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227 Publications visible to you, out of a total of 227
Genetic risk variants for dyslexia on chromosome 18 in a German cohort
Genetical Statistics and Systems Biology

Abstract (Expand)

Dyslexia is characterized by impaired reading and spelling. The disorder has a prevalence of about 5% in Germany, and a strong hereditary component. Several loci are thought to be involved in the … development of dyslexia. Scerri et al. identified eight potential dyslexia-associated single nucleotide polymorphisms (SNPs) in seven genes on chromosome 18 in an English-speaking population. Here, we present an association analysis that explores the relevance of these SNPs in a German population comprising 388 dyslexia cases and 364 control cases. In case-control analysis, three nominal SNP associations were replicated. The major alleles of NEDD4L-rs12606138 and NEDD4L-rs8094327 were risk associated [odds ratio (OR) = 1.35, 95% confidence interval (CI) = 1.0-1.7, P-value = 0.017 and OR = 1.39, 95% CI = 1.1-1.7, P-value = 0.007, respectively], and both SNPs were in strong linkage disequilibrium (r(2)  = 0.95). For MYO5B-rs555879, the minor allele was risk associated (OR = 1.31, 95% CI = 1.1-1.6, P-value = 0.011). The combined analysis of SNP sets using set enrichment analysis revealed a study-wide significant association for three SNPs with susceptibility for dyslexia. In summary, our results substantiate genetic markers in NEDD4L and MYO5B as risk factors for dyslexia and provide first evidence that the relevance of these markers is not restricted to the English language.

Authors: B. Mueller, P. Ahnert, J. Burkhardt, J. Brauer, I. Czepezauer, E. Quente, J. Boltze, A. Wilcke, H. Kirsten

Date Published: 1st Mar 2014

Publication Type: Journal article

Impact of molecular screening for point mutations and rearrangements in routine air-dried fine-needle aspiration samples of thyroid nodules
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND\backslashr\backslashnThe diagnostic limitations of thyroid fine-needle aspiration (FNA), such as the indeterminate category, can be partially overcome by molecular analyses. However, until … now, rearrangements have only been detected in fresh FNA material and the number of follicular thyroid carcinomas (FTCs) was rather low in previous studies. We aimed at investigating the impact of point mutations and rearrangement detection in a set of routine air-dried FNA smears with a higher percentage of FTCs.\backslashr\backslashnMETHODS\backslashr\backslashnRNA and DNA was extracted from 310 FNAs (164 indeterminate, 57 malignant, 89 benign) and corresponding formalin-fixed paraffin-embedded tissue (156 follicular adenomas [FAs], 32 FTCs, 44 papillary thyroid carcinomas [PTCs], 9 follicular variant PTCs, and 69 goiters). PAX8/PPARG and RET/PTC rearrangements were detected by qPCR, BRAF and RAS mutations by high-resolution melting PCR and by pyrosequencing.\backslashr\backslashnRESULTS\backslashr\backslashnForty-seven mutations were detected in the FNAs: 22 BRAF, 13 NRAS, and 3 HRAS mutations, 8 PAX8/PPARG, and one RET/PTC-rearrangement. While the presence of a BRAF and RET/PTC mutation was associated with cancer in 100% of samples each, the presence of a RAS and PAX8/PPARG mutation was associated with cancer in only 12% and 50% of samples, respectively. In the indeterminate group 4 of 25 carcinomas were identified by molecular FNA screening, which increased the sensitivity from 67% (cytology alone) to 75% (cytology plus molecular screening).\backslashr\backslashnCONCLUSION\backslashr\backslashnMolecular screening for point mutations and rearrangements is feasible in air-dried FNAs. Although the impact of detecting point mutations and rearrangements in FNAs has most likely been overestimated in previous studies, molecular FNA analyses improve presurgical diagnostics. The detection of BRAF mutations in FNA may improve the choice of surgery and postsurgical treatment. Further data are necessary to elucidate the true impact of detecting RAS and PAX8/PPARG mutations in FNAs. The inclusion of additional rare somatic mutations and miRNA markers might further improve the impact of molecular FNA diagnostics. BACKGROUND The diagnostic limitations of thyroid fine-needle aspiration (FNA), such as the indeterminate category, can be partially overcome by molecular analyses. However, until now, rearrangements have only been detected in fresh FNA material and the number of follicular thyroid carcinomas (FTCs) was rather low in previous studies. We aimed at investigating the impact of point mutations and rearrangement detection in a set of routine air-dried FNA smears with a higher percentage of FTCs. METHODS RNA and DNA was extracted from 310 FNAs (164 indeterminate, 57 malignant, 89 benign) and corresponding formalin-fixed paraffin-embedded tissue (156 follicular adenomas [FAs], 32 FTCs, 44 papillary thyroid carcinomas [PTCs], 9 follicular variant PTCs, and 69 goiters). PAX8/PPARG and RET/PTC rearrangements were detected by qPCR, BRAF and RAS mutations by high-resolution melting PCR and by pyrosequencing. RESULTS Forty-seven mutations were detected in the FNAs: 22 BRAF, 13 NRAS, and 3 HRAS mutations, 8 PAX8/PPARG, and one RET/PTC-rearrangement. While the presence of a BRAF and RET/PTC mutation was associated with cancer in 100% of samples each, the presence of a RAS and PAX8/PPARG mutation was associated with cancer in only 12% and 50% of samples, respectively. In the indeterminate group 4 of 25 carcinomas were identified by molecular FNA screening, which increased the sensitivity from 67% (cytology alone) to 75% (cytology plus molecular screening). CONCLUSION Molecular screening for point mutations and rearrangements is feasible in air-dried FNAs. Although the impact of detecting point mutations and rearrangements in FNAs has most likely been overestimated in previous studies, molecular FNA analyses improve presurgical diagnostics. The detection of BRAF mutations in FNA may improve the choice of surgery and postsurgical treatment. Further data are necessary to elucidate the true impact of detecting RAS and PAX8/PPARG mutations in FNAs. The inclusion of additional rare somatic mutations and miRNA markers might further improve the impact of molecular FNA diagnostics.

Authors: Markus Eszlinger, Annelise Krogdahl, Sina Münz, Christian Rehfeld, Eva Magrethe Precht Jensen, Carolina Ferraz, Eileen Bösenberg, Norbert Drieschner, Markus Scholz, Laszlo Hegedüs, Ralf Paschke

Date Published: 1st Feb 2014

Publication Type: Journal article

Modelling lymphoma therapy and outcome
Genetical Statistics and Systems Biology

Abstract (Expand)

Dose and time intensifications of chemotherapy improved the outcome of lymphoma therapy. However, recent study results show that too intense therapies can result in inferior tumour control. We hypothesise … that the immune system plays a key role in controlling residual tumour cells after treatment. More intense therapies result in a stronger depletion of immune cells allowing an early re-growth of the tumour.We propose a differential equations model of the dynamics and interactions of tumour and immune cells under chemotherapy. Major model features are an exponential tumour growth, a modulation of the production of effector cells by the presence of the tumour (immunogenicity), and mutual destruction of tumour and immune cells. Chemotherapy causes damage to both, immune and tumour cells. Growth rate, chemosensitivity, immunogenicity, and initial size of the tumour are assumed to be patient-specific, resulting in heterogeneity regarding therapy outcome. Maximum-entropy distributions of these parameters were estimated on the basis of clinical survival data. The resulting model can explain the outcome of five different chemotherapeutic regimens and corresponding hazard-ratios.We conclude that our model explains observed paradox effects in lymphoma therapy by the simple assumption of a relevant anti-tumour effect of the immune system. Heterogeneity of therapy outcomes can be explained by distributions of model parameters, which can be estimated on the basis of clinical survival data. We demonstrate how the model can be used to make predictions regarding yet untested therapy options.

Authors: Katja Roesch, Dirk Hasenclever, Markus Scholz

Date Published: 1st Feb 2014

Publication Type: Journal article

Cell cycle, oncogenic and tumor suppressor pathways regulate numerous long and macro non-protein-coding RNAs
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND\backslashr\backslashnThe genome is pervasively transcribed but most transcripts do not code for proteins, constituting non-protein coding RNAs. Despite increasing numbers of functional reports … of individual long noncoding RNAs (lncRNAs), assessing the extent of functionality among the non-coding transcriptional output of mammalian cells remains intricate. In the protein coding world, transcripts differentially expressed in the context of processes essential for the survival of multicellular organisms have been instrumental for the discovery of functionally relevant proteins and their deregulation is frequently associated with diseases. We therefore systematically identify lncRNAs expressed differentially in response to oncologically relevant processes, cell-cycle, p53-, and STAT3 pathway, using tiling arrays.\backslashr\backslashnRESULTS\backslashr\backslashnWe find that up to 80% of the pathway-triggered transcriptional response can be non-coding. Among these we identify very large macroRNAs with pathway-specific expression patterns and demonstrate that these are likely continuous transcripts. MacroRNAs contain elements conserved in mammals and sauropsids, which in part exhibit conserved RNA secondary structure. Comparing evolutionary rates of a macroRNA to adjacent protein coding genes suggests a local action of the transcript. Finally, in different grades of astrocytoma, a tumor disease unrelated to the initially used cell lines, macroRNAs are differentially expressed.\backslashr\backslashnCONCLUSIONS\backslashr\backslashnIt has been shown previously that the majority of expressed non-ribosomal transcripts are non-coding. We now conclude that differential expression triggered by signaling pathways gives rise to a similar abundance of non-coding content. It is thus unlikely that the prevalence of non-coding transcripts in the cell is a trivial consequence of leaky or random transcription events. BACKGROUND The genome is pervasively transcribed but most transcripts do not code for proteins, constituting non-protein-coding RNAs. Despite increasing numbers of functional reports of individual long non-coding RNAs (lncRNAs), assessing the extent of functionality among the non-coding transcriptional output of mammalian cells remains intricate. In the protein-coding world, transcripts differentially expressed in the context of processes essential for the survival of multicellular organisms have been instrumental in the discovery of functionally relevant proteins and their deregulation is frequently associated with diseases. We therefore systematically identified lncRNAs expressed differentially in response to oncologically relevant processes and cell-cycle, p53 and STAT3 pathways, using tiling arrays. RESULTS We found that up to 80% of the pathway-triggered transcriptional responses are non-coding. Among these we identified very large macroRNAs with pathway-specific expression patterns and demonstrated that these are likely continuous transcripts. MacroRNAs contain elements conserved in mammals and sauropsids, which in part exhibit conserved RNA secondary structure. Comparing evolutionary rates of a macroRNA to adjacent protein-coding genes suggests a local action of the transcript. Finally, in different grades of astrocytoma, a tumor disease unrelated to the initially used cell lines, macroRNAs are differentially expressed. CONCLUSIONS It has been shown previously that the majority of expressed non-ribosomal transcripts are non-coding. We now conclude that differential expression triggered by signaling pathways gives rise to a similar abundance of non-coding content. It is thus unlikely that the prevalence of non-coding transcripts in the cell is a trivial consequence of leaky or random transcription events.

Authors: Jörg Hackermüller, Kristin Reiche, Christian Otto, Nadine Hösler, Conny Blumert, Katja Brocke-Heidrich, Levin Böhlig, Anne Nitsche, Katharina Kasack, Peter Ahnert, Wolfgang Krupp, Kurt Engeland, Peter F. Stadler, Friedemann Horn

Date Published: 2014

Publication Type: Journal article

Validity, intra- and inter-observer reliability of automated devices for the assessment of ankle brachial index using photo-plethysmography
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND\backslashr\backslashnAnkle-brachial-Index (ABI) measured by manual Dopplersonography is an easily assessable marker of global cardiovascular risk. The aim of this study was to establish novel … photo-plethysmography (PPG)-based ABI assessments in an epidemiologic context and to compare its results with those of Doppler.\backslashr\backslashnMETHODS\backslashr\backslashnTwo devices for PPG-based ABI assessments (Vicorder, Vascular Explorer) were tested and compared against Doppler in 56 putatively healthy subjects. We determined acceptance, time requirements, agreement of repeat measurements, agreement with Doppler and intra- and inter-observer concordances for both devices and compared the results. Differences between cuff inflation- and deflation-based methods were also studied for Vascular Explorer.\backslashr\backslashnRESULTS\backslashr\backslashnAcceptance was similar for both devices but Vascular Explorer was more time consuming. Agreement of multiple measurements was moderate for both methods highlighting the importance of measurement replicates. Both automated devices showed significantly higher ABI compared to Doppler which can be traced back to higher brachial pressures (Vicorder) or higher ankle pressures (Vascular Explorer). This effect is more pronounced for Vascular Explorer but can be ameliorated using the deflation method of measurement. Intra-observer concordances were similar. Inter-observer concordance was non-significantly better for Vicorder.\backslashr\backslashnCONCLUSIONS\backslashr\backslashnBoth devices proved to be feasible in epidemiologic studies, but compared to Doppler, do not constitute an advantage regarding time requirement and accuracy of ABI assessment. Since PPG-based ABI values are inflated compared to Doppler, it will be necessary to adjust Doppler-based cut-offs for risk stratification. BACKGROUND Ankle-brachial-Index (ABI) measured by manual Dopplersonography is an easily assessable marker of global cardiovascular risk. The aim of this study was to establish novel photo-plethysmography (PPG)-based ABI assessments in an epidemiologic context and to compare its results with those of Doppler. METHODS Two devices for PPG-based ABI assessments (Vicorder, Vascular Explorer) were tested and compared against Doppler in 56 putatively healthy subjects. We determined acceptance, time requirements, agreement of repeat measurements, agreement with Doppler and intra- and inter-observer concordances for both devices and compared the results. Differences between cuff inflation- and deflation-based methods were also studied for Vascular Explorer. RESULTS Acceptance was similar for both devices but Vascular Explorer was more time consuming. Agreement of multiple measurements was moderate for both methods highlighting the importance of measurement replicates. Both automated devices showed significantly higher ABI compared to Doppler which can be traced back to higher brachial pressures (Vicorder) or higher ankle pressures (Vascular Explorer). This effect is more pronounced for Vascular Explorer but can be ameliorated using the deflation method of measurement. Intra-observer concordances were similar. Inter-observer concordance was non-significantly better for Vicorder. CONCLUSIONS Both devices proved to be feasible in epidemiologic studies, but compared to Doppler, do not constitute an advantage regarding time requirement and accuracy of ABI assessment. Since PPG-based ABI values are inflated compared to Doppler, it will be necessary to adjust Doppler-based cut-offs for risk stratification.

Authors: Andrej Teren, Frank Beutner, Kerstin Wirkner, Markus Loeffler, Markus Scholz

Date Published: 1st Dec 2013

Publication Type: Journal article

Analysis of a rare functional truncating mutation rs61757459 in vaspin (SERPINA12) on circulating vaspin levels
Genetical Statistics and Systems Biology

Abstract (Expand)

UNLABELLED\backslashr\backslashnA recent genome-wide association study suggests that genetic variation within the vaspin gene might contribute to the variability in circulating serum visceral adipose … tissue-derived serine protease inhibitor (vaspin) concentrations. Here, we analyzed the functional consequences of the rare variant rs61757459 predicting a premature stop codon and its impact on circulating serum vaspin concentrations. In order to identify genetic variation, we sequenced the vaspin gene in 48 nonrelated Caucasian subjects. Rs61757459 was subsequently genotyped in three metabolically well-characterized German cohorts (N = 4,019). We addressed the impact of rs61757459 on the crystal structure of vaspin and investigated its effects on vaspin expression in vivo as well as in vitro using various cell lines (Escherichia coli, HEK293). Along with previously reported common genetic variants, sequencing of vaspin revealed a rare variant (rs61757459; minor allele frequency: 1 %) which predicts a premature stop codon p.R211X. Heterozygous carriers of this mutation had lower circulating vaspin levels when compared with noncarriers. In silico structure analysis of the truncated vaspin, which was estimated to be 24.5 kDa, suggested misfolding and potential instability due to the absence of core structural domains. Indeed, the truncated protein was detected after recombinant expression in E. coli and in lysate, but not in supernatant of HEK293 cells. We conclude that rs61757459 is a functional mutation that results in a truncated protein whose instability likely results in reduced serum vaspin levels.\backslashr\backslashnKEY MESSAGE\backslashr\backslashnA rare variant (rs61757459) in vaspin coding for the stop codon p.R211X is related to lower circulating vaspin concentrations. Structure analysis suggests misfolding and instability due to the absence of core structural domains. The truncated protein is detectable after recombinant expression in E. coli and in lysate, but not in supernatant of HEK293 cells.

Authors: Jana Breitfeld, John T. Heiker, Yvonne Böttcher, Dorit Schleinitz, Anke Tönjes, Kerstin Weidle, Kerstin Krause, E. Bartholomeus Kuettner, Markus Scholz, Wieland Kiess, Norbert Sträter, Annette G. Beck-Sickinger, Michael Stumvoll, Antje Körner, Matthias Blüher, Peter Kovacs

Date Published: 1st Nov 2013

Publication Type: Journal article

Secretory phospholipase A(2)-IIA and cardiovascular disease: a mendelian randomization study
Genetical Statistics and Systems Biology

Abstract (Expand)

OBJECTIVES\backslashr\backslashnThis study sought to investigate the role of secretory phospholipase A2 (sPLA2)-IIA in cardiovascular disease.\backslashr\backslashnBACKGROUND\backslashr\backslashnHigher … circulating levels of sPLA2-IIA mass or sPLA2 enzyme activity have been associated with increased risk of cardiovascular events. However, it is not clear if this association is causal. A recent phase III clinical trial of an sPLA2 inhibitor (varespladib) was stopped prematurely for lack of efficacy.\backslashr\backslashnMETHODS\backslashr\backslashnWe conducted a Mendelian randomization meta-analysis of 19 general population studies (8,021 incident, 7,513 prevalent major vascular events [MVE] in 74,683 individuals) and 10 acute coronary syndrome (ACS) cohorts (2,520 recurrent MVE in 18,355 individuals) using rs11573156, a variant in PLA2G2A encoding the sPLA2-IIA isoenzyme, as an instrumental variable.\backslashr\backslashnRESULTS\backslashr\backslashnPLA2G2A rs11573156 C allele associated with lower circulating sPLA2-IIA mass (38% to 44%) and sPLA2 enzyme activity (3% to 23%) per C allele. The odds ratio (OR) for MVE per rs11573156 C allele was 1.02 (95% confidence interval [CI]: 0.98 to 1.06) in general populations and 0.96 (95% CI: 0.90 to 1.03) in ACS cohorts. In the general population studies, the OR derived from the genetic instrumental variable analysis for MVE for a 1-log unit lower sPLA2-IIA mass was 1.04 (95% CI: 0.96 to 1.13), and differed from the non-genetic observational estimate (OR: 0.69; 95% CI: 0.61 to 0.79). In the ACS cohorts, both the genetic instrumental variable and observational ORs showed a null association with MVE. Instrumental variable analysis failed to show associations between sPLA2 enzyme activity and MVE.\backslashr\backslashnCONCLUSIONS\backslashr\backslashnReducing sPLA2-IIA mass is unlikely to be a useful therapeutic goal for preventing cardiovascular events.

Authors: Michael V. Holmes, Tabassome Simon, Holly J. Exeter, Lasse Folkersen, Folkert W. Asselbergs, Montse Guardiola, Jackie A. Cooper, Jutta Palmen, Jaroslav A. Hubacek, Kathryn F. Carruthers, Benjamin D. Horne, Kimberly D. Brunisholz, Jessica L. Mega, Erik P A van Iperen, Mingyao Li, Maarten Leusink, Stella Trompet, Jeffrey J W Verschuren, G. Kees Hovingh, Abbas Dehghan, Christopher P. Nelson, Salma Kotti, Nicolas Danchin, Markus Scholz, Christiane L. Haase, Dietrich Rothenbacher, Daniel I. Swerdlow, Karoline B. Kuchenbaecker, Eleonora Staines-Urias, Anuj Goel, Ferdinand van ’t Hooft, Karl Gertow, Ulf de Faire, Andrie G. Panayiotou, Elena Tremoli, Damiano Baldassarre, Fabrizio Veglia, Lesca Miriam Holdt, Frank Beutner, Ron T. Gansevoort, Gerjan J. Navis, Irene Mateo Leach, Lutz P. Breitling, Hermann Brenner, Joachim Thiery, Dhayana Dallmeier, Anders Franco-Cereceda, Jolanda M A Boer, Jeffrey W. Stephens, Marten H. Hofker, Alain Tedgui, Albert Hofman, André G. Uitterlinden, Vera Adamkova, Jan Pitha, N. Charlotte Onland-Moret, Maarten J. Cramer, Hendrik M. Nathoe, Wilko Spiering, Olaf H. Klungel, Meena Kumari, Peter H. Whincup, David A. Morrow, Peter S. Braund, Alistair S. Hall, Anders G. Olsson, Pieter A. Doevendans, Mieke D. Trip, Martin D. Tobin, Anders Hamsten, Hugh Watkins, Wolfgang Koenig, Andrew N. Nicolaides, Daniel Teupser, Ian N M Day, John F. Carlquist, Tom R. Gaunt, Ian Ford, Naveed Sattar, Sotirios Tsimikas, Gregory G. Schwartz, Debbie A. Lawlor, Richard W. Morris, Manjinder S. Sandhu, Rudolf Poledne, Anke H Maitland-van der Zee, Kay-Tee Khaw, Brendan J. Keating, Pim van der Harst, Jackie F. Price, Shamir R. Mehta, Salim Yusuf, Jaqueline C M Witteman, Oscar H. Franco, J. Wouter Jukema, Peter de Knijff, Anne Tybjaerg-Hansen, Daniel J. Rader, Martin Farrall, Nilesh J. Samani, Mika Kivimaki, Keith A A Fox, Steve E. Humphries, Jeffrey L. Anderson, S. Matthijs Boekholdt, Tom M. Palmer, Per Eriksson, Guillaume Paré, Aroon D. Hingorani, Marc S. Sabatine, Ziad Mallat, Juan P. Casas, Philippa J. Talmud

Date Published: 1st Nov 2013

Publication Type: Journal article

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