Nicole Stark

Vorarlberg Institute for Vascular Investigation VIVIT, Feldkirch, Vorarlberg, Austria

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Publications (14)22.48 Total impact

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    ABSTRACT: The JAK2 V617F mutation is found in the majority of patients with myeloproliferative neoplasms (MPN), including essential thrombocythemia (ET), but also has been reported in individuals without overt MPN. A close relation of the JAK2 V617F mutation to atherothrombotic events has been described, at least in patients with MPN. The prevalence of the JAK2 V617F mutation and its clinical impact in coronary patients is unknown. To address this issue, DNA samples from 1,589 subjects undergoing coronary angiography with up to 11 years of follow up were genotyped using allele-specific real-time PCR assays. Prevalence of the JAK2 V617F mutation was 1.32% (n=21) in coronary patients. Two JAK2 V617F positive patients showed baseline platelet counts indicative for ET and a third patient developed ET during follow up, finally resulting in a percentage of 0.188% of ET cases. This corresponds to an up to 5-fold accumulation of ET cases in coronary patients compared to the general population. Our study showed no impact of the JAK2 V617F mutation on future atherothrombotic events or overall survival (HR=1.04 [0.33-3.27]; p=0.949 and HR=0.35 [0.05-2.46]; p=0.288, respectively). Therefore, our data suggest that JAK2 V617F positive coronary patients are not at increased risk for future atherothrombotic complications. Routine mutation screening in coronary patients is, therefore, not warranted. However, number of ET cases appears to be accumulated in coronary patients. For this reason, we recommend JAK2 V617F testing only in coronary patients showing abnormal blood cell counts for further clarification.
    Full-text · Article · Mar 2014 · American Journal of Hematology
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    ABSTRACT: Fetuin-A (AHSG) has been proposed as a new cardiovascular risk factor. Fetuin-A levels as well as AHSG single nucleotide polymorphisms (SNPs) have been associated with intima media thickness and incident vascular events, respectively. However, the association between AHSG variants and angiographically determined coronary artery disease (CAD) has not been reported yet. Therefore, we aimed at investigating the association of AHSG SNPs with angiographically characterized coronary atherosclerosis. We genotyped AHSG variants rs4917, rs2248690, rs2518136, and rs2077119 in a cross-sectional study including 1,649 patients undergoing coronary angiography. Significant CAD was diagnosed in the presence of coronary stenoses ≥50%. Variant rs2077119 deviates significantly from Hardy-Weinberg equilibrium and was excluded from further analysis. Neither under an additive, nor under a recessive or dominant model of inheritance, the association between investigated AHSG variants and angiographically determined CAD reached statistical significance. Haplotypes derived from these AHSG variants also were not significantly associated with coronary lesions. Further, no significant associations between investigated SNPs and the extent or severity of CAD could be observed (all p-values>0.05). Our data do not support a significant direct association between AHSG variants rs4917, rs2248690, and rs2518136 and clinical atherosclerosis as exemplified by angiographically characterized coronary atherosclerosis.
    No preview · Article · Jan 2012 · Clinica chimica acta; international journal of clinical chemistry
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    ABSTRACT: The newly discovered metastasis-associated in colon cancer-1 (MACC1) gene is a key regulator of the HGF/MET pathway. Deregulation of HGF/MET signaling is reported as a prognostic marker for tumorigenesis, early stage invasion, and metastasis. High expression levels of MACC1 have been associated with colon cancer metastasis and reduced survival. Potential links between the genetic diversity of the MACC1 locus and overall survival are unknown. We therefore investigated the association between MACC1 tagging single nucleotide polymorphisms (SNPs) and overall survival in a large cohort of colorectal cancer patients. The study included 318 subjects with histopathologically proven colorectal cancer at the Academic Teaching Hospital Feldkirch, Austria. Survival data were provided by the federal agency for statistics in Austria. Genomic DNA was isolated from formalin-fixed paraffin-embedded specimens; six tagging SNPs (rs1990172, rs3114446, rs10275612, rs3095007, rs3095009, and rs7780032), capturing most of the common variants of the MACC1 locus, were genotyped by SNaPshot assays. Over a mean follow up period of 5.3 (± 1.0) years, 94 deaths were recorded. Carriers of the G-allele of SNP rs1990172 showed a significantly decreased overall survival (additive HR = 1.38 [1.05-1.82]; p = 0.023). Multivariate analysis adjusted for age and UICC tumor stage confirmed this result (HR = 1.49 [1.12-1.98]; p = 0.007). Other investigated genetic variants of the MACC1 gene were not significantly associated with overall survival (p-values > 0.05). For the first time, our study investigated the influence of MACC1 tagging polymorphisms on overall survival suggesting SNP rs1990172 as a predictor for reduced overall survival in colorectal cancer patients. Further studies will be required to validate our findings.
    Full-text · Article · Jan 2012 · BMC Cancer
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    ABSTRACT: Genotyping of MACC1 SNPs by the SNaPshot® method.
    Preview · Dataset · Jan 2012
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    ABSTRACT: Table S2. MACC1 extension primer sequences.
    Preview · Dataset · Jan 2012
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    ABSTRACT: Table S4. Strength of pairwise linkage disequilibrium between each pair of genotyped SNPs expressed as r2 and D'.
    Preview · Dataset · Jan 2012
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    ABSTRACT: Table S3. Observed minor allele frequencies and genotyping frequencies and results from Hardy-Weinberg disequilibrium analysis.
    Preview · Dataset · Jan 2012
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    ABSTRACT: Table S1. MACC1 PCR primer sequences.
    Preview · Dataset · Jan 2012
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    ABSTRACT: Hypoxia in adipose tissue is suggested to be involved in the development of a chronic mild inflammation, which in obesity can further lead to insulin resistance. The effect of hypoxia on gene expression in adipocytes appears to play a central role in this inflammatory response observed in obesity. However, the global impact of hypoxia on transcriptional changes in human adipocytes is unclear. Therefore, we compared gene expression profiles of human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes under normoxic or hypoxic conditions to detect hypoxia-responsive genes in adipocytes by using whole human genome microarrays. Microarray analysis showed more than 500 significantly differentially regulated mRNAs after incubation of the cells under low oxygen levels. To gain further insight into the biological processes, hypoxia-regulated genes after 16 hours of hypoxia were classified according to their function. We identified an enrichment of genes involved in important biological processes such as glycolysis, response to hypoxia, regulation of cellular component movement, response to nutrient levels, regulation of cell migration, and transcription regulator activity. Real-time PCR confirmed eight genes to be consistently upregulated in response to 3, 6 and 16 hours of hypoxia. For adipocytes the hypoxia-induced regulation of these genes is shown here for the first time. Moreover in six of these eight genes we identified HIF response elements in the proximal promoters, specific for the HIF transcription factor family members HIF1A and HIF2A. In the present study, we demonstrated that hypoxia has an extensive effect on gene expression of SGBS adipocytes. In addition, the identified hypoxia-regulated genes are likely involved in the regulation of obesity, the incidence of type 2 diabetes, and the metabolic syndrome.
    Full-text · Article · Oct 2011 · PLoS ONE
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    ABSTRACT: Thrombozyten-Aktivierung und-Aggregation spielen eine Schlüsselrolle in der Thrombusbildung, welche nach einer atherosklerotischen Plaqueruptur bei akutem Koronarsyn-drom (ACS) oder in einem Stent nach perkutaner Koronar-intervention (PCI) auftreten kann [1–3]. Moderne Wirkstoffe in der Antiplättchentherapie, wie Thienopyridin-Derivate oder Cyclo-Pentyl-Triazolo-Pyrimidine, inhibieren die Adenosindiphosphat-(ADP-) abhängigen Mechanismen der Thrombozyten-Aktivierung durch Blockade des P2Y 12-Re-zeptors an der Thrombozytenoberfläche [4, 5]. Verabreichung eines solchen P2Y 12-Antagonisten, allein oder in Kombinati-on mit Aspirin, stellt deswegen eine Standardtherapie zur Ver-meidung ischämischer Ereignisse bei Risikopatienten dar. Clopidogrel (Plavix ®) ist ein Thienopyridin-Derivat der zwei-ten Generation. Clopidogrel ist eines der bestuntersuchten Medikamente in der Antiplättchentherapie und zählt zu den weltweit am meist verkauften Medikamenten [6]. Der klini-sche Nutzen von Clopidogrel hinsichtlich der Vermeidung schwerwiegender atherothrombotischer Ereignisse wurde in mehreren Studien bewiesen [7, 8]. Hierbei konnte allerdings auch eine hohe interindividuelle Variabilität des Ansprechens auf Clopidogrel beobachtet werden, sodass nicht alle Patien-ten von Clopidogrel profitieren. Diese interindividuelle Varia-bilität ist zum Teil genetisch bedingt. So gab kürzlich die U.S. " Food and Drug Administration " (FDA) eine Warnung aus, bei der auf die verminderte Wirksamkeit von Clopidogrel bei homozygoten Trägern einer " Loss-of-function "-Variante des CYP2C19-Gens hingewiesen wird [9].
    Full-text · Article · Oct 2011

  • No preview · Article · Jun 2011 · Atherosclerosis Supplements
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    ABSTRACT: Adipokines play a central role in the development of diseases associated with insulin resistance and obesity. Hypoxia in adipose tissue leads to a dysregulation of the expression of adipokines. The effect of hypoxia on the more recently identified adipokine apelin in human adipocytes is unclear. Therefore, we aimed at investigating the role of hypoxia on the expression of the adipokine apelin. Differentiated human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes were cultured under hypoxic conditions for varying time periods. A modular incubator chamber was used to create a hypoxic tissue culture environment (defined as 1% O(2), 94% N, and 5% CO(2)). In addition, hypoxic conditions were mimicked by using CoCl(2). The effect of hypoxia on the expression of the investigated adipokines was measured by real-time PCR and the secretion of apelin was quantified by ELISA. Induction of hypoxia significantly induced mRNA expression of leptin and apelin in differentiated SGBS adipocytes compared with the normoxic control condition. Expression of adiponectin was significantly decreased by hypoxia. In addition, the amount of secreted apelin protein in response to hypoxia was elevated compared to untreated cells. Furthermore, we could demonstrate that the observed hypoxia-induced induction of apelin mRNA expression is in the first phase dependent on HIF-1α. In our study, we could demonstrate for the first time that apelin expression and secretion by human adipocytes are strongly induced under hypoxic conditions and that the early response on hypoxia with apelin induction is dependent on HIF-1α.
    Full-text · Article · Mar 2011 · Hormone and Metabolic Research
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    ABSTRACT: Mutations in the oncogenes KRAS and BRAF have been identified as prognostic factors in patients with colorectal diseases and as predictors of negative outcome in epidermal growth factor receptor-targeted therapies. Therefore, accurate mutation detection in both genes, KRAS and BRAF, is of increasing clinical relevance. We aimed at optimizing allele-specific real-time PCR assays for the detection of common mutations in KRAS and the BRAF Val600Glu mutation using allele-specific PCR primers for allelic discrimination and probes (TaqMan) for quantification. Each reaction mix contains a co-amplified internal control to exclude false-negative results. Allele-specific real-time PCR assays were evaluated on plasmid model systems providing a mutation detection limit of 10 copies of mutant DNA in proportions as low as 1% of the total DNA. Furthermore, we analyzed 125 DNA samples prepared from archived, formalin-fixed, paraffin-embedded colorectal carcinomas and compared results with those obtained from direct-sequence analysis. All mutations determined by sequence analysis could be recovered by allele-specific PCR assays. In addition, allele-specific PCR assays clearly identified three additional samples affected by a mutation. We propose these allele-specific real-time PCR assays as a low-cost and fast diagnostic tool for accurate detection of KRAS and BRAF mutations that can be applied to clinical samples.
    Full-text · Article · Jan 2011 · The Journal of molecular diagnostics: JMD
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    ABSTRACT: Clopidogrel (Plavix® ) is a widely used antiplatelet agent. The drug is an inactive pro-drug and requires biotransformation by hepatic cytochrome P450 system to generate an active metabolite. Compared to other antiplatelet drugs such as prasugrel (Efient® ) or ticagrelor (Brilique® ), a high interindividual variability of the response to clopidogrel can be observed, which shows a strong genetic background. Strongest discriminators for reduced response to clopidogrel represent loss-of-function variants of the CYP2C19 gene. Here, CYP2C19*2 alleleaccounts for 95% of the non-functional alleles in the European population. Several studies have shown, that CYP2C19*2 allele exhibits a genedosage effect on inhibition of platelet aggregation. Further, carriers of the CYP2C19*2 allele are at increased risk for major adverse cardiovascular events and stent thromboses: Patients, who underwent PCI, who are carrying 1 or 2 CYP2C19 loss-of-function alleles, demonstrate a 55% and 80% increased risk, respectively, for major adverse cardiovascular events. Risk for stent thrombosis is 2.7-fold higher in heterozygote and 4-fold higher in homozygote carriers of a CYP2C19 loss-of-function allele. Several further DNA-polymorphisms of genes involved in the biologic mechanism of clopidogrel have been associated with poor drug response. One of these candidate genetic variants is a DNA-polymorphism of the ABCB1 (c.3425 C > T; rs1045642) gene, encoding the intestinal efflux transporter p-glycoprotein. Recently, a haplotype of the P2RY12 gene, encoding the target molecule of the active metabolite of clopidogrel, has been linked with clopidogrel resistance. Results on the influence of DNA-polymorphisms of cytochrome genes CYP3A4, CYP3A5 and CYP2C9, all participating in the activation of clopidogrel, are conflicting. Genetic tests are provided for loss-of-function variants of the CYP2C19 gene, particularly CYP2C19*2. However, the clinical benefit of CYP2C19*2 genotyping remains unclear.
    No preview · Article · Jan 2011 · Journal fur Kardiologie

Publication Stats

109 Citations
22.48 Total Impact Points

Institutions

  • 2011-2014
    • Vorarlberg Institute for Vascular Investigation VIVIT
      Feldkirch, Vorarlberg, Austria
  • 2012
    • Private University in the Principality of Liechtenstein
      Triesen, Triesen, Liechtenstein