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Haring R.,Institute of Clinical Chemistry and Laboratory Medicine | Wallaschofski H.,Institute of Clinical Chemistry and Laboratory Medicine | Teumer A.,Interfaculty Institute for Genetics and Functional Genomics | Kroemer H.,University of Greifswald | And 6 more authors.
Journal of Molecular Endocrinology | Year: 2013

DHEA is the major precursor of human sex steroid synthesis and is inactivated via sulfonation to DHEAS. A previous genome-wide association study related the single nucleotide polymorphism (SNP) rs2637125, located near the coding region of DHEA sulfotransferase, SULT2A1, to serum DHEAS concentrations. However, the functional relevance of this SNP with regard to DHEA sulfonation is unknown. Using data from 3300 participants of the population-based cohort Study of Health in Pomerania, we identified 43 individuals being homozygote for the minor allele of the SNP rs2637125 (AA) and selected two sex- and age-matched individuals with AG and GG genotype (nZ172) respectively. Steroid analysis including measurement of serum DHEA and DHEAS was carried out by liquid chromatography/mass spectrometry, employing steroid oxime analysis for enhancing the sensitivity of DHEA detection. We applied quantile regression models to compare median hormone levels across SULT2A1 genotypes. Median comparisons by SULT2A1 genotype (AA vs AG and GG genotypes respectively) showed no differences inthe considered hormones including DHEAS, DHEA, androstenedione, as well as cortisol and cortisone concentrations. SULT2A1 genotype also had no effect on the DHEA/DHEAS ratio. Sex-stratified analyses, as well as alternative use of the SULT2A1 SNP rs182420, yielded similar negative results. Genetic variants of SULT2A1 do not appear to have an effect on individual DHEA and DHEAS concentrations or the DHEA/DHEAS ratio as a marker of DHEA sulfonation capacity. © 2013 Society for Endocrinology. Source

Kohler T.P.,University of Greifswald | Gisch N.,Research Center Borstel | Binsker U.,University of Greifswald | Schlag M.,University of Tubingen | And 4 more authors.
Journal of Biological Chemistry | Year: 2014

Background: Adhesion of Gram-positive bacteria to host cells is facilitated by human thrombospondin 1 and vitronectin. Results: Repeating structures R1ab-R2ab of staphylococcal Atl interact with human thrombospondin 1 and vitronectin. Conclusion: The staphylococcal Atl repeats possess adhesive properties for human thrombospondin 1 and vitronectin. Significance: Repeats of Atl display multiple adhesive functions contributing to Staphylococcus-host interactions. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.. Source

Grabarczyk P.,University of Greifswald | Nahse V.,University of Greifswald | Delin M.,University of Greifswald | Przybylski G.,University of Greifswald | And 5 more authors.
PLoS ONE | Year: 2010

Background: The expression of BCL11B was reported in T-cells, neurons and keratinocytes. Aberrations of BCL11B locus leading to abnormal gene transcription were identified in human hematological disorders and corresponding animal models. Recently, the elevated levels of Bcl11b protein have been described in a subset of squameous cell carcinoma cases. Despite the rapidly accumulating knowledge concerning Bcl11b biology, the contribution of this protein to normal or transformed cell homeostasis remains open. Methodology/Principal Findings: Here, by employing an overexpression strategy we revealed formerly unidentified features of Bcl11b. Two different T-cell lines were forced to express BCL11B at levels similar to those observed in primary Tcell leukemias. This resulted in markedly increased resistance to radiomimetic drugs while no influence on death-receptor apoptotic pathway was observed. Apoptosis resistance triggered by BCL11B overexpression was accompanied by a cell cycle delay caused by accumulation of cells at G1. This cell cycle restriction was associated with upregulation of CDKN1C (p57) and CDKN2C (p18) cyclin dependent kinase inhibitors. Moreover, p27 and p130 proteins accumulated and the SKP2 gene encoding a protein of the ubiquitin-binding complex responsible for their degradation was repressed. Furthermore, the expression of the MYCN oncogene was silenced which resulted in significant depletion of the protein in cells expressing high BCL11B levels. Both cell cycle restriction and resistance to DNA-damage-induced apoptosis coincided and required the histone deacetylase binding N-terminal domain of Bcl11b. The sensitivity to genotoxic stress could be restored by the histone deacetylase inhibitor trichostatine A. Conclusions: The data presented here suggest a potential role of BCL11B in tumor survival and encourage developing Bcl11b-inhibitory approaches as a potential tool to specifically target chemoresistant tumor cells. © 2010 Grabarczyk et al. Source

Lieb W.,Framingham Heart Study | Lieb W.,University of Kiel | Chen M.-H.,Framingham Heart Study | Larson M.G.,Framingham Heart Study | And 14 more authors.
Circulation: Cardiovascular Genetics | Year: 2015

Background-Endothelial growth factors including angiopoietin-2 (Ang-2), its soluble receptor Tie-2 (sTie-2), and hepatocyte growth factor play important roles in angiogenesis, vascular remodeling, local tumor growth, and metastatic potential of various cancers. Circulating levels of these biomarkers have a heritable component (between 13% and 56%), but the underlying genetic variation influencing these biomarker levels is largely unknown. Methods and Results-We performed a genome-wide association study for circulating Ang-2, sTie-2, and hepatocyte growth factor in 3571 Framingham Heart Study participants and assessed replication of the top hits for Ang-2 and sTie-2 in 3184 participants of the Study of Health in Pomerania. In multivariable-adjusted models, sTie-2 and hepatocyte growth factor concentrations were associated with single-nucleotide polymorphisms in the genes encoding the respective biomarkers (top P=2.40×10-65 [rs2273720] and 3.64×10-19 [rs5745687], respectively). Likewise, rs2442517 in the MCPH1 gene (in which the Ang-2 gene is embedded) was associated with Ang-2 levels (P=5.05×10-8 in Framingham Heart Study and 8.39×10-5 in Study of Health in Pomerania). Furthermore, single-nucleotide polymorphisms in the AB0 gene were associated with sTie-2 (top single-nucleotide polymorphism rs8176693 with P=1.84×10-33 in Framingham Heart Study; P=2.53×10-30 in Study of Health in Pomerania) and Ang-2 (rs8176746 with P=2.07×10-8 in Framingham Heart Study; P=0.001 in Study of Health in Pomerania) levels on a genome-wide significant level. The top genetic loci were explained between 1.7% (Ang-2) and 11.2% (sTie-2) of the interindividual variation in biomarker levels. Conclusions-Genetic variation contributes to the interindividual variation in growth factor levels and explains a modest proportion of circulating hepatocyte growth factor, Ang-2, and Tie-2. This may potentially contribute to the familial susceptibility to cancer, a premise that warrants further studies. © 2015 American Heart Association, Inc. Source

Verhaaren B.F.J.,University of Texas Health Science Center at Houston | Smith J.A.,Medical Informatics | Adams H.H.,Clinical Chemistry | Beecham A.H.,Erasmus University Rotterdam | And 80 more authors.
Circulation: Cardiovascular Genetics | Year: 2015

Background-The burden of cerebral white matter hyperintensities (WMH) is associated with an increased risk of stroke, dementia, and death. WMH are highly heritable, but their genetic underpinnings are incompletely characterized. To identify novel genetic variants influencing WMH burden, we conducted a meta-analysis of multiethnic genome-wide association studies. Methods and Results-We included 21 079 middle-aged to elderly individuals from 29 population-based cohorts, who were free of dementia and stroke and were of European (n=17 936), African (n=1943), Hispanic (n=795), and Asian (n=405) descent. WMH burden was quantified on MRI either by a validated automated segmentation method or a validated visual grading scale. Genotype data in each study were imputed to the 1000 Genomes reference. Within each ethnic group, we investigated the relationship between each single-nucleotide polymorphism and WMH burden using a linear regression model adjusted for age, sex, intracranial volume, and principal components of ancestry. A meta-analysis was conducted for each ethnicity separately and for the combined sample. In the European descent samples, we confirmed a previously known locus on chr17q25 (P=2.7×10-19) and identified novel loci on chr10q24 (P=1.6×10-9) and chr2p21 (P=4.4×10-8). In the multiethnic meta-analysis, we identified 2 additional loci, on chr1q22 (P=2.0×10-8) and chr2p16 (P=1.5×10-8). The novel loci contained genes that have been implicated in Alzheimer disease (chr2p21 and chr10q24), intracerebral hemorrhage (chr1q22), neuroinflammatory diseases (chr2p21), and glioma (chr10q24 and chr2p16). Conclusions-We identified 4 novel genetic loci that implicate inflammatory and glial proliferative pathways in the development of WMH in addition to previously proposed ischemic mechanisms. © 2015 American Heart Association, Inc. Source

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