Biomedical subjects

Andreas Busjahn

Publications and source records attributed to Andreas Busjahn.

9 recordsLinked to original sources

PubMed2003

A common polymorphism in KCNH2 (HERG) hastens cardiac repolarization.

OBJECTIVE: Genetic variants of cardiac ion channels may influence cardiac repolarization. Thereby such variants may modulate the penetrance of primary electrical disorders, contribute to differences in susceptibility to drug-induced QT-prolongation between individuals, or contribute to rhythm disturbances in the context of structural heart disease. Since the current encoded by KCNH2 (HERG; I(Kr)) is a primary determinant of repolarization, we conducted association studies between the respective alleles of the common amino acid-changing polymorphism at codon 897 (2690A>C; K897T) within HERG and rate-corrected QT interval (QTc). METHODS AND RESULTS: Association analysis in Caucasian subjects (n=1030) revealed a significant association of this polymorphism with QTc (P=0.0025) with CC homozygotes having a significantly shorter QTc (388.5+/-2.9 ms) compared to AA homozygotes (398.5+/-0.9) and heterozygotes (AC, 397.2+/-1.2). The latter two genotypes were associated with comparable mean QTc's, suggesting that the 2690C-allele is recessive. After stratification by sex, the polymorphism was more predictive of QTc in females (P=0.0021), a finding that was replicated in a second population sample (n=352) from the same ethnic background (P=0.044). To assess whether this polymorphism could represent a 'functional' polymorphism, we compared the biophysical properties of K897- and T897-HERG channels by whole-cell voltage clamp. Compared to the K897 channel, the T897 channel displayed a shift of -7 mV in voltage dependence of activation and increased rates of current activation and deactivation. CONCLUSION: As confirmed in modeling studies, these changes are expected to shorten action potential duration by an increase in I(Kr). This recapitulates the shorter QTc in females homozygous for the 2690C-allele.

Action Potentials↗

PubMed2003

Membrane expression of proteinase 3 is genetically determined.

Isolated human neutrophils exhibit a bimodal membrane proteinase 3 (PR3) expression. PR3 is the main target antigen in Wegener granulomatosis (WG). Cells with low expression can be easily distinguished from cell subsets with high expression. In a recent study, a large neutrophil subset expressing membrane PR3 (mPR3+) was a risk factor for systemic ANCA-associated vasculitis. PR3 membrane expression patterns are quite stable in a given individual, raising the possibility of genetic variance. The aims of this study were: (1) to investigate the association of mPR3 expression and the risk of WG in an independent German cohort; (2) to test the hypothesis that mPR3 expression on neutrophils is genetically influenced; and (3) to investigate whether or not mPR3 expression is a function of intracellular PR3 content. mPR3 expression was assessed by FACS analysis in isolated human neutrophils. Neutrophil mPR3 expression was studied in 35 patients with WG, 15 patients with other inflammatory diseases, 125 healthy volunteers, and 27 (15 monozygotic and 12 dizygotic) pairs of twins. The intracellular PR3 content was assessed by intracellular flow cytometry and by Western blotting after separating mPR3 low and high expressing cells by FACSort. FACS analysis in a subset of 16 healthy subjects showed a highly conserved PR3 phenotype in two independent investigations >12 mo apart (r = 0.937). Patients with WG demonstrated a significantly higher percentage of mPR3+ neutrophils than healthy controls and patients with other inflammatory diseases. The mPR3+ percentage was highly correlated in MZ twins (r = 0.99) compared with DZ twins (r = 0.06). The intracellular PR3 content was not different in persons with low or high mPR3 expression, nor was the PR3 content different in cells with low or high mPR3 expression within a given individual. These data indicate that WG patients have a higher percentage of mPR3-expressing neutrophils. Furthermore, mPR3 expression is influenced by genetic variance. Finally, mPR3 expression is independent of intracellular PR3 content.

Adult↗

PubMed2003

Twin studies in the analysis of minor physiological differences between individuals.

To test the hypothesis that the serum and glucocorticoid regulated kinase (SGK1) is of relevance to blood pressure in man, we recruited monozygotic (MZ) (126 pairs) and dizygotic (DZ) (70 pairs) normotensive twin subjects and parents of DZ 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, D6S 1038, and D6S270) and two 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 QTL for blood pressure. We next performed association, using all DZ twins and an MZ member from each pair. We found significant associations between both SNP variants and blood pressure, as well as a significant interaction between the SNPs enhancing the effect. This combined effect of the polymorphisms was confirmed in an independent sample of 260 young normotensive men. These data, coupled with our earlier observations linking the insulin-like growth factor-1 gene locus to blood pressure lead us to conclude that the SGK1 gene is relevant to blood pressure regulation and probably to hypertension in man.

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

Beta-2 adrenergic receptor gene variations and coping styles in twins.

We tested the hypothesis that the beta-2 adrenergic receptor (beta-2 AR) gene locus, with known effects on blood pressure regulation, is also involved in psychological coping styles. 166 pairs of monozygotic (MZ) and dizygotic (DZ) twins and DZ twin parents were investigated. We found common genetic variance for the coping factor Emotional Coping and blood pressure. Using three microsatellites we found linkage between the beta-2 AR gene locus and the coping factor Active Coping. Using allele-specific PCR of all the single nucleotide polymorphisms (SNPs) in the gene causing amino acid substitutions we identified associations between the +491 G/A SNP and various coping factors. We conclude that the beta-2 AR gene is relevant to coping. These preliminary findings suggest a molecular genetic underpinning of the relationship between psychological and physiological phenotypes important to cardiovascular risk.

Adaptation, Psychological↗

PubMed2002

Classical twin studies and beyond.

Twin studies have been a valuable source of information about the genetic basis of complex traits. To maximize the potential of twin studies, large, worldwide registers of data on twins and their relatives have been established. Here, we provide an overview of the current resources for twin research. These can be used to obtain insights into the genetic epidemiology of complex traits and diseases, to study the interaction of genotype with sex, age and lifestyle factors, and to study the causes of co-morbidity between traits and diseases. Because of their design, these registers offer unique opportunities for selected sampling for quantitative trait loci linkage and association studies.

Female↗

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↗

PubMed2002

Twin registers across the globe: what's out there in 2002?

Twin research offers the greatest power for the genetic analysis of complex multifactorial traits and diseases in humans. Modern twin analyses extend beyond the classical twin study for estimating the heritability of a trait. The human genome project can fulfil its promises only after functional characterisation of single genes in the context of genetic background and environment. Twin research can make a major contribution in that regard. Twin research is greatly facilitated by the willingness, motivation, cooperation, and generosity of the participants and their families. A second important aspect is the availability of twin registries that serve as a resource for genetic epidemiology. Currently, there is no systematic overview of the twin collections worldwide. This special issue will help to overcome the limited accessibility of this resource by providing basic information on most of the existing twin registers. Furthermore, an additional goal is to facilitate collaboration between registers. Some basic principles, potentials, and problems will be exemplified by my personal experience in the Berlin Twin Study.

Attitude to Health↗