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Biomedical subjects

Sylvia Bähring

Publications and source records attributed to Sylvia Bähring.

10 recordsLinked to original sources
PubMed2006

New universal primers facilitate Pyrosequencing.

A cost-driving factor in Pyrosequencing is the need for single-stranded PCR products that are usually obtained by biotin-labeling of one primer. We designed new universal primers that allow the introduction of biotin during the specific PCR at either the forward or the reverse primer in a single reaction. When converting five human single nucleotide polymorphism assays from the standard format into the universal format, we obtained pyrograms of similar good quality. Although the universal nonhuman sequences are unlikely to form loop structures, we mostly failed to establish assays without using the proprietary software from Biotage AB. Nevertheless, our universal primer pair adds flexibility to the process of assay design due to optional strand selection and contributes to the reduction of genotyping costs.

Apolipoproteins↗
PubMed2004

Single nucleotide polymorphism map of five long-QT genes.

We screened a white population for single nucleotide polymorphisms (SNPs) in five long QT syndrome genes, namely, KCNQ1 (LQT1), HERG (LQT2), SCN5A (LQT3), KCNE1 (LQT5), and KCNE2 (LQT6). We found 35 SNPs, 10 of which have not been previously described. Ten SNPs were in KCNE1, six in HERG, eight in KCNQ1, four in KCNE2, and seven in SCN5A. Four SNPs were associated with QTc interval in our 141 subjects, one in KCNE1, one in KCNE2, and two in SCN5A. Two of these SNPs have not been described. We conclude that these five long QT syndrome genes contain common variants, some of which are associated with QTc interval in normal persons. We suggest that analysis of these SNPs in a much larger cohort would enable establishment of common haplotypes that are associated with QTc. These haplotypes could facilitate prediction of arrhythmia risk in the general population.

Cohort Studies↗
PubMed2004

Autosomal-dominant hypertension with type E brachydactyly is caused by rearrangement on the short arm of chromosome 12.

We are studying a Turkish family with autosomal-dominant hypertension and brachydactyly; affected persons die of stroke before 50 years of age. With interphase fluorescence in situ hybridization, we found a chromosome 12p deletion, reinsertion, and inversion in affected persons. This finding suggested that the hypertension could be caused by one or more of 3 genes, the ATP-dependent potassium channel Kir6.1, its regulator the sulfonyl urea receptor SUR2, and the phosphodiesterase PDE3A. We further studied 6 affected and 4 nonaffected persons. Buttocks biopsies were done, small vessels were tested on a myograph, and mRNA was extracted. We performed forearm blood flow studies with intrabrachial artery diazoxide, isoproterenol, and milrinone infusions. Systemic pharmacological testing was done with intravenous diazoxide, nitroprusside, and isoproterenol. PDE3A mRNA was high in vessels from 3 affected subjects, but not high in 3 others. The vessels responded similarly to forskolin, with or without glibenclamide, and to cromakalim. However, there was a suggestion that the dilatation after milrinone might be exaggerated. The forearm infusion studies showed no differences in the responses to diazoxide, isoproterenol, or milrinone. Systemically, affected persons showed a greater blood pressure response to diazoxide and nitroprusside, and a greater heart rate response to isoproterenol than nonaffected persons. The results shed doubt on Kir6.1 and SUR2. The differences in PDE3A expression and responses may be the result of hypertension rather than the cause. Although our 3 candidate genes are no longer likely, the rearrangement we describe greatly enhances the perspectives of this project.

Arteries↗
PubMed2004

Validation of fluorescence-labeled artificial nonhuman sequences for single-strand conformation polymorphism mutation detection in familial hypercholesterolemia.

We developed a two-in-one, polymerase chain reaction (PCR)-based method with a specific amplification step and a universal amplification step in one tube to screen for the presence of DNA variations. The method relies on fluorescence-labeled artificial nonhuman sequences for mutation detection. To document utility, we applied this method as a high-throughput capillary single-strand conformation polymorphism screening system to identify 30 mutations in the low-density lipoprotein receptor gene. The sensitivity of mutant allele detection compared to wild-type allele detection was 93%. We conclude that the "two-in-one PCR" is sensitive, simple, and cost effective.

Animals↗
PubMed2003

Genome-wide linkage reveals a locus for human essential (primary) hypertension on chromosome 12p.

Essential (primary) hypertension is an important risk factor for cardiovascular morbidity and mortality. Blood pressure is largely heritable; however, the genetic factors contributing to essential hypertension are mostly unknown. We examined a large Chinese kindred (n=387) and selected a subset of 94 individuals for genotyping. An additional 32 Chinese nuclear families with essential hypertension were also recruited. Genome-wide parametric linkage analysis identified a new locus for primary hypertension on chromosome 12p (parametric LOD score 3.44). This locus overlaps with the assigned locus that causes severe autosomal-dominant hypertension and brachydactyly, the only form of monogenic hypertension known to date that resembles primary hypertension. We suggest that this genomic region, spanning 18 annotated genes, will be of great relevance in elucidating new mechanisms for primary hypertension.

Adult↗
PubMed2002

Mutation in the ARH gene and a chromosome 13q locus influence cholesterol levels in a new form of digenic-recessive familial hypercholesterolemia.

We studied a Syrian family with 3 children who had low-density lipoprotein cholesterol (LDL) concentrations of 13.3, 12.2, and 8.6 mmol/L, respectively. Three other siblings and the parents all had LDL values <4.52 mmol/L, suggesting an autosomal-recessive mode of inheritance. The extended pedigree had 66 additional persons with normal LDL values. A genome-wide scan in the core family with 427 markers showed support for linkage on both chromosomes 1 and 13. Markers on chromosome 1 revealed a 3.07 multipoint LOD score between 1p36.1-p35, an 18-cM interval. Surprisingly, we also found linkage to 13q22-q32, a 14-cM interval, with a 3.08 LOD score. We had identified this locus earlier as containing a gene strongly influencing LDL in another Arab family with autosomal-dominant familial hypercholesterolemia and in normal dizygotic twins. We found evidence for an interaction between these loci. We next genotyped our twin panel and confirmed linkage of the 1p36.1-p35 locus to LDL (P<0.002) in this normal population. Elucidation of ARH, the LDL receptor adaptor protein at chromosome 1p35, caused us to sequence that gene. We first identified the genomic structure of ARH gene and then sequenced the gene in our family. We found an intron 1 acceptor splice-site mutation. This mutation was not found in any other family members, in 31 nonrelated Syrian persons, or in 30 Germans. Our results underscore the importance of ARH on chromosome 1 and the chromosome 13q locus to LDL, not only in families with unusual illnesses, but also to the general population.

Base Sequence↗
PubMed2002

The BK channel beta1 subunit gene is associated with human baroreflex and blood pressure regulation.

BACKGROUND: The baroreflex, which is important for the minute-to-minute regulation of blood pressure and heart rate, is influenced by genetic variance. Ion channels are important to baroreflex afferent and efferent function. Mice missing the beta1 subunit of the Ca2+-sensitive potassium channel (BK) are hypertensive and have a reset baroreflex. We tested the hypothesis that variants in the gene (KCNMB1) coding for the BK beta1 subunit are associated with baroreflex function. METHODS: We studied six single-nucleotide polymorphisms (SNPs) in KCNMB1. RESULTS: Four SNPs in intron 3, exon 4a, exon 4b and exon 4c gave significant results. For instance, exon 4b SNP AA individuals had higher heart rate variability, compared to CA, or CC persons, in particular in the high-frequency range. The low-frequency range showed no association. Consistent with the heart rate variability data, homozygous AA persons had greater baroreflex slopes than CA or CC persons, also in the high-frequency range. These associations could not be shown in the low-frequency range for heart rate variability and baroreflex slopes. CONCLUSIONS: These data support the notion that variants in channel genes may be responsible for the great range in heart rate variability and baroreflex function observed in humans. Such variation may also play a role in the development of hypertension.

Adult↗
PubMed2002

Serum- and glucocorticoid-regulated kinase (SGK1) gene and blood pressure.

The serum- and glucose-regulated kinase (SGK1) gene has recently been identified as an important aldosterone-induced protein kinase that mediates trafficking of the renal epithelial Na(+) channel (ENaC) to the cell membrane. Thus, SGK1 is an appealing candidate for blood pressure regulation and possibly essential hypertension. To test this hypothesis, we recruited monozygotic (126 pairs) and dizygotic (70 pairs) normotensive twin subjects and parents of dizygotic twins. Blood pressure was measured in a controlled fashion: recumbent, sitting, and upright. We documented genetic variance on blood pressure in all positions. We then relied on microsatellite markers at the SGK1 gene locus (D6S472, D6S1038, and D6S270) and 2 single nucleotide polymorphisms within the SGK1 gene. We found significant linkage of the SGK1 gene locus to diastolic blood pressure (P<0.0002) and suggestive evidence for linkage for systolic blood pressure (P<0.04), documenting the locus as a quantitative trait locus for blood pressure. We next performed association, using all dizygotic twins and a monozygotic member from each pair. We found significant associations between both single nucleotide polymorphism variants and blood pressure, as well as a significant interaction between the single nucleotide polymorphisms enhancing the effect. This combined effect of the polymorphisms was confirmed in an independent sample of 260 young normotensive men. We conclude that the SGK1 gene is relevant to blood pressure regulation and probably to hypertension in man.

Blood Pressure↗