Format
Sort by
Items per page

Send to

Choose Destination

Search results

Items: 1 to 20 of 57

1.
Front Genet. 2018 Jul 13;9:245. doi: 10.3389/fgene.2018.00245. eCollection 2018.

Novel Mutations in the Asparagine Synthetase Gene (ASNS) Associated With Microcephaly.

Author information

1
IFB AdiposityDiseases, Leipzig University Medical Center, University of Leipzig, Leipzig, Germany.
2
Division of Nephrology, Department of Internal Medicine, Leipzig University Medical Center, University of Leipzig, Leipzig, Germany.
3
Division of Neuropathology, Department of Diagnostic, Leipzig University Medical Center, University of Leipzig, Leipzig, Germany.
4
Hospital for Children and Adolescents, Faculty of Medicine, University of Leipzig, Leipzig, Germany.
5
Medizinisch-Experimentelles Zentrum, Faculty of Medicine, University of Leipzig, Leipzig, Germany.
6
Carl-Ludwig-Institute for Physiology, Faculty of Medicine, University of Leipzig, Leipzig, Germany.
7
Institute of Biochemistry, Faculty of Life Sciences, University of Leipzig, Leipzig, Germany.
8
Institute of Human Genetics, Martin Luther University Halle-Wittenberg, Halle, Germany.
9
Core Unit DNA Technologien, Faculty of Medicine, University of Leipzig, Leipzig, Germany.
10
Department of Neurogenetics, Max-Planck-Institute for Experimental Medicine, Göttingen, Germany.

Abstract

Microcephaly is a devastating condition defined by a small head and small brain compared to the age- and sex-matched population. Mutations in a number of different genes causative for microcephaly have been identified, e.g., MCPH1, WDR62, and ASPM. Recently, mutations in the gene encoding the enzyme asparagine synthetase (ASNS) were associated to microcephaly and so far 24 different mutations in ASNS causing microcephaly have been described. In a family with two affected girls, we identified novel compound heterozygous variants in ASNS (c.1165G > C, p.E389Q and c.601delA, p.M201Wfs28). The first mutation (E389Q) is a missense mutation resulting in the replacement of a glutamate residue evolutionary conserved from Escherichia coli to Homo sapiens by glutamine. Protein modeling based on the known crystal structure of ASNS of E. coli predicted a destabilization of the protein by E389Q. The second mutation (p.M201Wfs28) results in a premature stop codon after amino acid 227, thereby truncating more than half of the protein. The novel variants expand the growing list of microcephaly causing mutations in ASNS.

KEYWORDS:

asparagine synthetase; compound heterozygous; exome sequencing; genetic variants; microcephaly; mutation

2.
Nat Commun. 2018 Jul 27;9(1):2941. doi: 10.1038/s41467-018-04951-w.

Genome-wide association analyses identify 143 risk variants and putative regulatory mechanisms for type 2 diabetes.

Author information

1
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, 4072, Australia.
2
The Eye Hospital, School of Ophthalmology & Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, 325027, China.
3
Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, 51010, Estonia.
4
Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, 4072, Australia.
5
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, 4072, Australia. j.zeng@uq.edu.au.
6
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, 4072, Australia. jian.yang@uq.edu.au.
7
The Eye Hospital, School of Ophthalmology & Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, 325027, China. jian.yang@uq.edu.au.
8
Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, 4072, Australia. jian.yang@uq.edu.au.

Abstract

Type 2 diabetes (T2D) is a very common disease in humans. Here we conduct a meta-analysis of genome-wide association studies (GWAS) with ~16 million genetic variants in 62,892 T2D cases and 596,424 controls of European ancestry. We identify 139 common and 4 rare variants associated with T2D, 42 of which (39 common and 3 rare variants) are independent of the known variants. Integration of the gene expression data from blood (n = 14,115 and 2765) with the GWAS results identifies 33 putative functional genes for T2D, 3 of which were targeted by approved drugs. A further integration of DNA methylation (n = 1980) and epigenomic annotation data highlight 3 genes (CAMK1D, TP53INP1, and ATP5G1) with plausible regulatory mechanisms, whereby a genetic variant exerts an effect on T2D through epigenetic regulation of gene expression. Our study uncovers additional loci, proposes putative genetic regulatory mechanisms for T2D, and provides evidence of purifying selection for T2D-associated variants.

3.
Nat Commun. 2018 Jun 11;9(1):2282. doi: 10.1038/s41467-018-04558-1.

Identifying gene targets for brain-related traits using transcriptomic and methylomic data from blood.

Author information

1
Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, 4072, Australia.
2
Queensland Brain Institute, The University of Queensland, Brisbane, QLD, 4072, Australia.
3
The Eye Hospital, School of Ophthalmology & Optometry, Wenzhou Medical University, 325027, Wenzhou, Zhejiang, China.
4
Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK.
5
Department of Psychology, Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, 7 George Square, Edinburgh, EH8 9JZ, UK.
6
Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, 4072, Australia. jian.yang@uq.edu.au.
7
Queensland Brain Institute, The University of Queensland, Brisbane, QLD, 4072, Australia. jian.yang@uq.edu.au.
8
The Eye Hospital, School of Ophthalmology & Optometry, Wenzhou Medical University, 325027, Wenzhou, Zhejiang, China. jian.yang@uq.edu.au.

Abstract

Understanding the difference in genetic regulation of gene expression between brain and blood is important for discovering genes for brain-related traits and disorders. Here, we estimate the correlation of genetic effects at the top-associated cis-expression or -DNA methylation (DNAm) quantitative trait loci (cis-eQTLs or cis-mQTLs) between brain and blood (r b ). Using publicly available data, we find that genetic effects at the top cis-eQTLs or mQTLs are highly correlated between independent brain and blood samples ([Formula: see text] for cis-eQTLs and [Formula: see text] for cis-mQTLs). Using meta-analyzed brain cis-eQTL/mQTL data (n = 526 to 1194), we identify 61 genes and 167 DNAm sites associated with four brain-related phenotypes, most of which are a subset of the discoveries (97 genes and 295 DNAm sites) using data from blood with larger sample sizes (n = 1980 to 14,115). Our results demonstrate the gain of power in gene discovery for brain-related phenotypes using blood cis-eQTL/mQTL data with large sample sizes.

4.
Hum Mol Genet. 2018 Feb 1;27(3):546-558. doi: 10.1093/hmg/ddx413.

Genome-wide meta-analysis identifies novel determinants of circulating serum progranulin.

Author information

1
Department of Medicine, University of Leipzig, Leipzig 04103, Germany.
2
Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig 04107, Germany.
3
LIFE Research Center, University of Leipzig, Leipzig 04103, Germany.
4
Leipzig University Medical Center, IFB AdiposityDiseases, University of Leipzig, Leipzig 04103, Germany.
5
Research Unit of Molecular Epidemiology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg 85764, Germany.
6
German Research Center for Environmental Health, Institute of Epidemiology II, Helmholtz Center Munich, Neuherberg 85764, Germany.
7
German Center for Diabetes Research (DZD e.V.), Neuherberg 85764, Germany.
8
Department of Clinical Sciences, Diabetes and Endocrinology, Lund University and Lund University Diabetes Centre, CRC at Skåne University Hospital, Malmö 20502, Sweden.
9
Institute of Human Genetics, University of Leipzig, Leipzig 04103, Germany.
10
German Diabetes Center, Institute of Biometrics and Epidemiology, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf 40225, Germany.
11
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
12
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford OX3 7LE, UK.
13
Department of Genomics of Common Diseases, Imperial College London, London SW7 2AZ, UK.
14
Department of Social Services and Healthcare, Jakobstad 68601, Finland.
15
Folkhälsan Research Centre, Helsinki 00290, Finland.
16
Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig 04103, Germany.
17
Department of Endocrinology, Diabetes and Nutrition, Charité-Universitätsmedizin, Berlin 10117, Germany.
18
Department of Clinical Nutrition, German Institute of Human Nutrition, Nuthetal 14558, Germany.
19
Interdisciplinary Centre for Clinical Research, University of Leipzig, Leipzig 04103, Germany.

Abstract

Progranulin is a secreted protein with important functions in processes including immune and inflammatory response, metabolism and embryonic development. The present study aimed at identification of genetic factors determining progranulin concentrations. We conducted a genome-wide association meta-analysis for serum progranulin in three independent cohorts from Europe: Sorbs (N = 848) and KORA (N = 1628) from Germany and PPP-Botnia (N = 335) from Finland (total N = 2811). Single nucleotide polymorphisms (SNPs) associated with progranulin levels were replicated in two additional German cohorts: LIFE-Heart Study (Leipzig; N = 967) and Metabolic Syndrome Berlin Potsdam (Berlin cohort; N = 833). We measured mRNA expression of genes in peripheral blood mononuclear cells (PBMC) by micro-arrays and performed mRNA expression quantitative trait and expression-progranulin association studies to functionally substantiate identified loci. Finally, we conducted siRNA silencing experiments in vitro to validate potential candidate genes within the associated loci. Heritability of circulating progranulin levels was estimated at 31.8% and 26.1% in the Sorbs and LIFE-Heart cohort, respectively. SNPs at three loci reached study-wide significance (rs660240 in CELSR2-PSRC1-MYBPHL-SORT1, rs4747197 in CDH23-PSAP and rs5848 in GRN) explaining 19.4%/15.0% of the variance and 61%/57% of total heritability in the Sorbs/LIFE-Heart Study. The strongest evidence for association was at rs660240 (P = 5.75 × 10-50), which was also associated with mRNA expression of PSRC1 in PBMC (P = 1.51 × 10-21). Psrc1 knockdown in murine preadipocytes led to a consecutive 30% reduction in progranulin secretion. In conclusion, the present meta-GWAS combined with mRNA expression identified three loci associated with progranulin and supports the role of PSRC1 in the regulation of progranulin secretion.

5.
PLoS Comput Biol. 2017 Sep 18;13(9):e1005766. doi: 10.1371/journal.pcbi.1005766. eCollection 2017 Sep.

C-reactive protein upregulates the whole blood expression of CD59 - an integrative analysis.

Author information

1
Institute of Computer Science, University of Tartu, Tartu, Estonia.
2
Institute of Social and Preventive Medicine, Lausanne University Hospital, Lausanne, Switzerland.
3
Swiss Institute of Bioinformatics, Lausanne, Switzerland.
4
Estonian Genome Center, University of Tartu, Tartu, Estonia.
5
Molecular Pathology, Institute of Biomedical and Translational Medicine, University of Tartu, Tartu, Estonia.
6
Quretec Ltd, Tartu, Estonia.

Abstract

Elevated C-reactive protein (CRP) concentrations in the blood are associated with acute and chronic infections and inflammation. Nevertheless, the functional role of increased CRP in multiple bacterial and viral infections as well as in chronic inflammatory diseases remains unclear. Here, we studied the relationship between CRP and gene expression levels in the blood in 491 individuals from the Estonian Biobank cohort, to elucidate the role of CRP in these inflammatory mechanisms. As a result, we identified a set of 1,614 genes associated with changes in CRP levels with a high proportion of interferon-stimulated genes. Further, we performed likelihood-based causality model selection and Mendelian randomization analysis to discover causal links between CRP and the expression of CRP-associated genes. Strikingly, our computational analysis and cell culture stimulation assays revealed increased CRP levels to drive the expression of complement regulatory protein CD59, suggesting CRP to have a critical role in protecting blood cells from the adverse effects of the immune defence system. Our results show the benefit of integrative analysis approaches in hypothesis-free uncovering of causal relationships between traits.

PMID:
28922377
PMCID:
PMC5609773
DOI:
10.1371/journal.pcbi.1005766
[Indexed for MEDLINE]
Free PMC Article
Icon for Public Library of Science Icon for PubMed Central
6.
Atherosclerosis. 2017 Oct;265:197-206. doi: 10.1016/j.atherosclerosis.2017.08.030. Epub 2017 Sep 4.

Quantitative trait locus mapping in mice identifies phospholipase Pla2g12a as novel atherosclerosis modifier.

Author information

1
Institute of Laboratory Medicine, Ludwig Maximilians University Munich, Munich, Germany.
2
Department of Anatomy and Cell Biology, Faculty of Medicine, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.
3
Interdisciplinary Center for Clinical Research Leipzig (IZKF), Core-Unit DNA Technologies, University of Leipzig, Leipzig, Germany.
4
Institute of Food, Nutrition and Health, ETH Zurich, Schwerzenbach, Switzerland.
5
Institute of Laboratory Medicine, Ludwig Maximilians University Munich, Munich, Germany. Electronic address: lesca.holdt@med.uni-muenchen.de.

Abstract

BACKGROUND AND AIMS:

In a previous work, a female-specific atherosclerosis risk locus on chromosome (Chr) 3 was identified in an intercross of atherosclerosis-resistant FVB and atherosclerosis-susceptible C57BL/6 (B6) mice on the LDL-receptor deficient (Ldlr-/-) background. It was the aim of the current study to identify causative genes at this locus.

METHODS:

We established a congenic mouse model, where FVB.Chr3B6/B6 mice carried an 80 Mb interval of distal Chr3 on an otherwise FVB.Ldlr-/- background, to validate the Chr3 locus. Candidate genes were identified using genome-wide expression analyses. Differentially expressed genes were validated using quantitative PCRs in F0 and F2 mice and their functions were investigated in pathophysiologically relevant cells.

RESULTS:

Fine-mapping of the Chr3 locus revealed two overlapping, yet independent subloci for female atherosclerosis susceptibility: when transmitted by grandfathers to granddaughters, the B6 risk allele increased atherosclerosis and downregulated the expression of the secreted phospholipase Pla2g12a (2.6 and 2.2 fold, respectively); when inherited by grandmothers, the B6 risk allele induced vascular cell adhesion molecule 1 (Vcam1). Down-regulation of Pla2g12a and up-regulation of Vcam1 were validated in female FVB.Chr3B6/B6 congenic mice, which developed 2.5 greater atherosclerotic lesions compared to littermate controls (p=0.039). Pla2g12a was highly expressed in aortic endothelial cells in vivo, and knocking-down Pla2g12a expression by RNAi in cultured vascular endothelial cells or macrophages increased their adhesion to ECs in vitro.

CONCLUSIONS:

Our data establish Pla2g12a as an atheroprotective candidate gene in mice, where high expression levels in ECs and macrophages may limit the recruitment and accumulation of these cells in nascent atherosclerotic lesions.

KEYWORDS:

Cell adhesion; Inbred mouse strains; Quantitative trait locus (QTL) mapping; Secreted phospholipases; Vascular endothelial cells

[Indexed for MEDLINE]
Icon for Elsevier Science
7.
Circ Res. 2017 Sep 29;121(8):970-980. doi: 10.1161/CIRCRESAHA.117.311572. Epub 2017 Jul 19.

RNA-Seq Identifies Circulating miR-125a-5p, miR-125b-5p, and miR-143-3p as Potential Biomarkers for Acute Ischemic Stroke.

Author information

1
From the Institute for Stroke and Dementia Research, Klinikum der Universität München (S.T., M.P., R.M., N.S., M.D., V.K., I.S., J.B., A.L., N.P., M.D.), Graduate School of Systemic Neurosciences (S.T.), Institute of Laboratory Medicine, Klinikum der Universität München (B.H.N., D.T., L.M.H.), Department of Neurology, Klinikum der Universität München (M.K.), and Department of Neuroradiology, Klinikum der Universität München (F.D.), Ludwig-Maximilians-Universität LMU, Germany; Munich Cluster for Systems Neurology (SyNergy), Germany (S.T., A.L., N.P., M.D.); and Interdisciplinary Center for Clinical Research (IZKF), University of Leipzig, Germany (K.K.).
2
From the Institute for Stroke and Dementia Research, Klinikum der Universität München (S.T., M.P., R.M., N.S., M.D., V.K., I.S., J.B., A.L., N.P., M.D.), Graduate School of Systemic Neurosciences (S.T.), Institute of Laboratory Medicine, Klinikum der Universität München (B.H.N., D.T., L.M.H.), Department of Neurology, Klinikum der Universität München (M.K.), and Department of Neuroradiology, Klinikum der Universität München (F.D.), Ludwig-Maximilians-Universität LMU, Germany; Munich Cluster for Systems Neurology (SyNergy), Germany (S.T., A.L., N.P., M.D.); and Interdisciplinary Center for Clinical Research (IZKF), University of Leipzig, Germany (K.K.). martin.dichgans@med.uni-muenchen.de.

Abstract

RATIONALE:

Currently, there are no blood-based biomarkers with clinical utility for acute ischemic stroke (IS). MicroRNAs show promise as disease markers because of their cell type-specific expression patterns and stability in peripheral blood.

OBJECTIVE:

To identify circulating microRNAs associated with acute IS, determine their temporal course up to 90 days post-stroke, and explore their utility as an early diagnostic marker.

METHODS AND RESULTS:

We used RNA sequencing to study expression changes of circulating microRNAs in a discovery sample of 20 patients with IS and 20 matched healthy control subjects. We further applied quantitative real-time polymerase chain reaction in independent samples for validation (40 patients with IS and 40 matched controls), replication (200 patients with IS, 100 healthy control subjects), and in 72 patients with transient ischemic attacks. Sampling of patient plasma was done immediately upon hospital arrival. We identified, validated, and replicated 3 differentially expressed microRNAs, which were upregulated in patients with IS compared with both healthy control subjects (miR-125a-5p [1.8-fold; P=1.5×10-6], miR-125b-5p [2.5-fold; P=5.6×10-6], and miR-143-3p [4.8-fold; P=7.8×10-9]) and patients with transient ischemic attack (miR-125a-5p: P=0.003; miR-125b-5p: P=0.003; miR-143-3p: P=0.005). Longitudinal analysis of expression levels up to 90 days after stroke revealed a normalization to control levels for miR-125b-5p and miR-143-3p starting at day 2 while miR-125a-5p remained elevated. Levels of all 3 microRNAs depended on platelet numbers in a platelet spike-in experiment but were unaffected by chemical hypoxia in Neuro2a cells and in experimental stroke models. In a random forest classification, miR-125a-5p, miR-125b-5p, and miR-143-3p differentiated between healthy control subjects and patients with IS with an area under the curve of 0.90 (sensitivity: 85.6%; specificity: 76.3%), which was superior to multimodal cranial computed tomography obtained for routine diagnostics (sensitivity: 72.5%) and previously reported biomarkers of acute IS (neuron-specific enolase: area under the curve=0.69; interleukin 6: area under the curve=0.82).

CONCLUSIONS:

A set of circulating microRNAs (miR-125a-5p, miR-125b-5p, and miR-143-3p) associates with acute IS and might have clinical utility as an early diagnostic marker.

KEYWORDS:

biomarkers; microRNAs; stroke

PMID:
28724745
DOI:
10.1161/CIRCRESAHA.117.311572
[Indexed for MEDLINE]
Icon for Atypon
8.
Endocrine. 2016 Nov;54(2):440-447. Epub 2016 Jul 29.

Two-miRNA classifiers differentiate mutation-negative follicular thyroid carcinomas and follicular thyroid adenomas in fine needle aspirations with high specificity.

Author information

1
Department of Clinical Science, University of Bergen, Bergen, Norway.
2
Department of Nuclear Medicine and Endocrine Oncology, M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, and Institute of Automatic Control, Silesian University of Technology, Gliwice, Poland.
3
Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Warsaw, Poland.
4
IZKF Leipzig, University of Leipzig, Leipzig, Germany.
5
Computational Biology Unit, Department of Informatics, University of Bergen, Bergen, Norway.
6
Department of General, Visceral and Vascular Surgery, University of Halle-Wittenberg, Halle (Saale), Germany.
7
Department of General, Visceral, and Transplantation Surgery, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
8
Department of Pathology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.
9
Tumor Pathology Department, M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice, Poland.
10
Department of Endocrinology and Metabolism, Odense University Hospital, Odense, Denmark.
11
Division of Endocrinology and Metabolism, Departments of Medicine and Oncology and Arnie Charbonneau Cancer Institute, Cummings School of Medicine, University of Calgary, Calgary, AB, Canada.
12
Department of Oncology and Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada. markus.eszlinger1@ucalgary.ca.
13
Divisions of Endocrinology and Nephrology, University of Leipzig, Leipzig, Germany. markus.eszlinger1@ucalgary.ca.

Abstract

Diagnosis of thyroid by fine needle aspiration is challenging for the "indeterminate" category and can be supported by molecular testing. We set out to identify miRNA markers that could be used in a diagnostic setting to improve the discrimination of mutation-negative indeterminate fine needle aspirations. miRNA high-throughput sequencing was performed for freshly frozen tissue samples of 19 RAS and PAX8/PPARG mutation-negative follicular thyroid carcinomas, and 23 RAS and PAX8/PPARG mutation-negative follicular adenomas. Differentially expressed miRNAs were validated by quantitative polymerase chain reaction in a set of 44 fine needle aspiration samples representing 24 follicular thyroid carcinomas and 20 follicular adenomas. Twenty-six miRNAs characterized by a significant differential expression between follicular thyroid carcinomas and follicular adenomas were identified. Nevertheless, since no single miRNA had satisfactory predictive power, classifiers comprising two differentially expressed miRNAs were designed with the aim to improve the classification. Six two-miRNA classifiers were established and quantitative polymerase chain reaction validated in fine needle aspiration samples. Four out of six classifiers were characterized by a high specificity (≥94 %). The best two-miRNA classifier (miR-484/miR-148b-3p) identified thyroid malignancy with a sensitivity of 89 % and a specificity of 87 %. The high-throughput sequencing allowed the identification of subtle differences in the miRNA expression profiles of follicular thyroid carcinomas and follicular adenomas. While none of the differentially expressed miRNAs could be used as a stand-alone malignancy marker, the validation results for two-miRNA classifiers in an independent set of fine needle aspirations are very promising. The ultimate evaluation of these classifiers for their capability of discriminating mutation-negative indeterminate fine needle aspirations will require the evaluation of a sufficiently large number of fine needle aspirations with histological confirmation.

KEYWORDS:

Classifier; Fine needle aspiration cytology; Follicular thyroid adenoma; Follicular thyroid cancer; High-throughput sequencing; miRNA

PMID:
27473101
DOI:
10.1007/s12020-016-1021-7
[Indexed for MEDLINE]
Icon for Springer
9.
Nat Commun. 2016 Aug 19;7:12429. doi: 10.1038/ncomms12429.

Circular non-coding RNA ANRIL modulates ribosomal RNA maturation and atherosclerosis in humans.

Author information

1
Institute of Laboratory Medicine, Ludwig-Maximilians-University Munich, 81337 Munich, Germany.
2
LIFE-Leipzig Research Center for Civilization Diseases, Universität Leipzig, 04103 Leipzig, Germany.
3
Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany.
4
Department of Vascular and Endovascular Surgery, Ludwig-Maximilians-University Munich, 81337 Munich, Germany.
5
Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, 04103 Leipzig, Germany.
6
Institute for Medical Informatics, Statistics and Epidemiology, University Leipzig, 04107 Leipzig, Germany.
7
Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
8
Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
9
Interdisciplinary Center for Clinical Research, University Leipzig, 04103 Leipzig, Germany.

Abstract

Circular RNAs (circRNAs) are broadly expressed in eukaryotic cells, but their molecular mechanism in human disease remains obscure. Here we show that circular antisense non-coding RNA in the INK4 locus (circANRIL), which is transcribed at a locus of atherosclerotic cardiovascular disease on chromosome 9p21, confers atheroprotection by controlling ribosomal RNA (rRNA) maturation and modulating pathways of atherogenesis. CircANRIL binds to pescadillo homologue 1 (PES1), an essential 60S-preribosomal assembly factor, thereby impairing exonuclease-mediated pre-rRNA processing and ribosome biogenesis in vascular smooth muscle cells and macrophages. As a consequence, circANRIL induces nucleolar stress and p53 activation, resulting in the induction of apoptosis and inhibition of proliferation, which are key cell functions in atherosclerosis. Collectively, these findings identify circANRIL as a prototype of a circRNA regulating ribosome biogenesis and conferring atheroprotection, thereby showing that circularization of long non-coding RNAs may alter RNA function and protect from human disease.

10.
J Clin Invest. 2016 Sep 1;126(9):3383-8. doi: 10.1172/JCI84894. Epub 2016 Aug 8.

Recurrent EZH1 mutations are a second hit in autonomous thyroid adenomas.

Abstract

Autonomous thyroid adenomas (ATAs) are a frequent cause of hyperthyroidism. Mutations in the genes encoding the TSH receptor (TSHR) or the Gs protein α subunit (GNAS) are found in approximately 70% of ATAs. The involvement of other genes and the pathogenesis of the remaining cases are presently unknown. Here, we performed whole-exome sequencing in 19 ATAs that were paired with normal DNA samples and identified a recurrent hot-spot mutation (c.1712A>G; p.Gln571Arg) in the enhancer of zeste homolog 1 (EZH1) gene, which codes for a catalytic subunit of the polycomb complex. Targeted screening in an independent cohort confirmed that this mutation occurs with high frequency (27%) in ATAs. EZH1 mutations were strongly associated with known (TSHR, GNAS) or presumed (adenylate cyclase 9 [ADCY9]) alterations in cAMP pathway genes. Furthermore, functional studies revealed that the p.Gln571Arg EZH1 mutation caused increased histone H3 trimethylation and increased proliferation of thyroid cells. In summary, this study revealed that a hot-spot mutation in EZH1 is the second most frequent genetic alteration in ATAs. The association between EZH1 and TSHR mutations suggests a 2-hit model for the pathogenesis of these tumors, whereby constitutive activation of the cAMP pathway and EZH1 mutations cooperate to induce the hyperproliferation of thyroid cells.

PMID:
27500488
PMCID:
PMC5004945
DOI:
10.1172/JCI84894
[Indexed for MEDLINE]
Free PMC Article
Icon for American Society for Clinical Investigation Icon for PubMed Central
11.
Genes Dev. 2015 Oct 1;29(19):1998-2003. doi: 10.1101/gad.266486.115.

The Y3** ncRNA promotes the 3' end processing of histone mRNAs.

Author information

1
Institute of Molecular Medicine, Martin-Luther-University Halle-Wittenberg, Saxony-Anhalt 06120, Germany;
2
Institute of Pharmacy, Martin-Luther-University Halle-Wittenberg, Saxony-Anhalt 06120, Germany;
3
Interdisziplinäres Zentrum für Klinische Forschung, Core Unit DNA-Technologies, University Leipzig, Saxony 04103, Germany.

Abstract

We demonstrate that the Y3/Y3** noncoding RNAs (ncRNAs) bind to the CPSF (cleavage and polyadenylation specificity factor) and that Y3** associates with the 3' untranslated region (UTR) of histone pre-mRNAs. The depletion of Y3** impairs the 3' end processing of histone pre-mRNAs as well as the formation and protein dynamics of histone locus bodies (HLBs), the site of histone mRNA synthesis and processing. HLB morphology is also disturbed by knockdown of the CPSF but not the U7-snRNP components. In conclusion, we propose that the Y3** ncRNA promotes the 3' end processing of histone pre-mRNAs by enhancing the recruitment of the CPSF to histone pre-mRNAs at HLBs.

KEYWORDS:

CPSF; Y RNA; Y3**; histone locus body; histone mRNA processing

PMID:
26443846
PMCID:
PMC4604341
DOI:
10.1101/gad.266486.115
[Indexed for MEDLINE]
Free PMC Article
Icon for HighWire Icon for PubMed Central
12.
Sci Rep. 2015 Oct 5;5:14841. doi: 10.1038/srep14841.

Extensive weight loss reveals distinct gene expression changes in human subcutaneous and visceral adipose tissue.

Author information

1
Department of Biology and Biological Engineering, Chalmers University of Technology, SE-412 96, Gothenburg, Sweden.
2
Science for Life Laboratory, KTH - Royal Institute of Technology, SE-171 21, Stockholm, Sweden.
3
University of Leipzig, Department of Medicine, Leipzig, Germany.
4
Städtisches Klinikum Karlsruhe, Clinic of Visceral Surgery, Karlsruhe, Germany.
5
IFB Adiposity Diseases, Junior Research Group 2 "Animal models of obesity"
6
Core Unit DNA-Technologies, Interdisziplinäres Zentrum für Klinische Forschung (IZKF) Leipzig, Germany.

Abstract

Weight loss has been shown to significantly improve Adipose tissue (AT) function, however changes in AT gene expression profiles particularly in visceral AT (VAT) have not been systematically studied. Here, we tested the hypothesis that extensive weight loss in response to bariatric surgery (BS) causes AT gene expression changes, which may affect energy and lipid metabolism, inflammation and secretory function of AT. We assessed gene expression changes by whole genome expression chips in AT samples obtained from six morbidly obese individuals, who underwent a two step BS strategy with sleeve gastrectomy as initial and a Roux-en-Y gastric bypass as second step surgery after 12 ± 2 months. Global gene expression differences in VAT and subcutaneous (S)AT were analyzed through the use of genome-scale metabolic model (GEM) for adipocytes. Significantly altered gene expressions were PCR-validated in 16 individuals, which also underwent a two-step surgery intervention. We found increased expression of cell death-inducing DFFA-like effector a (CIDEA), involved in formation of lipid droplets in both fat depots in response to significant weight loss. We observed that expression of the genes associated with metabolic reactions involved in NAD+, glutathione and branched chain amino acid metabolism are significantly increased in AT depots after surgery-induced weight loss.

PMID:
26434764
PMCID:
PMC4593186
DOI:
10.1038/srep14841
[Indexed for MEDLINE]
Free PMC Article
Icon for Nature Publishing Group Icon for PubMed Central
13.
PLoS Genet. 2015 Sep 24;11(9):e1005510. doi: 10.1371/journal.pgen.1005510. eCollection 2015 Sep.

Integration of Genome-Wide SNP Data and Gene-Expression Profiles Reveals Six Novel Loci and Regulatory Mechanisms for Amino Acids and Acylcarnitines in Whole Blood.

Author information

1
LIFE Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig Germany; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany.
2
LIFE Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig Germany; Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany; Department for Cell Therapy, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany.
3
LIFE Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig Germany; Heart Center Leipzig, Leipzig, Germany.
4
LIFE Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig Germany; Institute for Laboratory Medicine, Ludwig-Maximilians University Munich, Munich, Germany.
5
LIFE Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig Germany; Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
6
Medical Department, Clinic for Endocrinology and Nephrology, University of Leipzig, Leipzig, Germany.
7
LIFE Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig Germany; Interdisciplinary Centre for Clinical Research, University of Leipzig, Leipzig, Germany.
8
Integrated Research and Treatment Center Adiposity Diseases, University of Leipzig, Leipzig Germany.
9
Medical Department, Clinic for Endocrinology and Nephrology, University of Leipzig, Leipzig, Germany; Integrated Research and Treatment Center Adiposity Diseases, University of Leipzig, Leipzig Germany.

Abstract

Profiling amino acids and acylcarnitines in whole blood spots is a powerful tool in the laboratory diagnosis of several inborn errors of metabolism. Emerging data suggests that altered blood levels of amino acids and acylcarnitines are also associated with common metabolic diseases in adults. Thus, the identification of common genetic determinants for blood metabolites might shed light on pathways contributing to human physiology and common diseases. We applied a targeted mass-spectrometry-based method to analyze whole blood concentrations of 96 amino acids, acylcarnitines and pathway associated metabolite ratios in a Central European cohort of 2,107 adults and performed genome-wide association (GWA) to identify genetic modifiers of metabolite concentrations. We discovered and replicated six novel loci associated with blood levels of total acylcarnitine, arginine (both on chromosome 6; rs12210538, rs17657775), propionylcarnitine (chromosome 10; rs12779637), 2-hydroxyisovalerylcarnitine (chromosome 21; rs1571700), stearoylcarnitine (chromosome 1; rs3811444), and aspartic acid traits (chromosome 8; rs750472). Based on an integrative analysis of expression quantitative trait loci in blood mononuclear cells and correlations between gene expressions and metabolite levels, we provide evidence for putative causative genes: SLC22A16 for total acylcarnitines, ARG1 for arginine, HLCS for 2-hydroxyisovalerylcarnitine, JAM3 for stearoylcarnitine via a trans-effect at chromosome 1, and PPP1R16A for aspartic acid traits. Further, we report replication and provide additional functional evidence for ten loci that have previously been published for metabolites measured in plasma, serum or urine. In conclusion, our integrative analysis of SNP, gene-expression and metabolite data points to novel genetic factors that may be involved in the regulation of human metabolism. At several loci, we provide evidence for metabolite regulation via gene-expression and observed overlaps with GWAS loci for common diseases. These results form a strong rationale for subsequent functional and disease-related studies.

PMID:
26401656
PMCID:
PMC4581711
DOI:
10.1371/journal.pgen.1005510
[Indexed for MEDLINE]
Free PMC Article
Icon for Public Library of Science Icon for PubMed Central
14.
BMC Public Health. 2015 Jul 22;15:691. doi: 10.1186/s12889-015-1983-z.

The LIFE-Adult-Study: objectives and design of a population-based cohort study with 10,000 deeply phenotyped adults in Germany.

Author information

1
LIFE - Leipzig Research Centre for Civilization Diseases, University of Leipzig, Leipzig, Germany. markus.loeffler@imise.uni-leipzig.de.
2
Institute for Medical Informatics, Statistics, and Epidemiology (IMISE), University of Leipzig, Haertelstrasse 16-18, 04107, Leipzig, Germany. markus.loeffler@imise.uni-leipzig.de.
3
LIFE - Leipzig Research Centre for Civilization Diseases, University of Leipzig, Leipzig, Germany.
4
Institute for Medical Informatics, Statistics, and Epidemiology (IMISE), University of Leipzig, Haertelstrasse 16-18, 04107, Leipzig, Germany.
5
Department of Sport and Exercise Psychology, University of Leipzig, Leipzig, Germany.
6
Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany.
7
Clinic of Cognitive Neurology, University of Leipzig, Leipzig, Germany.
8
Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig, Leipzig, Germany.
9
Department of Internal Medicine/Cardiology, Leipzig Heart Centre, Leipzig, Germany.
10
Interdisciplinary Centre for Bioinformatics, University of Leipzig, Leipzig, Germany.
11
Department of Psychosomatic Medicine and Psychotherapy, Universal Medical Centre Mainz, Mainz, Germany.
12
Department of Otorhinolaryngology, Section of Phoniatrics and Audiology, University of Leipzig, Leipzig, Germany.
13
Department of Medical Psychology and Medical Sociology, University of Leipzig, Leipzig, Germany.
14
Department of Cardiology-Angiology, University of Leipzig, Leipzig, Germany.
15
Department of Psychiatry and Psychotherapy, University of Leipzig, Leipzig, Germany.
16
Clinical Trial Centre Leipzig - Coordinating Centre for Clinical Trials, University of Leipzig, Leipzig, Germany.
17
Department of Electrophysiology, Leipzig Heart Centre, Leipzig, Germany.
18
Clinic of Psychosomatic Medicine and Psychotherapy, University of Leipzig, Leipzig, Germany.
19
Interdisciplinary Centre for Clinical Research (IZKF), University of Leipzig, Leipzig, Germany.
20
Institute of Social Medicine, Occupational Health and Public Health (ISAP), University of Leipzig, Leipzig, Germany.
21
Department of Pediatric Cardiology, Leipzig Heart Centre, Leipzig, Germany.
22
Department of Radiology, University of Leipzig, Leipzig, Germany.
23
Department of Ophthalmology, University of Leipzig, Leipzig, Germany.
24
Department of Dermatology, Venereology and Allergology, University of Leipzig, Leipzig, Germany.
25
Medical Department, Division of Endocrinology and Nephrology, University of Leipzig, Leipzig, Germany.

Abstract

BACKGROUND:

The LIFE-Adult-Study is a population-based cohort study, which has recently completed the baseline examination of 10,000 randomly selected participants from Leipzig, a major city with 550,000 inhabitants in the east of Germany. It is the first study of this kind and size in an urban population in the eastern part of Germany. The study is conducted by the Leipzig Research Centre for Civilization Diseases (LIFE). Our objective is to investigate prevalences, early onset markers, genetic predispositions, and the role of lifestyle factors of major civilization diseases, with primary focus on metabolic and vascular diseases, heart function, cognitive impairment, brain function, depression, sleep disorders and vigilance dysregulation, retinal and optic nerve degeneration, and allergies.

METHODS/DESIGN:

The study covers a main age range from 40-79 years with particular deep phenotyping in elderly participants above the age of 60. The baseline examination was conducted from August 2011 to November 2014. All participants underwent an extensive core assessment programme (5-6 h) including structured interviews, questionnaires, physical examinations, and biospecimen collection. Participants over 60 underwent two additional assessment programmes (3-4 h each) on two separate visits including deeper cognitive testing, brain magnetic resonance imaging, diagnostic interviews for depression, and electroencephalography.

DISCUSSION:

The participation rate was 33 %. The assessment programme was accepted well and completely passed by almost all participants. Biomarker analyses have already been performed in all participants. Genotype, transcriptome and metabolome analyses have been conducted in subgroups. The first follow-up examination will commence in 2016.

PMID:
26197779
PMCID:
PMC4509697
DOI:
10.1186/s12889-015-1983-z
[Indexed for MEDLINE]
Free PMC Article
Icon for BioMed Central Icon for PubMed Central
15.
Int J Cancer. 2015 Dec 15;137(12):2846-57. doi: 10.1002/ijc.29649. Epub 2015 Jul 6.

The role of HPV RNA transcription, immune response-related gene expression and disruptive TP53 mutations in diagnostic and prognostic profiling of head and neck cancer.

Author information

1
Clinic for Otorhinolaryngology, University Hospital Leipzig, Liebigstr. 10-14, 04103, Leipzig, Germany.
2
LIFE-Leipzig Research Center for Civilization Diseases, University of Leipzig, 04103, Leipzig, Germany.
3
Institute for Medical Informatics, Statistics and Epidemiology (IMISE), University of Leipzig, 04107, Leipzig, Germany.
4
Faculty of Medicine, Interdisciplinary Center for Clinical Research, University of Leipzig, 04103, Leipzig, Germany.
5
Clinic for Maxillofacial Surgery, University Hospital Leipzig, 04103, Leipzig, Germany.
6
Institute of Pathology, University Hospital Leipzig, 04103, Leipzig, Germany.
7
Division of Genome Modifications and Carcinogenesis (F020), Infection and Cancer Program, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69121, Heidelberg, Germany.
8
Research Group Molecular Mechanisms of Head and Neck Tumors, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
9
Section Experimental and Translational Head and Neck Oncology, Department of Otolaryngology, Head and Neck Surgery University Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany.
10
Faculty of Medicine, Institute of Environmental Medicine and Hygiene, University of Leipzig, 04103, Leipzig, Germany.
11
Institute of Clinical Immunology and Transfusion Medicine, University Hospital, 04103, Leipzig, Germany.

Abstract

Stratification of head and neck squamous cell carcinomas (HNSCC) based on HPV16 DNA and RNA status, gene expression patterns, and mutated candidate genes may facilitate patient treatment decision. We characterize head and neck squamous cell carcinomas (HNSCC) with different HPV16 DNA and RNA (E6*I) status from 290 consecutively recruited patients by gene expression profiling and targeted sequencing of 50 genes. We show that tumors with transcriptionally inactive HPV16 (DNA+ RNA-) are similar to HPV-negative (DNA-) tumors regarding gene expression and frequency of TP53 mutations (47%, 8/17 and 43%, 72/167, respectively). We also find that an immune response-related gene expression cluster is associated with lymph node metastasis, independent of HPV16 status and that disruptive TP53 mutations are associated with lymph node metastasis in HPV16 DNA- tumors. We validate each of these associations in another large data set. Four gene expression clusters which we identify differ moderately but significantly in overall survival. Our findings underscore the importance of measuring the HPV16 RNA (E6*I) and TP53-mutation status for patient stratification and identify associations of an immune response-related gene expression cluster and TP53 mutations with lymph node metastasis in HNSCC.

KEYWORDS:

APC; TP53; consensus clustering; gene expression; head and neck squamous cell carcinoma; human papillomavirus; neck metastasis

PMID:
26095926
DOI:
10.1002/ijc.29649
[Indexed for MEDLINE]
Free full text
Icon for Wiley
16.
Hum Mol Genet. 2015 Aug 15;24(16):4746-63. doi: 10.1093/hmg/ddv194. Epub 2015 May 27.

Dissecting the genetics of the human transcriptome identifies novel trait-related trans-eQTLs and corroborates the regulatory relevance of non-protein coding loci†.

Author information

1
Institute for Medical Informatics, Statistics and Epidemiology, LIFE - Leipzig Research Center for Civilization Diseases, Cognitive Genetics, Department of Cell Therapy.
2
Department for Computer Science, Analysis Strategies Group, Department of Diagnostics, Young Investigators Group Bioinformatics and Transcriptomics, Department Proteomics, Helmholtz Centre for Environmental Research - UFZ, Leipzig, Germany and.
3
Institute of Laboratory Medicine, Ludwig-Maximilians-University, Munich, Germany.
4
Institute for Medical Informatics, Statistics and Epidemiology, LIFE - Leipzig Research Center for Civilization Diseases.
5
LIFE - Leipzig Research Center for Civilization Diseases, Department of Internal Medicine/Cardiology, Heart Center.
6
Interdisciplinary Center for Clinical Research, Faculty of Medicine and .
7
LIFE - Leipzig Research Center for Civilization Diseases, Institute of Laboratory Medicine, University of Leipzig, Leipzig, Germany.
8
Department for Computer Science, RNomics Group, Department of Diagnostics, Fraunhofer Institute for Cell Therapy and Immunology- IZI, Leipzig, Germany, Young Investigators Group Bioinformatics and Transcriptomics, Department Proteomics, Helmholtz Centre for Environmental Research - UFZ, Leipzig, Germany and.
9
Institute for Medical Informatics, Statistics and Epidemiology, LIFE - Leipzig Research Center for Civilization Diseases, markus.scholz@imise.uni-leipzig.de.

Abstract

Genetics of gene expression (eQTLs or expression QTLs) has proved an indispensable tool for understanding biological pathways and pathomechanisms of trait-associated SNPs. However, power of most genome-wide eQTL studies is still limited. We performed a large eQTL study in peripheral blood mononuclear cells of 2112 individuals increasing the power to detect trans-effects genome-wide. Going beyond univariate SNP-transcript associations, we analyse relations of eQTLs to biological pathways, polygenetic effects of expression regulation, trans-clusters and enrichment of co-localized functional elements. We found eQTLs for about 85% of analysed genes, and 18% of genes were trans-regulated. Local eSNPs were enriched up to a distance of 5 Mb to the transcript challenging typically implemented ranges of cis-regulations. Pathway enrichment within regulated genes of GWAS-related eSNPs supported functional relevance of identified eQTLs. We demonstrate that nearest genes of GWAS-SNPs might frequently be misleading functional candidates. We identified novel trans-clusters of potential functional relevance for GWAS-SNPs of several phenotypes including obesity-related traits, HDL-cholesterol levels and haematological phenotypes. We used chromatin immunoprecipitation data for demonstrating biological effects. Yet, we show for strongly heritable transcripts that still little trans-chromosomal heritability is explained by all identified trans-eSNPs; however, our data suggest that most cis-heritability of these transcripts seems explained. Dissection of co-localized functional elements indicated a prominent role of SNPs in loci of pseudogenes and non-coding RNAs for the regulation of coding genes. In summary, our study substantially increases the catalogue of human eQTLs and improves our understanding of the complex genetic regulation of gene expression, pathways and disease-related processes.

PMID:
26019233
PMCID:
PMC4512630
DOI:
10.1093/hmg/ddv194
[Indexed for MEDLINE]
Free PMC Article
Icon for Silverchair Information Systems Icon for PubMed Central
17.
Mol Cell Endocrinol. 2015 Jan 5;399:43-9. doi: 10.1016/j.mce.2014.09.017. Epub 2014 Sep 26.

A two miRNA classifier differentiates follicular thyroid carcinomas from follicular thyroid adenomas.

Author information

1
Institute of Automatic Control, Silesian University of Technology, ul.Akademicka 16, 44-100 Gliwice, Poland; Department of Nuclear Medicine and Endocrine Oncology, M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch Wybrzeze AK 15, 44-101 Gliwice, Poland; Department of Clinical Science, University of Bergen, Postboks 7800, NO-5020 Bergen, Norway.
2
Department of Nuclear Medicine and Endocrine Oncology, M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch Wybrzeze AK 15, 44-101 Gliwice, Poland; Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Pasteura 3, Warsaw, Poland.
3
Department of Nuclear Medicine and Endocrine Oncology, M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch Wybrzeze AK 15, 44-101 Gliwice, Poland.
4
Department of General, Visceral and Vascular Surgery, University of Halle-Wittenberg, Halle (Saale), Germany.
5
Department of General, Visceral, and Transplantation Surgery, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
6
Department of Pathology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.
7
Tumor Pathology Department, M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch Wybrzeze AK 15, 44-101 Gliwice, Poland.
8
Department of Endocrinology and Metabolism, Odense University Hospital, Odense, Denmark.
9
IZKF Leipzig, University of Leipzig, Liebigstr.21, D-04103 Leipzig, Germany.
10
Division of Endocrinology and Nephrology, University of Leipzig, Liebigstr. 21, D-04103 Leipzig, Germany. Electronic address: Ralf.Paschke@medizin.uni-leipzig.de.
11
Division of Endocrinology and Nephrology, University of Leipzig, Liebigstr. 21, D-04103 Leipzig, Germany.

Abstract

The inherent diagnostic limitations of thyroid fine needle aspiration (FNA), especially in the "indeterminate" category, can be partially overcome by molecular analyses. We aimed at the identification of miRNAs that could be used to improve the discrimination of indeterminate FNAs. miRNA expression profiling was performed for 17 follicular carcinomas (FTCs) and 8 follicular adenomas (FAs). The microarray results underwent cross-comparison using three additional microarray data sets. Candidate miRNAs were validated by qPCR in an independent set of 32 FTCs and 46 FAs. Sixty-eight differentially expressed miRNAs were identified. Thirteen miRNAs could be confirmed by cross comparison. A two-miRNA-classifier was established improving the diagnostic applicability and resulted in a sensitivity of 82% and a specificity of 49%. We present a classifier that has the potential to be successfully evaluated in cytology material for its capability to discriminate (mutation negative) indeterminate cytologies and thereby improving the pre-surgical diagnostics of thyroid nodules.

KEYWORDS:

Classifier; Follicular thyroid adenoma; Follicular thyroid cancer

PMID:
25258301
DOI:
10.1016/j.mce.2014.09.017
[Indexed for MEDLINE]
Icon for Elsevier Science
18.
Mol Cell Endocrinol. 2014 Aug 5;393(1-2):39-45. doi: 10.1016/j.mce.2014.05.023. Epub 2014 Jun 8.

Somatic mutations in 33 benign and malignant hot thyroid nodules in children and adolescents.

Author information

1
Division of Endocrinology and Nephrology, University of Leipzig, Liebigstr. 21, D-04103 Leipzig, Germany. Electronic address: markus.eszlinger@medizin.uni-leipzig.de.
2
Department of Paediatric Endocrinology and Rheumatology, Poznan University of Medical Sciences, 27/33 Szpitalna Street, 60-572 Poznan, Poland. Electronic address: mniedzie@ump.edu.pl.
3
Division of Endocrinology and Nephrology, University of Leipzig, Liebigstr. 21, D-04103 Leipzig, Germany. Electronic address: eva.typlt@gmx.de.
4
Division of Endocrinology and Nephrology, University of Leipzig, Liebigstr. 21, D-04103 Leipzig, Germany. Electronic address: Holger.Jaeschke@medizin.uni-leipzig.de.
5
Division of Endocrinology and Nephrology, University of Leipzig, Liebigstr. 21, D-04103 Leipzig, Germany. Electronic address: Sandra.Huth@medizin.uni-leipzig.de.
6
Division of Endocrinology and Nephrology, University of Leipzig, Liebigstr. 21, D-04103 Leipzig, Germany. Electronic address: Joerg.Schaarschmidt@medizin.uni-leipzig.de.
7
Institute of Pathology, University of Leipzig, Liebigstr., D-04103 Leipzig, Germany. Electronic address: thomas.aigner@klinikum-coburg.de.
8
Laboratory of Pathology, Karol Jonscher's Clinical Hospital of Poznan University of Medical Sciences, 27/33 Szpitalna Street, 60-572 Poznan, Poland.
9
IZKF Leipzig, University of Leipzig, Liebigstr. 21, D-04103 Leipzig, Germany. Electronic address: knut.krohn@medizin.uni-leipzig.de.
10
Division of Endocrinology and Nephrology, University of Leipzig, Liebigstr. 21, D-04103 Leipzig, Germany. Electronic address: Eileen.Boesenberg@medizin.uni-leipzig.de.
11
Division of Endocrinology and Nephrology, University of Leipzig, Liebigstr. 20, D-04103 Leipzig, Germany. Electronic address: Ralf.Paschke@medizin.uni-leipzig.de.

Abstract

Hot thyroid nodules (HTNs) in children are rare. Their reported malignancy rate is higher than in adults. However molecular data are rare. We present clinical and molecular data for 33 consecutive (29 benign and 4 malignant) HTNs. 17/29 Benign HTNs (59%) harbored somatic TSHR mutations. The most commonly observed mutation was M453T (in 8/29 samples). T632I and D633Y mutations were each detected twice. All other TSHR mutations were each found in one sample, including the new A538T mutation. One NRAS mutation was detected in a benign HTN with a M453T mutation. A PAX8/PPARG rearrangement was found in one malignant HTN. A T632I mutation was detected in one hot papillary thyroid carcinoma. The percentage of TSHR mutation positive HTNs in children and adolescents is within the range observed in adults. Contrary to adults, the M453T mutation is the predominant TSHR mutation in HTNs of children and adolescents. The increased malignancy rate of HTNs of children does not appear to be associated with RAS, BRAF, PAX8/PPARG and RET/PTC mutations.

KEYWORDS:

Hyperthyroidism; Thyroid cancer; Thyroid nodule

PMID:
24915144
DOI:
10.1016/j.mce.2014.05.023
[Indexed for MEDLINE]
Icon for Elsevier Science
19.
Diabetes. 2014 Oct;63(10):3295-309. doi: 10.2337/db13-0933. Epub 2014 Apr 23.

Liver-restricted Repin1 deficiency improves whole-body insulin sensitivity, alters lipid metabolism, and causes secondary changes in adipose tissue in mice.

Author information

1
Department of Medicine, University of Leipzig, Leipzig, Germany.
2
IFB AdiposityDiseases, University of Leipzig, Leipzig, Germany.
3
Department of Laboratory Animal Science, University of Greifswald, Karlsburg, Germany.
4
Institute of Biochemistry, Medical Faculty, University of Leipzig, Leipzig, Germany.
5
Interdisciplinary Center for Clinical Research, Core Unit DNA Technologies, University of Leipzig, Leipzig, Germany.
6
Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.
7
Institute for Experimental Surgery, Rostock University Medical School, Rostock, Germany.
8
Department of Medicine, University of Leipzig, Leipzig, Germany IFB AdiposityDiseases, University of Leipzig, Leipzig, Germany.
9
Department of Medicine, University of Leipzig, Leipzig, Germany IFB AdiposityDiseases, University of Leipzig, Leipzig, Germany nora.kloeting@medizin.uni-leipzig.de.

Abstract

Replication initiator 1 (Repin1) is a zinc finger protein highly expressed in liver and adipose tissue and maps within a quantitative trait locus (QTL) for body weight and triglyceride (TG) levels in the rat. The QTL has further been supported as a susceptibility locus for dyslipidemia and related metabolic disorders in congenic and subcongenic rat strains. Here, we elucidated the role of Repin1 in lipid metabolism in vivo. We generated a liver-specific Repin1 knockout mouse (LRep1(-/-)) and systematically characterized the consequences of Repin1 deficiency in the liver on body weight, glucose and lipid metabolism, liver lipid patterns, and protein/mRNA expression. Hyperinsulinemic-euglycemic clamp studies revealed significantly improved whole-body insulin sensitivity in LRep1(-/-) mice, which may be due to significantly lower TG content in the liver. Repin1 deficiency causes significant changes in potential downstream target molecules including Cd36, Pparγ, Glut2 protein, Akt phosphorylation, and lipocalin2, Vamp4, and Snap23 mRNA expression. Mice with hepatic deletion of Repin1 display secondary changes in adipose tissue function, which may be mediated by altered hepatic expression of lipocalin2 or chemerin. Our findings indicate that Repin1 plays a role in insulin sensitivity and lipid metabolism by regulating key genes of glucose and lipid metabolism.

PMID:
24760138
DOI:
10.2337/db13-0933
[Indexed for MEDLINE]
Free full text
Icon for HighWire
20.
BMC Res Notes. 2014 Mar 13;7:144. doi: 10.1186/1756-0500-7-144.

Analysis options for high-throughput sequencing in miRNA expression profiling.

Author information

1
Interdisciplinary Center for Clinical Research (IZKF), University of Leipzig, Liebigstr, 21, 04103 Leipzig, Germany. krok@medizin.uni-leipzig.de.

Abstract

BACKGROUND:

Recently high-throughput sequencing (HTS) using next generation sequencing techniques became useful in digital gene expression profiling.Our study introduces analysis options for HTS data based on mapping to miRBase or counting and grouping of identical sequence reads. Those approaches allow a hypothesis free detection of miRNA differential expression.

METHODS:

We compare our results to microarray and qPCR data from one set of RNA samples. We use Illumina platforms for microarray analysis and miRNA sequencing of 20 samples from benign follicular thyroid adenoma and malignant follicular thyroid carcinoma. Furthermore, we use three strategies for HTS data analysis to evaluate miRNA biomarkers for malignant versus benign follicular thyroid tumors.

RESULTS:

High correlation of qPCR and HTS data was observed for the proposed analysis methods. However, qPCR is limited in the differential detection of miRNA isoforms. Moreover, we illustrate a much broader dynamic range of HTS compared to microarrays for small RNA studies. Finally, our data confirm hsa-miR-197-3p, hsa-miR-221-3p, hsa-miR-222-3p and both hsa-miR-144-3p and hsa-miR-144-5p as potential follicular thyroid cancer biomarkers.

CONCLUSIONS:

Compared to microarrays HTS provides a global profile of miRNA expression with higher specificity and in more detail. Summarizing of HTS reads as isoform groups (analysis pipeline B) or according to functional criteria (seed analysis pipeline C), which better correlates to results of qPCR are promising new options for HTS analysis. Finally, data opens future miRNA research perspectives for HTS and indicates that qPCR might be limited in validating HTS data in detail.

PMID:
24625073
PMCID:
PMC4007773
DOI:
10.1186/1756-0500-7-144
[Indexed for MEDLINE]
Free PMC Article
Icon for BioMed Central Icon for PubMed Central

Supplemental Content

Loading ...
Support Center