concentrations nor between the LPL gene locus and the various other lipid fractions. Our data suggest a significant influence of the macrophage scavenger receptor gene locus on HDL-C and weak influence on TG levels. We suggest that inherited variability in the macrophage scavenger receptor gene has an influence on serum lipid concentrations.

Adult↗
PubMed1997

Phenotypic variation in patients heterozygous for familial defective apolipoprotein B (FDB) in three European countries.

A glutamine-for-arginine substitution at amino acid position 3500 of apolipoprotein B (apo B) causes synthesis of LDL with reduced binding affinity to the LDL receptor (LDLR). The associated clinical syndrome has been named familial defective apolipoprotein B- 100 (FDB). In 205 FDB patients from Germany (n = 73). The Netherlands (n = 87), and Denmark (n = 45), we tried to assess determinants of variation in lipid concentrations. Besides age, sex, and geographic origin, variation in the LDLR gene was the most powerful determinant of variation in total cholesterol and LDL cholesterol levels. Polymorphic variation in the LDLR gene (SfaNI, exon 2; Nco I, exon 18) was associated with total cholesterol (TC) and LDL cholesterol (LDL-C) variation in women (SfaNI: P = .04 and .03 for TC and LDL-C, respectively; Nco I; P = .003 and .006, respectively), whereas the Ava II (exon 13) and the Pvu II (intron 15) polymorphisms were not. Combined information from all three LDLR exon polymorphisms showed that subjects with at least one S + A + N + allele had 13% to 20% higher TC than non-S + A + N + subjects (P = .02 [TC, men]; P = .01 [LDL-C, men]; P = .005 [TC, women]; and P = .004 [LDL-C, women]) and, together with age and geographic origin, accounted for 20% (women) and 19% (men) of the variation in LDL-C. The expected association of the apo E genotypes (e3e2, e3e3, and e3e4) with cholesterol concentrations was seen in S + A + N + but not in non-S + A + N + subjects and in P-P- but not in P + P + or P + P- subjects. With regard to clinical expression, FDB patients had lower TC and LDL-C levels and a lower prevalence of cardiovascular disease than 101 Danish patients with familial hypercholesterolemia.

Adult↗
PubMed1997

Angiotensin-converting enzyme and angiotensinogen gene polymorphisms, plasma levels, cardiac dimensions. A twin study.

We tested the hypotheses that angiotensin-converting enzyme insertion/deletion (I/D) and angiotensinogen 235 methionine/threonine (M/T) substitution gene polymorphisms influence angiotensin-converting enzyme and angiotensiongen serum concentrations and cardiac dimensions in 91 monozygotic and 41 dizygotic twin pairs. Cardiac dimensions were determined echocardiographically. Angiotensin-converting enzyme levels were 24 +/- 11, 43 +/- 18, and 58 +/- 24 U/L for the II, ID, and DD genotypes, respectively (P < .01). Posterior wall thickness was 8.1 +/- 1.3, 8.6 +/- 1.7, and 8.9 +/- 1.9 mm for these genotypes (P < .05). Angiotensin-converting enzyme levels were correlated with posterior wall thickness (r = .15, P < .05). The intrapair differences in angiotensin converting enzyme levels for monozygotic, concordant dizygotic, and discordant dizygotic twins were 1.36 +/- 1.6, 1.86 +/- 1.6, and 17.25 +/- 4.3 U/L, respectively. The angiotensinogen M/T genotypes exerted no influence on cardiac dimensions or on angiotensinogen concentrations. The additive genetic effect on angiotensin-converting enzyme levels (0.49), on posterior wall thickness (0.26), and on septum thickness (0.37) was significant (P < .01), although shared and nonshared environmental effects were also identified. Our data confirm the impressive effect that the angiotensin-converting enzyme D allele exerts on angiotensin-converting enzyme plasma levels. Furthermore, our data also suggest that the angiotensin-converting enzyme gene locus is primarily responsible for angiotensin-converting enzyme plasma levels. Our twin study also indicates that the angiotensin-converting enzyme gene locus is genetically linked to posterior wall thickness. The correlation between angiotensin-converting enzyme levels and posterior wall thickness suggests that this effect is exerted by angiotensin-converting enzyme. We were unable to demonstrate genetic linkage between the angiotensinogen gene locus and cardiac dimensions in this study.

Adult↗
PubMed1997

Neurovascular compression at the ventrolateral medulla in autosomal dominant hypertension and brachydactyly.

BACKGROUND AND PURPOSE: Autosomal dominant hypertension with brachydactyly features severe hypertension that causes stroke usually before the age of 50 years. We recently characterized the hypertension as featuring normal renin, aldosterone, and catecholamine responses and mapped the gene responsible to chromosome 12p. Since angiography in an affected subject had earlier shown tortuous vessels, we performed magnetic resonance tomography (MRT) angiography to look for possible neurovascular anomalies (NVA), which have been previously associated with hypertension. NVA can be caused by a looping posterior inferior cerebellar or vertebral artery. Experimental and clinical evidence suggests that NVA may cause hypertension by a compression of the ventrolateral medulla. METHODS: We performed MRT in 15 hypertensive affected (aged 14 to 57 years) and 12 normotensive nonaffected (aged 12 to 59 years) family members. We then tested for linkage between the hypertension-brachydactyly phenotypes and the presence of NVA. RESULTS: All 15 affected persons had MRT evidence for NVA. All had left-sided posterior inferior cerebellar artery or vertebral artery loops, while 6 had bilateral NVA. None of the nonaffected family members had NVA. The phenotypes were linked with an LOD score of 9.2 given a penetrance of 99%. CONCLUSIONS: Autosomal dominant hypertension and brachydactyly regularly feature NVA, which is frequently bilateral. The early age at which NVA was identified suggests that the condition is primary. We suggest that NVA may be involved in the pathogenesis of this form of hypertension and perhaps essential hypertension as well. Further studies are necessary to address the question of causation.

Abnormalities, Multiple↗
PubMed1997

Twin zygosity. Automated determination with microsatellites.

OBJECTIVE: Twin zygosity determinations can be performed with anthropologic, serologic and genetic markers; however, these methods are more than occasionally inefficient, often expensive and sometimes inaccurate. We used microsatellites as DNA markers and developed a largely automated, rapid and efficient method of determining zygosity. STUDY DESIGN: We used five highly polymorphic short tandem repeat loci, coamplified by polymerase chain reaction (PCR) using fluorescence-labeled primers. Thirty-six samples were simultaneously analyzed by electrophoresis and laser detection. The PCR products were sized by automated fragment analysis. RESULTS: We typed 132 pairs of monozygotic (MZ) and dizygotic (DZ) twins. With five markers, the probability that any twin pair was MZ if all markers were concordant was 99%. CONCLUSION: This method is a rapid and reliable approach to zygosity detection.

Adult↗
PubMed1997

The usefulness of three biallelic restriction fragment length polymorphisms versus a polymorphic dinucleotide tandem repeat polymorphism at the low-density-lipoprotein receptor gene locus for diagnosis of familial hypercholesterolemia.

Indirect molecular diagnosis of familial hypercholesterolemia is possible based on genetic linkage analysis of DNA polymorphisms at the low-density-lipoprotein receptor gene locus in family studies. The use of biallelic restriction fragment length polymorphisms, however, is restricted by their low degree of heterogeneity, and therefore several of these markers have to be combined. To overcome these restrictions we examined the value and applicability of an (AT)n tandem repeat polymorphism at the 3' untranslated region of the gene, alone and in combination with three biallelic restriction fragment length polymorphisms in 35 independent healthy subjects and in familial hypercholesterolemia families with 23 parents and 52 children. For each family one of the parents had the clinical diagnosis of familial hypercholesterolemia. The probands were genotyped using the TaqI, HincII and NcoI restriction fragment length polymorphism and the (AT)n tandem repeat polymorphism of the gene. The heterozygosity index (0.60) and the polymorphism information content (PIC value) (0.53) of the ATn repeat polymorphism were higher compared to each single biallelic restriction fragment length polymorphism (heterozygosity index 0.26-0.54; PIC value 0.24-0.36). The combined PIC value of all three biallelic restriction fragment length polymorphisms (0.79) was comparable to the combination of the HincII and the ATn polymorphism (0.74). Using these two markers, a definitive molecular diagnosis could be made in 36 children from 15 parents compared to just 12 parents and their children using the three biallelic restriction fragment length polymorphisms. We conclude that the ATn tandem repeat polymorphisms is useful for indirect molecular diagnosis of familial hypercholesterolemia in affected families.

Chromosome Mapping↗
PubMed1996

Analysis of novel apolipoprotein B mutations using a modified U937 cell line LDL binding assay.

The U937 myelomonocyte proliferation assay can be used to detect patients with familial defective apolipoprotein B-100 (FDB). Previous studies have employed electronic cell counting to assess cell proliferation. We simplified the assay using 3H-thymidine incorporation DNA analysis to measure cell growth. We tested the modified method by analyzing the effects of different concentrations of native low density lipoproteins (LDL), methylated LDL, as well as LDLs obtained from patients with FDB on cell growth. Methylation of LDL to various degrees reduced cell proliferation correspondingly, and LDLs obtained from FDB patients decreased cell growth confirming that the modified method was able to detect binding defective species of LDL. We applied this method to analyze three novel apoB polymorphisms recently characterized in this laboratory (apoB His1896-->Arg, apoB Asn1887-->Ser, apoB Ala4454-->Thr), which did not significantly alter U937 cell proliferation. Our results show that this simplified assay can be used for screening for LDL variants with defective binding.

Alleles↗
PubMed1996

Angiotensin-converting enzyme and heart chymase gene polymorphisms in hypertrophic cardiomyopathy.

We examined the insertion/deletion polymorphism in the angiotensin-converting enzyme gene and identified polymorphisms in the heart chymase gene to test the hypothesis that these angiotensin II-producing enzymes are associated with a monogenic cardiac disease (50 patients and 50 control subjects) as a model of cardiac hypertrophy. We found that the angiotensin-converting enzyme DD genotype was present more often in patients than in control subjects and identified a possible interaction with 1 of the chymase polymorphisms.

Adult↗