Publications by authors named "Monika Stoll"

128 Publications

Evolutionarily conserved transcriptional landscape of the heart defining the chamber specific physiology.

Genomics 2021 Sep 8;113(6):3782-3792. Epub 2021 Sep 8.

Institute of Human Genetics, Division of Genetic Epidemiology, University of Muenster, Muenster, Germany; Department of Biochemistry, Genetic Epidemiology and Statistical Genetics, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, the Netherlands. Electronic address:

Cardiovascular disease (CVD) remains the leading cause of death worldwide. A deeper characterization of regional transcription patterns within different heart chambers may aid to improve our understanding of the molecular mechanisms involved in myocardial function and further, our ability to develop novel therapeutic strategies. Here, we used RNA sequencing to determine differentially expressed protein coding (PC) and long non-coding (lncRNA) transcripts within the heart chambers across seven vertebrate species and identified evolutionarily conserved chamber specific genes, lncRNAs and pathways. We investigated lncRNA homologs based on sequence, secondary structure, synteny and expressional conservation and found most lncRNAs to be conserved by synteny. Regional co-expression patterns of transcripts are modulated by multiple factors, including genomic overlap, strandedness and transcript biotype. Finally, we provide a community resource designated EvoACTG, which informs researchers on the conserved yet intertwined nature of the coding and non-coding cardiac transcriptome across popular model organisms in CVD research.
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http://dx.doi.org/10.1016/j.ygeno.2021.09.002DOI Listing
September 2021

Genomic instability in the naturally and prematurely aged myocardium.

Proc Natl Acad Sci U S A 2021 Sep;118(36)

Department of Molecular Genetics, Faculty of Science and Engineering, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6229 ER Maastricht, The Netherlands;

Genomic instability, the unresolved accumulation of DNA variants, is hypothesized as one of the contributors to the natural aging process. We assessed the frequency of unresolved DNA damage reaching the transcriptome of the murine myocardium during the course of natural aging and in hearts from four distinct mouse models of premature aging with established aging-related cardiac dysfunctions. RNA sequencing and variant calling based on total RNA sequencing was compared between hearts from naturally aging mice, mice with cardiomyocyte-specific deficiency of , a component of the DNA repair machinery, mice with reduced mitochondrial antioxidant capacity, -deficient mice with reduced telomere length, and a mouse model of human Hutchinson-Gilford progeria syndrome (HGPS). Our results demonstrate that no enrichment in variants is evident in the naturally aging murine hearts until 2 y of age from the HGPS mouse model or mice with reduced telomere lengths. In contrast, a dramatic accumulation of variants was evident in cardiomyocyte-specific knockout mice with deficient DNA repair machinery, in mice with reduced mitochondrial antioxidant capacity, and in the intestine, liver, and lung of naturally aging mice. Our data demonstrate that genomic instability does not evidently contribute to naturally aging of the mouse heart in contrast to other organs and support the contention that the endogenous DNA repair machinery is remarkably active to maintain genomic integrity in cardiac cells throughout life.
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http://dx.doi.org/10.1073/pnas.2022974118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8433522PMC
September 2021

A genetic variant alters the secondary structure of the lncRNA H19 and is associated with dilated cardiomyopathy.

RNA Biol 2021 Jul 27:1-7. Epub 2021 Jul 27.

Department of Genetic Epidemiology, Institute of Human Genetics, University of Münster, Münster, Germany.

lncRNAs are at the core of many regulatory processes and have also been recognized to be involved in various complex diseases. They affect gene regulation through direct interactions with RNA, DNA or proteins. Accordingly, lncRNA structure is likely to be essential for their regulatory function. Point mutations, which manifest as SNPs (single nucleotide polymorphisms) in genome screens, can substantially alter their function and, subsequently, the expression of their downstream regulated genes. To test the effect of SNPs on structure, we investigated lncRNAs associated with dilated cardiomyopathy. Among 322 human candidate lncRNAs, we demonstrate first the significant association of an SNP located in lncRNA H19 using data from 1084 diseased and 751 control patients. H19 is generally highly expressed in the heart, with a complex expression pattern during heart development. Next, we used MFE (minimum free energy) folding to demonstrate a significant refolding in the secondary structure of this 861 nt long lncRNA. Since MFE folding may overlook the importance of sub-optimal structures, we showed that this refolding also manifests in the overall Boltzmann structure ensemble. There, the composition of structures is tremendously affected in their thermodynamic probabilities through the genetic variant. Finally, we confirmed these results experimentally, using SHAPE-Seq, corroborating that SNPs affecting such structures may explain hidden genetic variance not accounted for through genome wide association studies. Our results suggest that structural changes in lncRNAs, and lncRNA H19 in particular, affect regulatory processes and represent optimal targets for further in-depth studies probing their molecular interactions.
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http://dx.doi.org/10.1080/15476286.2021.1952756DOI Listing
July 2021

Insights into evolution and coexistence of the colibactin- and yersiniabactin secondary metabolite determinants in enterobacterial populations.

Microb Genom 2021 06;7(6)

Institute of Hygiene, University of Münster, Münster, Germany.

The bacterial genotoxin colibactin interferes with the eukaryotic cell cycle by causing dsDNA breaks. It has been linked to bacterially induced colorectal cancer in humans. Colibactin is encoded by a 54 kb genomic region in . The colibactin genes commonly co-occur with the yersiniabactin biosynthetic determinant. Investigating the prevalence and sequence diversity of the colibactin determinant and its linkage to the yersiniabactin operon in prokaryotic genomes, we discovered mainly species-specific lineages of the colibactin determinant and classified three main structural settings of the colibactin-yersiniabactin genomic region in . The colibactin gene cluster has a similar but not identical evolutionary track to that of the yersiniabactin operon. Both determinants could have been acquired on several occasions and/or exchanged independently between enterobacteria by horizontal gene transfer. Integrative and conjugative elements play(ed) a central role in the evolution and structural diversity of the colibactin-yersiniabactin genomic region. Addition of an activating and regulating module () to the biosynthesis and transport module () represents the most recent step in the evolution of the colibactin determinant. In a first attempt to correlate colibactin expression with individual lineages of colibactin determinants and different bacterial genetic backgrounds, we compared colibactin expression of selected enterobacterial isolates . Colibactin production in the tested species and strains was more homogeneous and generally higher than that in most of the isolates studied. Our results improve the understanding of the diversity of colibactin determinants and its expression level, and may contribute to risk assessment of colibactin-producing enterobacteria.
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http://dx.doi.org/10.1099/mgen.0.000577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8461471PMC
June 2021

Leukocyte gene expression in post-thrombotic syndrome.

Thromb Res 2021 06 8;202:40-42. Epub 2021 Mar 8.

Thrombosis Expertise Center, Heart+Vascular Center, Maastricht University Medical Center (MUMC), Maastricht, the Netherlands; Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands.

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http://dx.doi.org/10.1016/j.thromres.2021.03.007DOI Listing
June 2021

Single- and Multimarker Genome-Wide Scans Evidence Novel Genetic Risk Modifiers for Venous Thromboembolism.

Thromb Haemost 2021 Sep 16;121(9):1169-1180. Epub 2021 Feb 16.

Institute for Clinical Chemistry and Coagulation Center, University Hospital Schleswig Holstein, Kiel/Lübeck, Germany.

Previous genome-wide association studies (GWASs) have established several susceptibility genes for venous thromboembolism (VTE) and suggested many others. However, a large proportion of the genetic variance in VTE remains unexplained. Here, we report genome-wide single- and multimarker as well as gene-level associations with VTE in 964 cases and 899 healthy controls of European ancestry. We report 19 loci at the genome-wide level of association ( ≤ 5 × 10). Our results add to the strong support for the association of genetic variants in , , and with VTE, and identify several loci that have not been previously associated with VTE. Altogether, our novel findings suggest that 20 susceptibility genes for VTE were newly discovered by our study. These genes may impact the production and prothrombotic functions of platelets, endothelial cells, and white and red blood cells. Moreover, the majority of these genes have been previously associated with cardiovascular diseases and/or risk factors for VTE. Future studies are warranted to validate our findings and to investigate the shared genetic architecture with susceptibility factors for other cardiovascular diseases impacting VTE risk.
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http://dx.doi.org/10.1055/s-0041-1723988DOI Listing
September 2021

Dynamic risk assessment to improve quality of care in patients with atrial fibrillation: the 7th AFNET/EHRA Consensus Conference.

Europace 2021 03;23(3):329-344

Atrial Fibrillation NETwork (AFNET), Münster, Germany.

Aims: The risk of developing atrial fibrillation (AF) and its complications continues to increase, despite good progress in preventing AF-related strokes.

Methods And Results: This article summarizes the outcomes of the 7th Consensus Conference of the Atrial Fibrillation NETwork (AFNET) and the European Heart Rhythm Association (EHRA) held in Lisbon in March 2019. Sixty-five international AF specialists met to present new data and find consensus on pressing issues in AF prevention, management and future research to improve care for patients with AF and prevent AF-related complications. This article is the main outcome of an interactive, iterative discussion between breakout specialist groups and the meeting plenary. AF patients have dynamic risk profiles requiring repeated assessment and risk-based therapy stratification to optimize quality of care. Interrogation of deeply phenotyped datasets with outcomes will lead to a better understanding of the cardiac and systemic effects of AF, interacting with comorbidities and predisposing factors, enabling stratified therapy. New proposals include an algorithm for the acute management of patients with AF and heart failure, a call for a refined, data-driven assessment of stroke risk, suggestions for anticoagulation use in special populations, and a call for rhythm control therapy selection based on risk of AF recurrence.

Conclusion: The remaining morbidity and mortality in patients with AF needs better characterization. Likely drivers of the remaining AF-related problems are AF burden, potentially treatable by rhythm control therapy, and concomitant conditions, potentially treatable by treating these conditions. Identifying the drivers of AF-related complications holds promise for stratified therapy.
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http://dx.doi.org/10.1093/europace/euaa279DOI Listing
March 2021

Climate change facilitates a parasite's host exploitation via temperature-mediated immunometabolic processes.

Glob Chang Biol 2021 Jan 10;27(1):94-107. Epub 2020 Nov 10.

Institute for Evolution and Biodiversity, Animal Evolutionary Ecology, University of Münster, Münster, Germany.

Global climate change can influence organismic interactions like those between hosts and parasites. Rising temperatures may exacerbate the exploitation of hosts by parasites, especially in ectothermic systems. The metabolic activity of ectotherms is strongly linked to temperature and generally increases when temperatures rise. We hypothesized that temperature change in combination with parasite infection interferes with the host's immunometabolism. We used a parasite, the avian cestode Schistocephalus solidus, which taps most of its resources from the metabolism of an ectothermic intermediate host, the three-spined stickleback. We experimentally exposed sticklebacks to this parasite, and studied liver transcriptomes 50 days after infection at 13°C and 24°C, to assess their immunometabolic responses. Furthermore, we monitored fitness parameters of the parasite and examined immunity and body condition of the sticklebacks at 13°C, 18°C and 24°C after 36, 50 and 64 days of infection. At low temperatures (13°C), S. solidus growth was constrained, presumably also by the more active stickleback's immune system, thus delaying its infectivity for the final host to 64 days. Warmer temperature (18°C and 24°C) enhanced S. solidus growth, and it became infective to the final host already after 36 days. Overall, S. solidus produced many more viable offspring after development at elevated temperatures. In contrast, stickleback hosts had lower body conditions, and their immune system was less active at warm temperature. The stickleback's liver transcriptome revealed that mainly metabolic processes were differentially regulated between temperatures, whereas immune genes were not strongly affected. Temperature effects on gene expression were strongly enhanced in infected sticklebacks, and even in exposed-but-not-infected hosts. These data suggest that the parasite exposure in concert with rising temperature, as to be expected with global climate change, shifted the host's immunometabolism, thus providing nutrients for the enormous growth of the parasite and, at the same time suppressing immune defence.
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http://dx.doi.org/10.1111/gcb.15402DOI Listing
January 2021

Non-Coding RNA Databases in Cardiovascular Research.

Noncoding RNA 2020 Sep 2;6(3). Epub 2020 Sep 2.

Genetic Epidemiology and Statistical Genetics, Department of Biochemistry, CARIM School for Cardiovascular Diseases, Maastricht University, 6229 ER Maastricht, The Netherlands.

Cardiovascular diseases (CVDs) are of multifactorial origin and can be attributed to several genetic and environmental components. CVDs are the leading cause of mortality worldwide and they primarily damage the heart and the vascular system. Non-coding RNA (ncRNA) refers to functional RNA molecules, which have been transcribed into DNA but do not further get translated into proteins. Recent transcriptomic studies have identified the presence of thousands of ncRNA molecules across species. In humans, less than 2% of the total genome represents the protein-coding genes. While the role of many ncRNAs is yet to be ascertained, some long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) have been associated with disease progression, serving as useful diagnostic and prognostic biomarkers. A plethora of data repositories specialized in ncRNAs have been developed over the years using publicly available high-throughput data from next-generation sequencing and other approaches, that cover various facets of ncRNA research like basic and functional annotation, expressional profile, structural and molecular changes, and interaction with other biomolecules. Here, we provide a compendium of the current ncRNA databases relevant to cardiovascular research.
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http://dx.doi.org/10.3390/ncrna6030035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549374PMC
September 2020

ADAMTS12, a new candidate gene for pediatric stroke.

PLoS One 2020 20;15(8):e0237928. Epub 2020 Aug 20.

Institute of Human Genetics, Genetic Epidemiology, University of Münster, Münster, Germany.

We recently reported a family-based genome wide association study (GWAS) for pediatric stroke pointing our attention to two significantly associated genes of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) gene family ADAMTS2 (rs469568, p = 8x10-6) and ADAMTS12 (rs1364044, p = 2.9x10-6). To further investigate these candidate genes, we applied a targeted resequencing approach on 48 discordant sib-pairs for pediatric stroke followed by genotyping of the detected non-synonymous variants in the full cohort of 270 offspring trios and subsequent fine mapping analysis. We identified eight non-synonymous SNPs in ADAMTS2 and six in ADAMTS12 potentially influencing the respective protein function. These variants were genotyped within a cohort of 270 affected offspring trios, association analysis revealed the ADAMTS12 variant rs77581578 to be significantly under-transmitted (p = 6.26x10-3) to pediatric stroke patients. The finding was validated in a pediatric venous thromboembolism (VTE) cohort of 189 affected trios. Subsequent haplotype analysis of ADAMTS12 detected a significantly associated haplotype comprising the originally identified GWAS variant. Several ADAMTS genes such as ADAMTS13 are involved in thromboembolic disease process. Here, we provide further evidence for ADAMTS12 to likely play a role in pediatric stroke. Further functional studies are warranted to assess the functional role of ADAMTS12 in the pathogenesis of stroke.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0237928PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446847PMC
October 2020

Reduced left atrial cardiomyocyte PITX2 and elevated circulating BMP10 predict atrial fibrillation after ablation.

JCI Insight 2020 08 20;5(16). Epub 2020 Aug 20.

Institute of Cardiovascular Sciences and.

BACKGROUNDGenomic and experimental studies suggest a role for PITX2 in atrial fibrillation (AF). To assess if this association is relevant for recurrent AF in patients, we tested whether left atrial PITX2 affects recurrent AF after AF ablation.METHODSmRNA concentrations of PITX2 and its cardiac isoform, PITX2c, were quantified in left atrial appendages (LAAs) from patients undergoing thoracoscopic AF ablation, either in whole LAA tissue (n = 83) or in LAA cardiomyocytes (n = 52), and combined with clinical parameters to predict AF recurrence. Literature suggests that BMP10 is a PITX2-repressed, atrial-specific, secreted protein. BMP10 plasma concentrations were combined with 11 cardiovascular biomarkers and clinical parameters to predict recurrent AF after catheter ablation in 359 patients.RESULTSReduced concentrations of cardiomyocyte PITX2, but not whole LAA tissue PITX2, were associated with AF recurrence after thoracoscopic AF ablation (16% decreased recurrence per 2-(ΔΔCt) increase in PITX2). RNA sequencing, quantitative PCR, and Western blotting confirmed that BMP10 is one of the most PITX2-repressed atrial genes. Left atrial size (HR per mm increase [95% CI], 1.055 [1.028, 1.082]); nonparoxysmal AF (HR 1.672 [1.206, 2.318]), and elevated BMP10 (HR 1.339 [CI 1.159, 1.546] per quartile increase) were predictive of recurrent AF. BMP10 outperformed 11 other cardiovascular biomarkers in predicting recurrent AF.CONCLUSIONSReduced left atrial cardiomyocyte PITX2 and elevated plasma concentrations of the PITX2-repressed, secreted atrial protein BMP10 identify patients at risk of recurrent AF after ablation.TRIAL REGISTRATIONClinicalTrials.gov NCT01091389, NL50069.018.14, Dutch National Registry of Clinical Research Projects EK494-16.FUNDINGBritish Heart Foundation, European Union (H2020), Leducq Foundation.
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http://dx.doi.org/10.1172/jci.insight.139179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455124PMC
August 2020

Induction of ICER is superseded by smICER, challenging the impact of ICER under chronic beta-adrenergic stimulation.

FASEB J 2020 08 30;34(8):11272-11291. Epub 2020 Jun 30.

Institute of Pharmacology and Toxicology, University of Münster, Münster, Germany.

ICER (inducible cAMP early repressor) isoforms are transcriptional repressors encoded by the Crem (cAMP responsive element modulator) gene. They were linked to the regulation of a multitude of cellular processes and pathophysiological mechanisms. Here, we show for the first time that two independent induction patterns for CREM repressor isoforms exist in the heart, namely for ICER and smICER (small ICER), which are induced in response to β-adrenergic stimulation in a transient- and saturation-like manner, respectively. This time-shifted induction pattern, driven by two internal promoters in the Crem gene, leads to the predominant transcription of smIcer after prolonged β-adrenergic stimulation. Using an ICER knockout mouse model with preserved smICER induction, we show that the transient-like induction of Icer itself has minor effects on gene regulation, cardiac hypertrophy or contractile function in the heart. We conclude that the functions previously linked to ICER may be rather attributed to smICER, also beyond the cardiac background.
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http://dx.doi.org/10.1096/fj.201902301RRDOI Listing
August 2020

Role of prothrombin 19911 A>G polymorphism, blood group and male gender in patients with venous thromboembolism: Results of a German cohort study.

J Thromb Thrombolysis 2021 Feb;51(2):494-501

UKSH, Institute of Clinical Chemistry, Hemostasis Unit, Arnold-Heller-Str. 3 Building 17, Kiel, 24105, Germany.

The role of the A>G polymorphism at position 19911 in the prothrombin gene (factor [F] 2 at rs3136516) as a risk factor for venous thromboembolism [VTE] is still unclear. To evaluate the presence of the F2 polymorphism in VTE patients compared to healthy blood donors and to adjust the results for common inherited thrombophilias [IT], age at onset and blood group [BG], and to calculate the risk of VTE recurrence. We investigated 1012 Caucasian patients with a diagnosis of VTE for the presence of the F2 rs3136516 polymorphism and compared these with 902 healthy blood donors. Odds ratios [OR] together with their 95% confidence intervals were calculated adjusted for F5 at rs6025, F2 at rs1799963, blood group, age and gender. In addition, we evaluated the risk of recurrent VTE during patient follow-up calculating hazard ratios [HR] together with their 95% CI. Compared with the AA wildtype, the F2 GG and AG genotypes (rs3136516) were associated with VTE (OR 1.48 and 1.45). The OR in F5 carriers compared to controls was 5.68 and 2.38 in patients with F2 (rs1799963). BG "non-O" was significantly more often diagnosed in patients compared to BG "O" (OR 2.74). VTE recurrence more often occurred in males (HR 2.3) and in carriers with combined thrombophilia (HR 2.11). Noteworthy, the rs3136516 polymorphism alone was not associated significantly with recurrence. In Caucasian patients with VTE the F2 GG/GA genotypes (rs3136516) were moderate risk factors for VTE. Recurrence was associated with male gender and combined thrombophilia.
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http://dx.doi.org/10.1007/s11239-020-02169-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886710PMC
February 2021

A Year in the Life of the EU-CardioRNA COST Action: CA17129 Catalysing Transcriptomics Research in Cardiovascular Disease.

Noncoding RNA 2020 05 18;6(2). Epub 2020 May 18.

Cardiovascular Research Unit, Luxembourg Institute of Health, L-1445 Strassen, Luxembourg.

The EU-CardioRNA Cooperation in Science and Technology (COST) Action is a European-wide consortium established in 2018 with 31 European country members and four associate member countries to build bridges between translational researchers from academia and industry who conduct research on non-coding RNAs, cardiovascular diseases and similar research areas. EU-CardioRNA comprises four core working groups (WG1-4). In the first year since its launch, EU-CardioRNA met biannually to exchange and discuss recent findings in related fields of scientific research, with scientific sessions broadly divided up according to WG. These meetings are also an opportunity to establish interdisciplinary discussion groups, brainstorm ideas and make plans to apply for joint research grants and conduct other scientific activities, including knowledge transfer. Following its launch in Brussels in 2018, three WG meetings have taken place. The first of these in Lisbon, Portugal, the second in Istanbul, Turkey, and the most recent in Maastricht, The Netherlands. Each meeting includes a scientific session from each WG. This meeting report briefly describes the highlights and key take-home messages from each WG session in this first successful year of the EU-CardioRNA COST Action.
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http://dx.doi.org/10.3390/ncrna6020017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7345156PMC
May 2020

Dichotomy between the transcriptomic landscape of naturally versus accelerated aged murine hearts.

Sci Rep 2020 05 18;10(1):8136. Epub 2020 May 18.

Department of Molecular Genetics, Faculty of Science and Engineering; Maastricht University, Maastricht, The Netherlands.

We investigated the transcriptomic landscape of the murine myocardium along the course of natural aging and in three distinct mouse models of premature aging with established aging-related cardiac dysfunction. Genome-wide total RNA-seq was performed and the expression patterns of protein-coding genes and non-coding RNAs were compared between hearts from naturally aging mice, mice with cardiac-specific deficiency of a component of the DNA repair machinery, mice with reduced mitochondrial antioxidant capacity and mice with reduced telomere length. Our results demonstrate that no dramatic changes are evident in the transcriptomes of naturally senescent murine hearts until two years of age, in contrast to the transcriptome of accelerated aged mice. Additionally, these mice displayed model-specific alterations of the expression levels of protein-coding and non-coding genes with hardly any overlap with age-related signatures. Our data demonstrate very limited similarities between the transcriptomes of all our murine aging models and question their reliability to study human cardiovascular senescence.
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http://dx.doi.org/10.1038/s41598-020-65115-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235007PMC
May 2020

CD163 expression defines specific, IRF8-dependent, immune-modulatory macrophages in the bone marrow.

J Allergy Clin Immunol 2020 11 19;146(5):1137-1151. Epub 2020 Mar 19.

Institute of Immunology, University of Muenster, Muenster, Germany. Electronic address:

Background: Scavenger receptor CD163 is exclusively expressed on monocytes/macrophages and is widely used as a marker for alternatively activated macrophages. However, the role of CD163 is not yet clear.

Objectives: We sought to examine the function of CD163 in steady-state as well as in sterile and infectious inflammation.

Methods: Expression of CD163 was analyzed under normal and inflammatory conditions in mice. Functional relevance of CD163 was investigated in models of inflammation in wild-type and CD163 mice.

Results: We describe a subpopulation of bone marrow-resident macrophages (BMRMs) characterized by a high expression of CD163 and functionally distinct from classical bone marrow-derived macrophages. Development of CD163 BMRMs is strictly dependent on IFN regulatory factor-8. CD163 BMRMs show a specific transcriptome and cytokine secretion pattern demonstrating a specific immunomodulatory profile of these cells. Accordingly, CD163 mice show a stronger inflammation in allergic contact dermatitis, indicating a regulatory role of CD163. However, CD163 mice are highly susceptible to S aureus infections, demonstrating the relevance of CD163 for antimicrobial defense as well.

Conclusions: Our data indicate that anti-inflammatory and immunosuppressive mechanisms are not necessarily associated with a decreased antimicrobial activity. In contrast, our data define a novel macrophage population that controls overwhelming inflammation on one hand but is also necessary for an effective control of infections on the other hand.
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http://dx.doi.org/10.1016/j.jaci.2020.02.034DOI Listing
November 2020

Teriflunomide treatment for multiple sclerosis modulates T cell mitochondrial respiration with affinity-dependent effects.

Sci Transl Med 2019 05;11(490)

Sanofi Genzyme, Cambridge, MA 02142, USA.

Interference with immune cell proliferation represents a successful treatment strategy in T cell-mediated autoimmune diseases such as rheumatoid arthritis and multiple sclerosis (MS). One prominent example is pharmacological inhibition of dihydroorotate dehydrogenase (DHODH), which mediates de novo pyrimidine synthesis in actively proliferating T and B lymphocytes. Within the TERIDYNAMIC clinical study, we observed that the DHODH inhibitor teriflunomide caused selective changes in T cell subset composition and T cell receptor repertoire diversity in patients with relapsing-remitting MS (RRMS). In a preclinical antigen-specific setup, DHODH inhibition preferentially suppressed the proliferation of high-affinity T cells. Mechanistically, DHODH inhibition interferes with oxidative phosphorylation (OXPHOS) and aerobic glycolysis in activated T cells via functional inhibition of complex III of the respiratory chain. The affinity-dependent effects of DHODH inhibition were closely linked to differences in T cell metabolism. High-affinity T cells preferentially use OXPHOS during early activation, which explains their increased susceptibility toward DHODH inhibition. In a mouse model of MS, DHODH inhibitory treatment resulted in preferential inhibition of high-affinity autoreactive T cell clones. Compared to T cells from healthy controls, T cells from patients with RRMS exhibited increased OXPHOS and glycolysis, which were reduced with teriflunomide treatment. Together, these data point to a mechanism of action where DHODH inhibition corrects metabolic disturbances in T cells, which primarily affects profoundly metabolically active high-affinity T cell clones. Hence, DHODH inhibition may promote recovery of an altered T cell receptor repertoire in autoimmunity.
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http://dx.doi.org/10.1126/scitranslmed.aao5563DOI Listing
May 2019

Catalyzing Transcriptomics Research in Cardiovascular Disease: The CardioRNA COST Action CA17129.

Noncoding RNA 2019 03 29;5(2). Epub 2019 Mar 29.

Research Unit of Biomedicine, University of Oulu, 90014 Oulu, Finland.

Cardiovascular disease (CVD) remains the leading cause of death worldwide and, despite continuous advances, better diagnostic and prognostic tools, as well as therapy, are needed. The human transcriptome, which is the set of all RNA produced in a cell, is much more complex than previously thought and the lack of dialogue between researchers and industrials and consensus on guidelines to generate data make it harder to compare and reproduce results. This European Cooperation in Science and Technology (COST) Action aims to accelerate the understanding of transcriptomics in CVD and further the translation of experimental data into usable applications to improve personalized medicine in this field by creating an interdisciplinary network. It aims to provide opportunities for collaboration between stakeholders from complementary backgrounds, allowing the functions of different RNAs and their interactions to be more rapidly deciphered in the cardiovascular context for translation into the clinic, thus fostering personalized medicine and meeting a current public health challenge. Thus, this Action will advance studies on cardiovascular transcriptomics, generate innovative projects, and consolidate the leadership of European research groups in the field.COST (European Cooperation in Science and Technology) is a funding organization for research and innovation networks (www.cost.eu).
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http://dx.doi.org/10.3390/ncrna5020031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6630366PMC
March 2019

Analysis of the genomic architecture of a complex trait locus in hypertensive rat models links to kidney damage.

Elife 2019 03 22;8. Epub 2019 Mar 22.

Institute of Clinical Pharmacology and Toxicology, Berlin Institute of Health, Berlin, Germany.

Unraveling the genetic susceptibility of complex diseases such as chronic kidney disease remains challenging. Here, we used inbred rat models of kidney damage associated with elevated blood pressure for the comprehensive analysis of a major albuminuria susceptibility locus detected in these models. We characterized its genomic architecture by congenic substitution mapping, targeted next-generation sequencing, and compartment-specific RNA sequencing analysis in isolated glomeruli. This led to prioritization of transmembrane protein as a novel potential target. is differentially expressed in glomeruli of allele-specific rat models during onset of albuminuria. Patients with focal segmental glomerulosclerosis exhibited specific TMEM63C loss in podocytes. Functional analysis in zebrafish revealed a role for in mediating the glomerular filtration barrier function. Our data demonstrate that integrative analysis of the genomic architecture of a complex trait locus is a powerful tool for identification of new targets such as for further translational investigation.
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http://dx.doi.org/10.7554/eLife.42068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6478434PMC
March 2019

Transcriptomic and proteomic analysis of iris tissue and aqueous humor in juvenile idiopathic arthritis-associated uveitis.

J Autoimmun 2019 06 15;100:75-83. Epub 2019 Mar 15.

Department of Ophthalmology and Ophtha-Lab at St. Franziskus-Hospital, Münster, Germany; Department of Ophthalmology, University of Duisburg-Essen, Essen, Germany.

Gene and protein expression profiles of iris biopsies, aqueous humor (AqH), and sera in patients with juvenile idiopathic arthritis-associated uveitis (JIAU) in comparison to control patients with primary open-angle glaucoma (POAG) and HLA-B27-positive acute anterior uveitis (AAU) were investigated. Via RNA Sequencing (RNA-Seq) and mass spectrometry-based protein expression analyses 136 genes and 56 proteins could be identified as being significantly differentially expressed (DE) between the JIAU and POAG group. Gene expression of different immunoglobulin (Ig) components as well as of the B cell-associated factors ID3, ID1, and EBF1 was significantly upregulated in the JIAU group as compared to POAG patients. qRT-PCR analysis showed a significantly higher gene expression of the B cell-related genes CD19, CD20, CD27, CD138, and MZB1 in the JIAU group. At the protein level, a significantly higher expression of Ig components in JIAU than in POAG was confirmed. The B cell-associated protein MZB1 showed a higher expression in JIAU patients than in POAG which was confirmed by western blot analysis. Using bead-based immunoassay analysis we were able to detect a significantly higher concentration of the B cell-activating and survival factors BAFF, APRIL, and IL-6 in the AqH of JIAU and AAU patients than in POAG patients. The intraocularly upregulated B cell-specific genes and proteins in iris tissue suggest that B cells participate in the immunopathology of JIAU. The intracameral environment in JIAU may facilitate local effector and survival functions of B cells, leading to disease course typical for anterior uveitis.
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http://dx.doi.org/10.1016/j.jaut.2019.03.004DOI Listing
June 2019

Suppressor of Cytokine Signaling 1 is Involved in Gene Regulation Which Controls the Survival of Ly6C Monocytes in Mice.

Cell Physiol Biochem 2019 28;52(2):336-353. Epub 2019 Feb 28.

Department of Genetic Epidemiology, Institute of Human Genetics, University of Münster, Münster, Germany.

Background/aims: Inflammatory processes are controlled by the fine-tuned balance of monocyte subsets. In mice, different subsets of monocytes can be distinguished by the expression of Ly6C that is highly expressed on inflammatory monocytes (Ly6C) and to a lesser extent on patrolling monocytes (Ly6C). Our previous study revealed an accumulation of Ly6C monocytes in atherosclerotic-prone mice bearing a deficiency in suppressor of cytokine signaling (SOCS)-1 leading to an increased atherosclerotic burden. To decipher the underlying mechanisms, we performed a genome-wide analysis of SOCS-1-dependent gene regulation in Ly6C and Ly6C monocytes.

Methods: In monocyte subsets from SOCS-1competent and -deficient mice differentially regulated genes were identified using an Illumina mRNA microarray (45,200 transcripts), which were randomly validated by qPCR. Principal component analysis was performed to further characterize mRNA profiles in monocyte subsets. To unravel potential regulatory mechanisms behind the differential mRNA expression, in silico analysis of a transcription factor (TF) network correlating with SOCS-1-dependent mRNA expression was carried out and combined with a weighted correlation network analysis (WGCNA).

Results: mRNA analysis in monocyte subsets revealed 46 differentially regulated genes by 2-fold or more. Principal component analysis illustrated a distinct separation of mRNA profiles in monocyte subsets from SOCS-1-deficient mice. Notably, two cell surface receptors crucially involved in the determination of monocyte differentiation and survival, C-X3-C chemokine receptor 1 (CX3CR1) and colony stimulating factor 1 receptor (CSF1R), were identified to be regulated by SOCS-1. Moreover, in silico analysis of a TF network in combination with the WGCNA revealed genes coding for PPAR-γ, NUR77 and several ETSdomain proteins that act as pivotal inflammatory regulators.

Conclusion: Our study reveals that SOCS-1 is implicated in a TF network regulating the expression of central transcription factors like PPAR-γ and NUR77 thereby influencing the expression of CX3CR1 and CSF1R that are known to be pivotal for the survival of Ly6C monocytes.
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http://dx.doi.org/10.33594/000000024DOI Listing
March 2019

A novel isoform of myosin 18A (Myo18Aγ) is an essential sarcomeric protein in mouse heart.

J Biol Chem 2019 05 8;294(18):7202-7218. Epub 2019 Feb 8.

From the Institut für Molekulare Zellbiologie,

Whereas myosin 18B (Myo18B) is known to be a critical sarcomeric protein, the function of myosin 18A (Myo18A) is unclear, although it has been implicated in cell motility and Golgi shape. Here, we show that homozygous deletion (homozygous tm1a, tm1b, or tm1d alleles) of in mouse is embryonic lethal. Reminiscent of , was highly expressed in the embryo heart, and cardiac-restricted deletion in mice was embryonic lethal. Surprisingly, using Western blot analysis, we were unable to detect the known isoforms of Myo18A, Myo18Aα and Myo18Aβ, in mouse heart using a custom C-terminal antibody. However, alternative anti-Myo18A antibodies detected a larger than expected protein, and RNA-Seq analysis indicated that a novel Myo18A transcript is expressed in mouse ventricular myocytes (and human heart). Cloning and sequencing revealed that this cardiac isoform, denoted Myo18Aγ, lacks the PDZ-containing N terminus of Myo18Aα but includes an alternative N-terminal extension and a long serine-rich C terminus. EGFP-tagged Myo18Aγ expressed in ventricular myocytes localized to the level of A-bands in sarcomeres, and knockout embryos at day 10.5 exhibited disorganized sarcomeres with wavy thick filaments. We additionally generated myeloid-restricted knockout mice to investigate the role of Myo18A in nonmuscle cells, exemplified by macrophages, which express more Myo18Aβ than Myo18Aα, but no defects in cell shape, motility, or Golgi shape were detected. In summary, we have identified a previously unrecognized sarcomere component, a large novel isoform (denoted Myo18Aγ) of Myo18A. Thus, both members of class XVIII myosins are critical components of cardiac sarcomeres.
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http://dx.doi.org/10.1074/jbc.RA118.004560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6509511PMC
May 2019

Evolutionary Patterns of Non-Coding RNA in Cardiovascular Biology.

Noncoding RNA 2019 Jan 31;5(1). Epub 2019 Jan 31.

Institute of Human Genetics, Department of Genetic Epidemiology, University of Münster, 48149 Münster, Germany.

Cardiovascular diseases (CVDs) affect the heart and the vascular system with a high prevalence and place a huge burden on society as well as the healthcare system. These complex diseases are often the result of multiple genetic and environmental risk factors and pose a great challenge to understanding their etiology and consequences. With the advent of next generation sequencing, many non-coding RNA transcripts, especially long non-coding RNAs (lncRNAs), have been linked to the pathogenesis of CVD. Despite increasing evidence, the proper functional characterization of most of these molecules is still lacking. The exploration of conservation of sequences across related species has been used to functionally annotate protein coding genes. In contrast, the rapid evolutionary turnover and weak sequence conservation of lncRNAs make it difficult to characterize functional homologs for these sequences. Recent studies have tried to explore other dimensions of interspecies conservation to elucidate the functional role of these novel transcripts. In this review, we summarize various methodologies adopted to explore the evolutionary conservation of cardiovascular non-coding RNAs at sequence, secondary structure, syntenic, and expression level.
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http://dx.doi.org/10.3390/ncrna5010015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6468844PMC
January 2019

Genome-wide association meta-analysis of 30,000 samples identifies seven novel loci for quantitative ECG traits.

Eur J Hum Genet 2019 06 24;27(6):952-962. Epub 2019 Jan 24.

Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital-The Capital Region, Copenhagen, Denmark.

Genome-wide association studies (GWAS) of quantitative electrocardiographic (ECG) traits in large consortia have identified more than 130 loci associated with QT interval, QRS duration, PR interval, and heart rate (RR interval). In the current study, we meta-analyzed genome-wide association results from 30,000 mostly Dutch samples on four ECG traits: PR interval, QRS duration, QT interval, and RR interval. SNP genotype data was imputed using the Genome of the Netherlands reference panel encompassing 19 million SNPs, including millions of rare SNPs (minor allele frequency < 5%). In addition to many known loci, we identified seven novel locus-trait associations: KCND3, NR3C1, and PLN for PR interval, KCNE1, SGIP1, and NFKB1 for QT interval, and ATP2A2 for QRS duration, of which six were successfully replicated. At these seven loci, we performed conditional analyses and annotated significant SNPs (in exons and regulatory regions), demonstrating involvement of cardiac-related pathways and regulation of nearby genes.
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http://dx.doi.org/10.1038/s41431-018-0295-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777533PMC
June 2019

Recurrent stroke: the role of thrombophilia in a large international pediatric stroke population.

Haematologica 2019 08 24;104(8):1676-1681. Epub 2019 Jan 24.

Department of Paediatric Haematology/Oncology, University of Münster, Münster, Germany

Risk factors for arterial ischemic stroke in children include vasculopathy and prothrombotic risk factors but their relative importance to recurrent stroke is uncertain. Data on recurrent stroke from databases held in Canada (Toronto), Germany (Kiel-Lübeck/Münster), and the UK (London/Southampton) were pooled. Data were available from 894 patients aged 1 month to 18 years at first stroke (median age, 6 years) with a median follow-up of 35 months. Among these 894 patients, 160 (17.9%) had a recurrence between 1 day and 136 months after the first stroke (median, 3.1 months). Among 288 children with vasculopathy, recurrence was significantly more common [hazard ratio (HR) 2.5, 95% confidence interval (95% CI) 1.92-3.5] compared to the rate in children without vasculopathy. Adjusting for vasculopathy, isolated antithrombin deficiency (HR 3.9; 95% CI: 1.4-10.9), isolated elevated lipoprotein (a) (HR 2.3; 95% CI: 1.3-4.1), and the presence of more than one prothrombotic risk factor (HR 1.9; 95% CI: 1.12-3.2) were independently associated with an increased risk of recurrence. Recurrence rates calculated per 100 person-years were 10 (95% CI: 3-24) for antithrombin deficiency, 6 (95% CI: 4-9) for elevated lipoprotein (a), and 13 (95% CI: 7-20) for the presence of more than one prothrombotic risk factor. Identifying children at increased risk of a second stroke is important in order to intensify measures aimed at preventing such recurrences.
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http://dx.doi.org/10.3324/haematol.2018.211433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6669164PMC
August 2019

Complement 5a Receptor Polymorphisms Are Associated With Panton-Valentine Leukocidin-positive Staphylococcus aureus Colonization in African Pygmies.

Clin Infect Dis 2019 02;68(5):854-856

Institute of Medical Microbiology, University Hospital Münster.

Panton-Valentine leukocidin (PVL) is common in African Staphylococcus aureus and can be associated with skin and soft tissue infection. PVL-positive S. aureus colonization is associated with a variant of complement receptor 5a, the cellular target of the lukS PVL subunit.
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http://dx.doi.org/10.1093/cid/ciy666DOI Listing
February 2019

LncRNA secondary structure in the cardiovascular system.

Noncoding RNA Res 2017 Sep 12;2(3-4):137-142. Epub 2017 Dec 12.

Department of Genetic Epidemiology, Institute of Human Genetics, University of Münster, Münster, Germany.

Long non-coding RNAs (lncRNAs) have been increasingly studied during the past decade. This led to an immense number of annotated transcripts, out of which many were linked to a diverse range of biological mechanisms and diseases. Due to the variety of their regulatory potential, they are seen as an important link in understanding complex epigenetic mechanisms. Prominent examples of lncRNAs in the cardiovascular system are ANRIL, Braveheart, MALAT1 and HOTAIR which have been excessively studied. But despite the impressive number of described transcripts, only a few examples are characterized functionally. One way to do this is to identify accessible structural domains in the RNA secondary structure which have the ability to bind to DNA, RNA or proteins. Through recent improvements in computational as well as experimental methods, this exploration of secondary structure became not only more efficient than traditional methods like crystallization, but also feasible to investigate whole genome RNA structures. The purpose of this review is to highlight the recent advances in secondary structure probing methods and how these can be applied in order to investigate the functional roles of lncRNAs in the cardiovascular system.
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http://dx.doi.org/10.1016/j.ncrna.2017.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6084829PMC
September 2017

Nur77 serves as a molecular brake of the metabolic switch during T cell activation to restrict autoimmunity.

Proc Natl Acad Sci U S A 2018 08 2;115(34):E8017-E8026. Epub 2018 Aug 2.

Department of Neurology with Institute of Translational Neurology, University Hospital Muenster, 48149 Muenster, Germany;

T cells critically depend on reprogramming of metabolic signatures to meet the bioenergetic demands during activation and clonal expansion. Here we identify the transcription factor Nur77 as a cell-intrinsic modulator of T cell activation. Nur77-deficient T cells are highly proliferative, and lack of Nur77 is associated with enhanced T cell activation and increased susceptibility for T cell-mediated inflammatory diseases, such as CNS autoimmunity, allergic contact dermatitis and collagen-induced arthritis. Importantly, Nur77 serves as key regulator of energy metabolism in T cells, restricting mitochondrial respiration and glycolysis and controlling switching between different energy pathways. Transcriptional network analysis revealed that Nur77 modulates the expression of metabolic genes, most likely in close interaction with other transcription factors, especially estrogen-related receptor α. In summary, we identify Nur77 as a transcriptional regulator of T cell metabolism, which elevates the threshold for T cell activation and confers protection in different T cell-mediated inflammatory diseases.
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http://dx.doi.org/10.1073/pnas.1721049115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6112725PMC
August 2018

Targeted resequencing of a locus for heparin-induced thrombocytopenia on chromosome 5 identified in a genome-wide association study.

J Mol Med (Berl) 2018 08 22;96(8):765-775. Epub 2018 Jun 22.

Department of Genetic Epidemiology, Institute of Human Genetics, University Hospital Münster, Münster, Germany.

Immune-mediated heparin-induced thrombocytopenia (HIT) is the clinically most important adverse drug reaction (ADR) in response to heparin therapy characterized by a prothrombotic state despite a decrease in platelet count. We conducted a genome-wide association study in 96 suspected HIT cases and 96 controls to explore the genetic predisposition for HIT within a case-control pharmacovigilance study followed by replication in additional 86 cases and 86 controls from the same study. One single nucleotide polymorphism (SNP, rs1433265, P = 6.5 × 10, odds ratio (OR) 2.79) from 16 identified SNPs was successfully replicated (P = 1.5 × 10, OR 2.77; combined data set P = 2.7 × 10, OR 2.77) and remained the most strongly associated SNP after imputing locus genotypes. Fine mapping revealed a significantly associated risk-conferring haplotype (P = 4.9 × 10, OR 2.41). In order to find rare variants contributing to the association signals, we applied a targeted resequencing approach in a subgroup of 73 HIT patients and 23 controls for the regions with the 16 most strongly HIT-associated SNPs. C-alpha testing was applied to test for the impact of rare variants and we detected two candidate genes, the discoidin domain receptor tyrosine kinase 1 (DDR1, P = 3.6 × 10) and the multiple C2 and transmembrane domain containing 2 (MCTP2, P = 4.5 × 10). For the genes interactor of little elongation complex ELL subunit 1 (ICE1) and a disintegrin-like and metalloproteinase with thrombospondin type 1 motif, 16 (ADAMTS16) nearby rs1433265, we identified several missense variants. Although replication in an independent population is warranted, these findings provide a basis for future studies aiming to identify and characterize genetic susceptibility factors for HIT. KEY MESSAGES: We identified and validated a HIT-associated locus on chromosome 5. Targeted NGS analysis for rare variants identifies DDR1 and MCTP2 as novel candidates. In addition, missense variants for ADAMTS16 and ICE1 were identified in the locus.
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http://dx.doi.org/10.1007/s00109-018-1661-6DOI Listing
August 2018
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