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188 Publications visible to you, out of a total of 188
ANRIL expression is associated with atherosclerosis risk at chromosome 9p21
Genetical Statistics and Systems Biology

Abstract (Expand)

OBJECTIVE\backslashr\backslashnWe tested the hypothesis that expression of transcripts adjacent to the chromosome 9p21 (Chr9p21) locus of coronary artery disease was affected by the genotype at this … locus and associated with atherosclerosis risk.\backslashr\backslashnMETHODS AND RESULTS\backslashr\backslashnWe replicated the locus for coronary artery disease (P=0.007; OR=1.28) and other manifestations of atherosclerosis such as carotid plaque (P=0.003; OR=1.31) in the Leipzig Heart Study, a cohort of 1134 patients with varying degree of angiographically assessed coronary artery disease. Expression analysis in peripheral blood mononuclear cells (n=1098) revealed that transcripts EU741058 and NR_003529 of antisense noncoding RNA in the INK4 locus (ANRIL) were significantly increased in carriers of the risk haplotype (P=2.1x10(-12) and P=1.6x10(-5), respectively). In contrast, transcript DQ485454 remained unaffected, suggesting differential expression of ANRIL transcripts at Chr9p21. Results were replicated in whole blood (n=769) and atherosclerotic plaque tissue (n=41). Moreover, expression of ANRIL transcripts was directly correlated with severity of atherosclerosis (EU741058 and NR_003529; P=0.02 and P=0.001, respectively). No consistent association of Chr9p21 or atherosclerosis was found with expression of other genes such as CDKN2A, CDKN2B, C9orf53, and MTAP.\backslashr\backslashnCONCLUSIONS\backslashr\backslashnOur data provide robust evidence for an association of ANRIL but not CDKN2A, CDKN2B, C9orf53, and MTAP, with atherosclerosis and Chr9p21 genotype in a large cohort.

Authors: Lesca Miriam Holdt, Frank Beutner, Markus Scholz, Stephan Gielen, Gábor Gäbel, Hendrik Bergert, Gerhard Schuler, Joachim Thiery, Daniel Teupser

Date Published: 1st Mar 2010

Publication Type: Journal article

Transplantation of placenta-derived mesenchymal stromal cells upon experimental stroke in rats
Genetical Statistics and Systems Biology

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The beneficial effects of bone marrow-derived mesenchymal stromal cell (MSC) administration following experimental stroke have already been described. Despite several promising characteristics, … placenta-derived MSC have not been used in models of focal ischemia. The aim of the current study is to investigate the impact of intravenously transplanted placenta-derived MSC on post-stroke recovery. Permanent occlusion of the middle cerebral artery was induced in spontaneously hypertensive rats. MSC were obtained from the human maternal or fetal placenta and intravenously administered after 24 h (single transplantation) or after 8 h and 24 h (dual transplantation). Sensorimotor deficits were quantified for 60 days using the beam walk test and the modified Neurological Severity Score system. Infarct volume was determined in vivo by means of magnetic resonance imaging on days 1, 8, 29 and 60. Astroglial reactivity was semiquantitatively ascertained within a small and a broad region adjacent to the lesion border. The double infusion of placental MSC was superior to single transplantation in the functional tests. However, a significant difference to the control group in all outcome parameters was observed only for maternally derived MSC. These findings suggest that placental tissue constitutes a promising source for experimental stroke therapies. The beneficial effects of bone marrow-derived mesenchymal stromal cell (MSC) administration following experimental stroke have already been described. Despite several promising characteristics, placenta-derived MSC have not been used in models of focal ischemia. The aim of the current study is to investigate the impact of intravenously transplanted placenta-derived MSC on post-stroke recovery. Permanent occlusion of the middle cerebral artery was induced in spontaneously hypertensive rats. MSC were obtained from the human maternal or fetal placenta and intravenously administered after 24 h (single transplantation) or after 8 h and 24 h (dual transplantation). Sensorimotor deficits were quantified for 60 days using the beam walk test and the modified Neurological Severity Score system. Infarct volume was determined in vivo by means of magnetic resonance imaging on days 1, 8, 29 and 60. Astroglial reactivity was semiquantitatively ascertained within a small and a broad region adjacent to the lesion border. The double infusion of placental MSC was superior to single transplantation in the functional tests. However, a significant difference to the control group in all outcome parameters was observed only for maternally derived MSC. These findings suggest that placental tissue constitutes a promising source for experimental stroke therapies.

Authors: Alexander Kranz, Daniel-Christoph Wagner, Manja Kamprad, Markus Scholz, Uwe Richard Schmidt, Franziska Nitzsche, Zami Aberman, Frank Emmrich, Ute-Maria Riegelsberger, Johannes Boltze

Date Published: 1st Feb 2010

Publication Type: Journal article

Comparison of estimators for measures of linkage disequilibrium
Genetical Statistics and Systems Biology

Abstract (Expand)

The measurement of biallelic pair-wise association called linkage disequilibrium (LD) is an important issue in order to understand the genomic architecture. A plethora of measures of association in two … by two tables have been proposed in the literature. Beside the problem of choosing an appropriate measure, the problem of their estimation has been neglected in the literature. It needs to be emphasized that the definition of a measure and the choice of an estimator function for it are conceptually unrelated tasks. In this paper, we compare the performance of various estimators for the three popular LD measures D’, r and Y in a simulation study for small to moderate samples sizes (N\textless=500). The usual frequency-plug-in estimators can lead to unreliable or undefined estimates. Estimators based on the computationally expensive volume measures have been proposed recently as a remedy to this well-known problem. We confirm that volume estimators have better expected mean square error than the naive plug-in estimators. But they are outperformed by estimators plugging-in easy to calculate non-informative Bayesian probability estimates into the theoretical formulae for the measures. Fully Bayesian estimators with non-informative Dirichlet priors have comparable accuracy but are computationally more expensive. We recommend the use of non-informative Bayesian plug-in estimators based on Jeffreys’ prior, in particular when dealing with SNP array data where the occurrence of small table entries and table margins is likely.

Authors: Markus Scholz, Dirk Hasenclever

Date Published: 2010

Publication Type: Journal article

A pharmacokinetic model of filgrastim and pegfilgrastim application in normal mice and those with cyclophosphamide-induced granulocytopaenia
Genetical Statistics and Systems Biology

Abstract (Expand)

OBJECTIVES\backslashr\backslashnRecombinant human granulocyte colony-stimulating factor (rhG-CSF) is widely used as treatment for granulocytopaenia during cytotoxic chemotherapy; however, optimal … scheduling of this pharmaceutical is unknown. Biomathematical models can help to pre-select optimal application schedules but precise pharmacokinetic properties of the pharmaceuticals are required at first. In this study, we have aimed to construct a pharmacokinetic model of G-CSF derivatives filgrastim and pegfilgrastim in mice.\backslashr\backslashnMETHODS\backslashr\backslashnHealthy CD-1 mice and those with cyclophosphamide-induced granulocytopaenia were studied after administration of filgrastim and pegfilgrastim in different dosing and timing schedules. Close meshed time series of granulocytes and G-CSF plasma concentrations were determined. An ordinary differential equations model of pharmacokinetics was constructed on the basis of known mechanisms of drug distribution and degradation.\backslashr\backslashnRESULTS\backslashr\backslashnPredictions of the model fit well with all experimental data for both filgrastim and pegfilgrastim. We obtained a unique parameter setting for all experimental scenarios. Differences in pharmacokinetics between filgrastim and pegfilgrastim can be explained by different estimates of model parameters rather than by different model mechanisms. Parameter estimates with respect to distribution and clearance of the drug derivatives are in agreement with qualitative experimental results.\backslashr\backslashnCONCLUSION\backslashr\backslashnDynamics of filgrastim and pegfilgrastim plasma levels can be explained by the same pharmacokinetic model but different model parameters. Beause of a strong clearance mechanism mediated by granulocytes, granulocytotic and granulocytopaenic conditions must be studied simultaneously to construct a reliable model. The pharmacokinetic model will be extended to a murine model of granulopoiesis under chemotherapy and G-CSF application.

Authors: Markus Scholz, Manuela Ackermann, Christoph Engel, Frank Emmrich, Markus Loeffler, Manja Kamprad

Date Published: 1st Dec 2009

Publication Type: Journal article

Pharmacokinetic and pharmacodynamic modelling of the novel human granulocyte colony-stimulating factor derivative Maxy-G34 and pegfilgrastim in rats
Genetical Statistics and Systems Biology

Abstract (Expand)

OBJECTIVES\backslashr\backslashnThis study aims to compare pharmacokinetics and pharmacodynamics of pegfilgrastim, a pharmaceutical recombinant human granulocyte colony-stimulating factor (rhG-CSF), … with that of a newly developed reagent, Maxy-G34. This comparison was performed using rat experiments and biomathematical modelling of granulopoiesis.\backslashr\backslashnMETHODS\backslashr\backslashnHealthy rats and those with cyclophosphamide-induced neutropenia were treated with either pegfilgrastim or Maxy-G34 under various schedules. Time courses of absolute neutrophil count (ANC) and G-CSF serum level were measured and we constructed a combined pharmacokinetic/pharmacodynamic model of both drugs. Neutropenic episodes were assessed by experimental data and model simulations.\backslashr\backslashnRESULTS\backslashr\backslashnBoth Pegfilgrastim and Maxy-G34 showed strong dose-dependent efficacy in reducing neutropenic episodes. However, time courses of ANC and G-CSF serum levels were markedly different. The biomathematical model showed good agreement with these data. We estimated that differences between the two drugs could be explained by lower bioavailability and reduced elimination of Maxy-G34. Based on the data and model interpolations, we estimated that Maxy-G34 is superior in reducing neutropenic episodes. Also, we predicted that G-CSF administration 48 h after cyclophosphamide would be superior to its administration after 2 or 24 h, for both derivatives.\backslashr\backslashnCONCLUSION\backslashr\backslashnMaxy-G34 is a highly potent drug for stimulation of neutrophil production in rats. By our modelling approach, we quantified differences between Maxy-G34 and pegfilgrastim, related to pharmacokinetic parameters. Model simulations can be used to estimate optimal dosing and timing options in the present preclinical rat model.

Authors: Markus Scholz, Christoph Engel, D. Apt, S. L. Sankar, E. Goldstein, Markus Loeffler

Date Published: 1st Dec 2009

Publication Type: Journal article

Genetic variation and recent positive selection in worldwide human populations: evidence from nearly 1 million SNPs
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND\backslashr\backslashnGenome-wide scans of hundreds of thousands of single-nucleotide polymorphisms (SNPs) have resulted in the identification of new susceptibility variants to common diseases … and are providing new insights into the genetic structure and relationships of human populations. Moreover, genome-wide data can be used to search for signals of recent positive selection, thereby providing new insights into the genetic adaptations that occurred as modern humans spread out of Africa and around the world.\backslashr\backslashnMETHODOLOGY\backslashr\backslashnWe genotyped approximately 500,000 SNPs in 255 individuals (5 individuals from each of 51 worldwide populations) from the Human Genome Diversity Panel (HGDP-CEPH). When merged with non-overlapping SNPs typed previously in 250 of these same individuals, the resulting data consist of over 950,000 SNPs. We then analyzed the genetic relationships and ancestry of individuals without assigning them to populations, and we also identified candidate regions of recent positive selection at both the population and regional (continental) level.\backslashr\backslashnCONCLUSIONS\backslashr\backslashnOur analyses both confirm and extend previous studies; in particular, we highlight the impact of various dispersals, and the role of substructure in Africa, on human genetic diversity. We also identified several novel candidate regions for recent positive selection, and a gene ontology (GO) analysis identified several GO groups that were significantly enriched for such candidate genes, including immunity and defense related genes, sensory perception genes, membrane proteins, signal receptors, lipid binding/metabolism genes, and genes involved in the nervous system. Among the novel candidate genes identified are two genes involved in the thyroid hormone pathway that show signals of selection in African Pygmies that may be related to their short stature.

Authors: David López Herráez, Marc Bauchet, Kun Tang, Christoph Theunert, Irina Pugach, Jing Li, Madhusudan R. Nandineni, Arnd Gross, Markus Scholz, Mark Stoneking

Date Published: 18th Nov 2009

Publication Type: Journal article

Association of the X-chromosomal genes TIMP1 and IL9R with rheumatoid arthritis
Genetical Statistics and Systems Biology

Abstract (Expand)

OBJECTIVE\backslashr\backslashnRheumatoid arthritis (RA) is an inflammatory joint disease with features of an autoimmune disease with female predominance. Candidate genes located on the X-chromosome … were selected for a family trio-based association study.\backslashr\backslashnMETHODS\backslashr\backslashnA total of 1452 individuals belonging to 3 different sample sets were genotyped for 16 single-nucleotide polymorphisms (SNP) in 7 genes. The first 2 sets consisted of 100 family trios, each of French Caucasian origin, and the third of 284 additional family trios of European Caucasian origin. Subgroups were analyzed according to sex of patient and presence of anti-cyclic citrullinated peptide (anti-CCP) autoantibodies.\backslashr\backslashnRESULTS\backslashr\backslashnFour SNP were associated with RA in the first sample set and were genotyped in the second set. In combined analysis of sets 1 and 2, evidence remained for association of 3 SNP in the genes UBA1, TIMP1, and IL9R. These were again genotyped in the third sample set. Two SNP were associated with RA in the joint analysis of all samples: rs6520278 (TIMP1) was associated with RA in general (p = 0.035) and rs3093457 (IL9R) with anti-CCP-positive RA patients (p = 0.037) and male RA patients (p = 0.010). A comparison of the results with data from whole-genome association studies further supports an association of RA with TIMPL The sex-specific association of rs3093457 (IL9R) was supported by the observation that men homozygous for rs3093457-CC are at a significantly higher risk to develop RA than women (risk ratio male/female = 2.98; p = 0.048).\backslashr\backslashnCONCLUSION\backslashr\backslashnWe provide evidence for an association of at least 2 X-chromosomal genes with RA: TIMP1 (rs6520278) and IL9R (rs3093457).

Authors: Jana Burkhardt, Elisabeth Petit-Teixeira, Vitor Hugo Teixeira, Holger Kirsten, Sophie Garnier, Sandra Ruehle, Christian Oeser, Grit Wolfram, Markus Scholz, Paola Migliorini, Alejandro Balsa, Renè Westhovens, Pilar Barrera, Helena Alves, Dora Pascual-Salcedo, Stefano Bombardieri, Jan Dequeker, Timothy R. Radstake, Piet van Riel, Leo van de Putte, Thomas Bardin, Bernard Prum, Ulrike Buchegger-Podbielski, Frank Emmrich, Inga Melchers, François Cornelis, Peter Ahnert

Date Published: 8th Oct 2009

Publication Type: Journal article

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