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3. Comparison of HapMap and 1000 Genomes Reference Panels in a Large-Scale Genome-Wide Association Study

Author

de Vries, Paul S, Sabater-Lleal, Maria, Chasman, Daniel I, Trompet, Stella, Ahluwalia, Tarunveer S, Teumer, Alexander, Kleber, Marcus E, Chen, Ming-Huei, Wang, Jie Jin, Attia, John R, Marioni, Riccardo E, Steri, Maristella, Weng, Lu-Chen, Pool, Rene, Grossmann, Vera, Brody, Jennifer A, Venturini, Cristina, Tanaka, Toshiko, Rose, Lynda M, Oldmeadow, Christopher, Mazur, Johanna, Basu, Saonli, Frånberg, Mattias, Yang, Qiong, Ligthart, Symen, Hottenga, Jouke J, Rumley, Ann, Mulas, Antonella, de Craen, Anton JM, Grotevendt, Anne, Taylor, Kent D, Delgado, Graciela E, Kifley, Annette, Lopez, Lorna M, Berentzen, Tina L, Mangino, Massimo, Bandinelli, Stefania, Morrison, Alanna C, Hamsten, Anders, Tofler, Geoffrey, de Maat, Moniek PM, Draisma, Harmen HM, Lowe, Gordon D, Zoledziewska, Magdalena, Sattar, Naveed, Lackner, Karl J, Völker, Uwe, McKnight, Barbara, Huang, Jie, Holliday, Elizabeth G, McEvoy, Mark A, Starr, John M, Hysi, Pirro G, Hernandez, Dena G, Guan, Weihua, Rivadeneira, Fernando, McArdle, Wendy L, Slagboom, P Eline, Zeller, Tanja, Psaty, Bruce M, Uitterlinden, André G, de Geus, Eco JC, Stott, David J, Binder, Harald, Hofman, Albert, Franco, Oscar H, Rotter, Jerome I, Ferrucci, Luigi, Spector, Tim D, Deary, Ian J, März, Winfried, Greinacher, Andreas, Wild, Philipp S, Cucca, Francesco, Boomsma, Dorret I, Watkins, Hugh, Tang, Weihong, Ridker, Paul M, Jukema, Jan W, Scott, Rodney J, Mitchell, Paul, Hansen, Torben, O'Donnell, Christopher J, Smith, Nicholas L, Strachan, David P, and Dehghan, Abbas

Subjects
Epidemiology, Biological Sciences, Health Sciences, Genetics, Human Genome, Genome-Wide Association Study, HapMap Project, Humans, General Science & Technology
Abstract

An increasing number of genome-wide association (GWA) studies are now using the higher resolution 1000 Genomes Project reference panel (1000G) for imputation, with the expectation that 1000G imputation will lead to the discovery of additional associated loci when compared to HapMap imputation. In order to assess the improvement of 1000G over HapMap imputation in identifying associated loci, we compared the results of GWA studies of circulating fibrinogen based on the two reference panels. Using both HapMap and 1000G imputation we performed a meta-analysis of 22 studies comprising the same 91,953 individuals. We identified six additional signals using 1000G imputation, while 29 loci were associated using both HapMap and 1000G imputation. One locus identified using HapMap imputation was not significant using 1000G imputation. The genome-wide significance threshold of 5×10-8 is based on the number of independent statistical tests using HapMap imputation, and 1000G imputation may lead to further independent tests that should be corrected for. When using a stricter Bonferroni correction for the 1000G GWA study (P-value < 2.5×10-8), the number of loci significant only using HapMap imputation increased to 4 while the number of loci significant only using 1000G decreased to 5. In conclusion, 1000G imputation enabled the identification of 20% more loci than HapMap imputation, although the advantage of 1000G imputation became less clear when a stricter Bonferroni correction was used. More generally, our results provide insights that are applicable to the implementation of other dense reference panels that are under development.

Published
2017

4. A meta-analysis of 120 246 individuals identifies 18 new loci for fibrinogen concentration

Author

de Vries, Paul S, Chasman, Daniel I, Sabater-Lleal, Maria, Chen, Ming-Huei, Huffman, Jennifer E, Steri, Maristella, Tang, Weihong, Teumer, Alexander, Marioni, Riccardo E, Grossmann, Vera, Hottenga, Jouke J, Trompet, Stella, Müller-Nurasyid, Martina, Zhao, Jing Hua, Brody, Jennifer A, Kleber, Marcus E, Guo, Xiuqing, Wang, Jie Jin, Auer, Paul L, Attia, John R, Yanek, Lisa R, Ahluwalia, Tarunveer S, Lahti, Jari, Venturini, Cristina, Tanaka, Toshiko, Bielak, Lawrence F, Joshi, Peter K, Rocanin-Arjo, Ares, Kolcic, Ivana, Navarro, Pau, Rose, Lynda M, Oldmeadow, Christopher, Riess, Helene, Mazur, Johanna, Basu, Saonli, Goel, Anuj, Yang, Qiong, Ghanbari, Mohsen, Willemsen, Gonneke, Rumley, Ann, Fiorillo, Edoardo, de Craen, Anton JM, Grotevendt, Anne, Scott, Robert, Taylor, Kent D, Delgado, Graciela E, Yao, Jie, Kifley, Annette, Kooperberg, Charles, Qayyum, Rehan, Lopez, Lorna M, Berentzen, Tina L, Räikkönen, Katri, Mangino, Massimo, Bandinelli, Stefania, Peyser, Patricia A, Wild, Sarah, Trégouët, David-Alexandre, Wright, Alan F, Marten, Jonathan, Zemunik, Tatijana, Morrison, Alanna C, Sennblad, Bengt, Tofler, Geoffrey, de Maat, Moniek PM, de Geus, Eco JC, Lowe, Gordon D, Zoledziewska, Magdalena, Sattar, Naveed, Binder, Harald, Völker, Uwe, Waldenberger, Melanie, Khaw, Kay-Tee, Mcknight, Barbara, Huang, Jie, Jenny, Nancy S, Holliday, Elizabeth G, Qi, Lihong, Mcevoy, Mark G, Becker, Diane M, Starr, John M, Sarin, Antti-Pekka, Hysi, Pirro G, Hernandez, Dena G, Jhun, Min A, Campbell, Harry, Hamsten, Anders, Rivadeneira, Fernando, Mcardle, Wendy L, Slagboom, P Eline, Zeller, Tanja, Koenig, Wolfgang, Psaty, Bruce M, Haritunians, Talin, Liu, Jingmin, Palotie, Aarno, Uitterlinden, André G, Stott, David J, Hofman, Albert, and Franco, Oscar H

Subjects
Biological Sciences, Genetics, Human Genome, 2.1 Biological and endogenous factors, Adult, Aged, Aged, 80 and over, Female, Fibrinogen, Genetic Loci, Genome-Wide Association Study, Humans, INDEL Mutation, Male, Middle Aged, Polymorphism, Single Nucleotide, White People, Medical and Health Sciences, Genetics & Heredity
Abstract

Genome-wide association studies have previously identified 23 genetic loci associated with circulating fibrinogen concentration. These studies used HapMap imputation and did not examine the X-chromosome. 1000 Genomes imputation provides better coverage of uncommon variants, and includes indels. We conducted a genome-wide association analysis of 34 studies imputed to the 1000 Genomes Project reference panel and including ∼120 000 participants of European ancestry (95 806 participants with data on the X-chromosome). Approximately 10.7 million single-nucleotide polymorphisms and 1.2 million indels were examined. We identified 41 genome-wide significant fibrinogen loci; of which, 18 were newly identified. There were no genome-wide significant signals on the X-chromosome. The lead variants of five significant loci were indels. We further identified six additional independent signals, including three rare variants, at two previously characterized loci: FGB and IRF1. Together the 41 loci explain 3% of the variance in plasma fibrinogen concentration.

Published
2016

14. Additional file 1 of CONET: copy number event tree model of evolutionary tumor history for single-cell data

Author

Markowska, Magda, Cąkała, Tomasz, Miasojedow, BłaŻej, Aybey, Bogac, Juraeva, Dilafruz, Mazur, Johanna, Ross, Edith, Staub, Eike, and Szczurek, Ewa

Abstract

Additional file 1 Supplementary information. It includes CONET run settings used in the presented results (Section S1), the run settings for the compared methods (Section S2), the comparison of MEDALT trees on different CN calling input for the xenograft breast cancer SA501X3F data (Section S3), the comparison of event discovery for short and long events (Section S4), the performance of CONET using different priors on per-breakpoint data simulated from the model (Section S5), the evaluation of the count discrepancy penalty for scDNA-seq data sample (Section S6), a recommended procedure for setting CONET regularization parameters (Section S7) and Figs. S1–S14.

Published
2022
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15. Genome-wide association study with additional genetic and post-transcriptional analyses reveals novel regulators of plasma factor XI levels

Author

Sennblad, Bengt, Basu, Saonli, Mazur, Johanna, Suchon, Pierre, Martinez-Perez, Angel, van Hylckama Vlieg, Astrid, Truong, Vinh, Li, Yuhuang, Gådin, Jesper R., Tang, Weihong, Grossman, Vera, de Haan, Hugoline G., Handin, Niklas, Silveira, Angela, Souto, Juan Carlos, Franco-Cereceda, Anders, Morange, Pierre-Emmanuel, Gagnon, France, Soria, Jose Manuel, Eriksson, Per, Hamsten, Anders, Maegdefessel, Lars, Rosendaal, Frits R., Wild, Philipp, Folsom, Aaron R., Trégouët, David-Alexandre, and Sabater-Lleal, Maria

Published
2017
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16. Genome-wide association meta-analysis of corneal curvature identifies novel loci and shared genetic influences across axial length and refractive error

Author

Fan, Qiao, Pozarickij, Alfred, Tan, Nicholas Y. Q., Guo, Xiaobo, Verhoeven, Virginie J. M., Vitart, Veronique, Guggenheim, Jeremy A., Miyake, Masahiro, Tideman, J. Willem L., Khawaja, Anthony P., Zhang, Liang, MacGregor, Stuart, Höhn, René, Chen, Peng, Biino, Ginevra, Wedenoja, Juho, Saffari, Seyed Ehsan, Tedja, Milly S., Xie, Jing, Lanca, Carla, Wang, Ya Xing, Sahebjada, Srujana, Mazur, Johanna, Mirshahi, Alireza, Martin, Nicholas G., Yazar, Seyhan, Pennell, Craig E., Yap, Maurice, Haarman, Annechien E. G., Enthoven, Clair A., Polling, JanRoelof, Hewitt, Alex W., Jaddoe, Vincent W. V., Van Duijn, Cornelia M., Hayward, Caroline, Polasek, Ozren, Tai, E-Shyong, Yoshikatsu, Hosoda, Hysi, Pirro G., Young, Terri L., Tsujikawa, Akitaka, Wang, Jie Jing, Mitchell, Paul, Pfeiffer, Norbert, Pärssinen, Olavi, Foster, Paul J., Fossarello, Maurizio, Yip, Shea Ping, Williams, Cathy, Hammond, Christopher J., Jonas, Jost B., He, Mingguang, Mackey, David A., Wong, Tien-Yin, Klaver, Caroline C. W., Saw, Seang-Mei, Baird, Paul N., Cheng, Ching-Yu, Bailey-Wilson, Joan E., Veluchamy, Amutha Barathi, Burdon, Kathryn P., Campbell, Harry, Chen, Li Jia, Chew, Emily Y., Craig, Jamie E., Cumberland, Phillippa M., Deangelis, Margaret M., Delcourt, Cécile, Ding, Xiaohu, Evans, David M., Gharahkhani, Puya, Iglesias, Adriana I., Haller, Toomas, Han, Xikun, Hoang, Quan, Igo, Robert P., Iyengar, Sudha K., Kähönen, Mika, Kaprio, Jaakko, Klein, Barbara E., Klein, Ronald, Lass, Jonathan H., Lee, Kris, Lehtimäki, Terho, Lewis, Deyana D., Li, Qing, Li, Shi-Ming, Lyytikäinen, Leo-Pekka, Meguro, Akira, Metspalu, Andres, Middlebrooks, Candace D., Mizuki, Nobuhisa, Musolf, Anthony M., Nickels, Stefan, Oexle, Konrad, Pang, Chi Pui, Paterson, Andrew D., Rahi, Jugnoo S., Raitakari, Olli, Rudan, Igor, Stambolian, Dwight, Simpson, Claire L., Wang, Ningli, Bin Wei, Wen, Williams, Katie M., Wilson, James F., Wojciechowski, Robert, Yamashiro, Kenji, Yam, Jason C. S., Zhou, Xiangtian, Aslam, Tariq, Barman, Sarah A., Barrett, Jenny H., Bishop, Paul, Blows, Peter, Bunce, Catey, Carare, Roxana O., Chakravarthy, Usha, Chan, Michelle, Chua, Sharon Y. L., Crabb, David P., Cumberland, Philippa M., Day, Alexander, Desai, Parul, Dhillon, Bal, Dick, Andrew D., Egan, Cathy, Ennis, Sarah, Fruttiger, Marcus, Gallacher, John E. J., Garway-Heath, David F., Gibson, Jane, Gore, Dan, Hardcastle, Alison, Harding, Simon P., Hogg, Ruth E., Keane, Pearse A., Khaw, Sir Peng T., Lascaratos, Gerassimos, Lotery, Andrew J., Macgillivray, Tom, Mackie, Sarah, Martin, Keith, McGaughey, Michelle, McGuinness, Bernadette, McKay, Gareth J., McKibbin, Martin, Mitry, Danny, Moore, Tony, Morgan, James E., Muthy, Zaynah A., O’Sullivan, Eoin, Owen, Chris G., Patel, Praveen, Paterson, Euan, Peto, Tunde, Petzold, Axel, Rudnikca, Alicja R., Self, Jay, Sivaprasad, Sobha, Steel, David, Stratton, Irene, Strouthidis, Nicholas, Sudlow, Cathie, Thomas, Dhanes, Trucco, Emanuele, Tufail, Adnan, Vernon, Stephen A., Viswanathan, Ananth C., Williams, Katie, Woodside, Jayne V., Yates, Max M., Yip, Jennifer, Zheng, Yalin, Verhoeven, Virginie J. M. [0000-0001-7359-7862], Vitart, Veronique [0000-0002-4991-3797], Guggenheim, Jeremy A. [0000-0001-5164-340X], Khawaja, Anthony P. [0000-0001-6802-8585], Zhang, Liang [0000-0001-9264-170X], MacGregor, Stuart [0000-0001-6731-8142], Wedenoja, Juho [0000-0002-6155-0378], Saffari, Seyed Ehsan [0000-0002-6473-4375], Tedja, Milly S. [0000-0003-0356-9684], Lanca, Carla [0000-0001-9918-787X], Wang, Ya Xing [0000-0003-2749-7793], Martin, Nicholas G. [0000-0003-4069-8020], Yap, Maurice [0000-0003-4687-4101], Hewitt, Alex W. [0000-0002-5123-5999], Jaddoe, Vincent W. V. [0000-0003-2939-0041], Hayward, Caroline [0000-0002-9405-9550], Hysi, Pirro G. [0000-0001-5752-2510], Young, Terri L. [0000-0001-6994-9941], Wang, Jie Jing [0000-0001-9491-4898], Pfeiffer, Norbert [0000-0002-5766-2617], Foster, Paul J. [0000-0002-4755-177X], Hammond, Christopher J. [0000-0002-3227-2620], Jonas, Jost B. [0000-0003-2972-5227], Klaver, Caroline C. W. [0000-0002-2355-5258], Baird, Paul N. [0000-0002-1305-3502], and Apollo - University of Cambridge Repository

Subjects
genetic structures, 45, 692/699/3161/3163, 631/208/727/2000, 631/208/205/2138, 45/43, article, sense organs, eye diseases
Abstract

Corneal curvature, a highly heritable trait, is a key clinical endophenotype for myopia - a major cause of visual impairment and blindness in the world. Here we present a trans-ethnic meta-analysis of corneal curvature GWAS in 44,042 individuals of Caucasian and Asian with replication in 88,218 UK Biobank data. We identified 47 loci (of which 26 are novel), with population-specific signals as well as shared signals across ethnicities. Some identified variants showed precise scaling in corneal curvature and eye elongation (i.e. axial length) to maintain eyes in emmetropia (i.e. HDAC11/FBLN2 rs2630445, RBP3 rs11204213); others exhibited association with myopia with little pleiotropic effects on eye elongation. Implicated genes are involved in extracellular matrix organization, developmental process for body and eye, connective tissue cartilage and glycosylation protein activities. Our study provides insights into population-specific novel genes for corneal curvature, and their pleiotropic effect in regulating eye size or conferring susceptibility to myopia.

Published
2021
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17. Genome-wide association meta-analysis of corneal curvature identifies novel loci and shared genetic influences across axial length and refractive error

Author

Fan, Qiao, Pozarickij, Alfred, Tan, Nicholas Y. Q., Guo, Xiaobo, Verhoeven, Virginie J. M., Vitart, Veronique, Guggenheim, Jeremy A., Miyake, Masahiro, Tideman, J. Willem L., Khawaja, Anthony P., Zhang, Liang, MacGregor, Stuart, Höhn, René, Chen, Peng, Biino, Ginevra, Wedenoja, Juho, Saffari, Seyed Ehsan, Tedja, Milly S., Xie, Jing, Lanca, Carla, Wang, Ya Xing, Sahebjada, Srujana, Mazur, Johanna, Mirshahi, Alireza, Martin, Nicholas G., Yazar, Seyhan, Pennell, Craig E., Yap, Maurice, Haarman, Annechien E. G., Enthoven, Clair A., Polling, JanRoelof, Consortium for Refractive Error and Myopia (CREAM), UK Biobank Eye and Vision Consortium, Barman, Sarah A., Hewitt, Alex W., Jaddoe, Vincent W. V., van Duijn, Cornelia M., Hayward, Caroline, Polasek, Ozren, Tai, E-Shyong, Yoshikatsu, Hosoda, Hysi, Pirro G., Young, Terri L., Tsujikawa, Akitaka, Wang, Jie Jing, Mitchell, Paul, Pfeiffer, Norbert, Pärssinen, Olavi, Foster, Paul J., Fossarello, Maurizio, Yip, Shea Ping, Williams, Cathy, Hammond, Christopher J., Jonas, Jost B., He, Mingguang, Mackey, David A., Wong, Tien-Yin, Klaver, Caroline C. W., Saw, Seang-Mei, Baird, Paul N., and Cheng, Ching-Yu

Subjects
genetic structures, sense organs, eye diseases, biological
Abstract

Corneal curvature, a highly heritable trait, is a key clinical endophenotype for myopia - a major cause of visual impairment and blindness in the world. Here we present a trans-ethnic meta-analysis of corneal curvature GWAS in 44,042 individuals of Caucasian and Asian with replication in 88,218 UK Biobank data. We identified 47 loci (of which 26 are novel), with population-specific signals as well as shared signals across ethnicities. Some identified variants showed precise scaling in corneal curvature and eye elongation (i.e. axial length) to maintain eyes in emmetropia (i.e. HDAC11/FBLN2 rs2630445, RBP3 rs11204213); others exhibited association with myopia with little pleiotropic effects on eye elongation. Implicated genes are involved in extracellular matrix organization, developmental process for body and eye, connective tissue cartilage and glycosylation protein activities. Our study provides insights into population-specific novel genes for corneal curvature, and their pleiotropic effect in regulating eye size or conferring susceptibility to myopia.

Published
2020

23. Dissolution and dissolution/permeation experiments for predicting systemic exposure following oral administration of the BCS class II drug clarithromycin

Author

Junyaprasert Varaporn Buraphacheep, Ackermann Maximilian, Holm Rene, Langguth Peter, Morakul Boontida, Mazur Johanna, and Forner Kristin

Subjects
Male, Cell Membrane Permeability, Chemistry, Pharmaceutical, Administration, Oral, Pharmaceutical Science, Excipient, 02 engineering and technology, Absorption (skin), 030226 pharmacology & pharmacy, Excipients, 03 medical and health sciences, 0302 clinical medicine, In vivo, Clarithromycin, medicine, Animals, Humans, Intestinal Mucosa, Rats, Wistar, Solubility, Dissolution, Chromatography, Chemistry, Permeation, 021001 nanoscience & nanotechnology, Rats, Mucus, Intestinal Absorption, Poloxamer 407, Caco-2 Cells, 0210 nano-technology, Ex vivo, medicine.drug
Abstract

In order to save time and resources in early drug development, in vitro methods that correctly predict the formulation effect on oral drug absorption are necessary. The aim of this study was to 1) evaluate various BCS class II drug formulations with in vitro methods and in vivo in order to 2) determine which in vitro method best correlates with the in vivo results. Clarithromycin served as model compound in formulations with different particle sizes and content of excipients. The performed in vitro experiments were dissolution and dissolution/permeation experiments across two types of membrane, Caco-2 cells and excised rat intestinal sheets. The in vivo study was performed in rats. The oral absorption was enhanced by downsizing drug particles and by increasing the excipient concentration. This correlated strongly with the flux across Caco-2 cells but not with the other in vitro experiments. The insufficient correlation with the dissolution experiments can be partly explained by excipient caused problems during the filtration step. The very poor correlation of the in vivo data with the flux across excised rat intestinal sheets might be due to an artificially enlarged mucus layer ex vivo. In conclusion, downsizing BCS class II drug particles and the addition of surfactants enhanced the in vivo absorption, which was best depicted by dissolution/permeation experiments across Caco-2 cells. This setup is proposed as best model to predict the in vivo formulation effect. Also, this is the first study to evaluate the impact of the nature of the permeation membrane in dissolution/permeation experiments.

Published
2017
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24. Expressional analysis of disease-relevant signalling-pathways in primary tumours and metastasis of head and neck cancers

Author

Goesswein, Dorothee, Habtemichael, Negusse, Gerhold-Ay, Aslihan, Mazur, Johanna, Wünsch, Désirée, Knauer, Shirley K., Künzel, Julian, Matthias, Christoph, Strieth, Sebastian, and Stauber, Roland H.

Subjects
Male, Squamous Cell Carcinoma of Head and Neck, Science, Gene Expression Profiling, 610 Medizin, Receptor Protein-Tyrosine Kinases, Middle Aged, Prognosis, Article, 610 Medical sciences, Lymphatic Metastasis, Medicine, Humans, Female, Biologie, Signal Transduction
Abstract

Head and neck squamous cell carcinoma (HNSCC) often metastasize to lymph nodes resulting in poor prognosis for patients. Unfortunately, the underlying molecular mechanisms contributing to tumour aggressiveness, recurrences, and metastasis are still not fully understood. However, such knowledge is key to identify biomarkers and drug targets to improve prognosis and treatments. Consequently, we performed genome-wide expression profiling of 15 primary HNSSCs compared to corresponding lymph node metastases and non-malignant tissue of the same patient. Differentially expressed genes were bioinformatically exploited applying stringent filter criteria, allowing the discrimination between normal mucosa, primary tumours, and metastases. Signalling networks involved in invasion contain remodelling of the extracellular matrix, hypoxia-induced transcriptional modulation, and the recruitment of cancer associated fibroblasts, ultimately converging into a broad activation of PI3K/AKT-signalling pathway in lymph node metastasis. Notably, when we compared the diagnostic and prognostic value of sequencing data with our expression analysis significant differences were uncovered concerning the expression of the receptor tyrosine kinases EGFR and ERBB2, as well as other oncogenic regulators. Particularly, upregulated receptor tyrosine kinase combinations for individual patients varied, implying potential compensatory and resistance mechanisms against specific targeted therapies. Collectively, we here provide unique transcriptional profiles for disease predictions and comprehensively analyse involved signalling pathways in advanced HNSCC. OA gold - CA extern

Published
2018

26. Reconstructing nonlinear dynamic models of gene regulation using stochastic sampling

Author

Reinelt Gerhard, Ritter Daniel, Mazur Johanna, and Kaderali Lars

Subjects
Computer applications to medicine. Medical informatics, R858-859.7, Biology (General), QH301-705.5
Abstract

Abstract Background The reconstruction of gene regulatory networks from time series gene expression data is one of the most difficult problems in systems biology. This is due to several reasons, among them the combinatorial explosion of possible network topologies, limited information content of the experimental data with high levels of noise, and the complexity of gene regulation at the transcriptional, translational and post-translational levels. At the same time, quantitative, dynamic models, ideally with probability distributions over model topologies and parameters, are highly desirable. Results We present a novel approach to infer such models from data, based on nonlinear differential equations, which we embed into a stochastic Bayesian framework. We thus address both the stochasticity of experimental data and the need for quantitative dynamic models. Furthermore, the Bayesian framework allows it to easily integrate prior knowledge into the inference process. Using stochastic sampling from the Bayes' posterior distribution, our approach can infer different likely network topologies and model parameters along with their respective probabilities from given data. We evaluate our approach on simulated data and the challenge #3 data from the DREAM 2 initiative. On the simulated data, we study effects of different levels of noise and dataset sizes. Results on real data show that the dynamics and main regulatory interactions are correctly reconstructed. Conclusions Our approach combines dynamic modeling using differential equations with a stochastic learning framework, thus bridging the gap between biophysical modeling and stochastic inference approaches. Results show that the method can reap the advantages of both worlds, and allows the reconstruction of biophysically accurate dynamic models from noisy data. In addition, the stochastic learning framework used permits the computation of probability distributions over models and model parameters, which holds interesting prospects for experimental design purposes.

Published
2009
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27. Kinome Profiling of Regulatory T Cells: A Closer Look into a Complex Intracellular Network

Author

Tuettenberg, Andrea, Hahn, Susanne A., Mazur, Johanna, Gerhold-Ay, Aslihan, Scholma, Jetse, Marg, Iris, Ulges, Alexander, Satoh, Kazuki, Bopp, Tobias, Joore, Jos, Jonuleit, Helmut, and Developmental BioEngineering

Subjects
Adult, Proteomics, Cell biology, Blood cells, Blotting, Western, Immunology, 610 Medizin, T cells, lcsh:Medicine, Gene Expression, chemical and pharmacologic phenomena, Lymphocyte Activation, Real-Time Polymerase Chain Reaction, Research and Analysis Methods, T-Lymphocytes, Regulatory, Biochemistry, Spectrum Analysis Techniques, 610 Medical sciences, Cellular types, Genetics, Humans, Post-Translational Modification, Phosphorylation, lcsh:Science, Immune Response, Medicine and health sciences, Biology and life sciences, lcsh:R, Immune cells, Proteins, hemic and immune systems, Regulatory T cells, Flow Cytometry, Enzymes, ErbB Receptors, Cytoskeletal Proteins, Animal cells, Spectrophotometry, Linear Models, Enzymology, White blood cells, lcsh:Q, Cytophotometry, Peptides, Protein Kinases, Signal Transduction, Research Article
Abstract

Regulatory T cells (Treg) are essential for T cell homeostasis and maintenance of peripheral tolerance. They prevent activation of auto-reactive T effector cells (Teff) in the context of autoimmunity and allergy. Otherwise, Treg also inhibit effective immune responses against tumors. Besides a number of Treg-associated molecules such as Foxp3, CTLA-4 or GARP, known to play critical roles in Treg differentiation, activation and function, the involvement of additional regulatory elements is suggested. Herein, kinase activities seem to play an important role in Treg fine tuning. Nevertheless, our knowledge regarding the complex intracellular signaling pathways controlling phenotype and function of Treg is still limited and based on single kinase cascades so far. To gain a more comprehensive insight into the pathways determining Treg function we performed kinome profiling using a phosphorylation-based kinome array in human Treg at different activation stages compared to Teff. Here we have determined intriguing quantitative differences in both populations. Resting and activated Treg showed an altered pattern of CD28-dependent kinases as well as of those involved in cell cycle progression. Additionally, significant up-regulation of distinct kinases such as EGFR or CK2 in activated Treg but not in Teff not only resemble data we obtained in previous studies in the murine system but also suggest that those specific molecular activation patterns can be used for definition of the activation and functional state of human Treg. Taken together, detailed investigation of kinome profiles opens the possibility to identify novel molecular mechanisms for a better understanding of Treg biology but also for development of effective immunotherapies against unwanted T cell responses in allergy, autoimmunity and cancer.

Published
2015

28. Optimization of the Ussing chamber setup with excised rat intestinal segments for dissolution/permeation experiments of poorly soluble drugs

Author

Forner, Kristin, Roos, Carl, Dahlgren, David, Kesisoglou, Filippos, Konerding, Moritz A., Mazur, Johanna, Lennernäs, Hans, Langguth, Peter, Forner, Kristin, Roos, Carl, Dahlgren, David, Kesisoglou, Filippos, Konerding, Moritz A., Mazur, Johanna, Lennernäs, Hans, and Langguth, Peter

Abstract

Context: Prediction of the in vivo absorption of poorly soluble drugs may require simultaneous dissolution/permeation experiments. In vivo predictive media have been modified for permeation experiments with Caco-2 cells, but not for excised rat intestinal segments. Objective: The present study aimed at improving the setup of dissolution/permeation experiments with excised rat intestinal segments by assessing suitable donor and receiver media. Methods: The regional compatibility of rat intestine in Ussing chambers with modified Fasted and Fed State Simulated Intestinal Fluids (Fa/FeSSIFmod) as donor media was evaluated via several parameters that reflect the viability of the excised intestinal segments. Receiver media that establish sink conditions were investigated for their foaming potential and toxicity. Dissolution/permeation experiments with the optimized conditions were then tested for two particle sizes of the BCS class II drug aprepitant. Results: Fa/FeSSIFmod were toxic for excised rat ileal sheets but not duodenal sheets, the compatibility with jejunal segments depended on the bile salt concentration. A non-foaming receiver medium containing bovine serum albumin (BSA) and Antifoam B was nontoxic. With these conditions, the permeation of nanosized aprepitant was higher than of the unmilled drug formulations. Discussion: The compatibility of Fa/FeSSIFmod depends on the excised intestinal region. The chosen conditions enable dissolution/permeation experiments with excised rat duodenal segments. The experiments correctly predicted the superior permeation of nanosized over unmilled aprepitant that is observed in vivo. Conclusion: The optimized setup uses FaSSIF(mod) as donor medium, excised rat duodenal sheets as permeation membrane and a receiver medium containing BSA and Antifoam B.

Published
2017
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29. Comparison of HapMap and 1000 Genomes Reference Panels in a Large-Scale Genome-Wide Association Study

Author

de Vries, Paul S., Sabater-Lleal, Maria, Chasman, Daniel I., Trompet, Stella, Ahluwalia, Tarunveer S., Teumer, Alexander, Kleber, Marcus E., Chen, Ming-Huei, Wang, Jie Jin, Attia, John R., Marioni, Riccardo E., Steri, Maristella, Weng, Lu-Chen, Pool, Rene, Grossmann, Vera, Brody, Jennifer A., Venturini, Cristina, Tanaka, Toshiko, Rose, Lynda M., Oldmeadow, Christopher, Mazur, Johanna, Basu, Saonli, Frånberg, Mattias, Yang, Qiong, Ligthart, Symen, Hottenga, Jouke J., Rumley, Ann, Mulas, Antonella, de Craen, Anton J. M., Grotevendt, Anne, Taylor, Kent D., Delgado, Graciela E., Kifley, Annette, Lopez, Lorna M., Berentzen, Tina L., Mangino, Massimo, Bandinelli, Stefania, Morrison, Alanna C., Hamsten, Anders, Tofler, Geoffrey, de Maat, Moniek P. M., Draisma, Harmen H. M., Lowe, Gordon D., Zoledziewska, Magdalena, Sattar, Naveed, Lackner, Karl J., Voelker, Uwe, McKnight, Barbara, Huang, Jie, Holliday, Elizabeth G., McEvoy, Mark A., Starr, John M., Hysi, Pirro G., Hernandez, Dena G., Guan, Weihua, Rivadeneira, Fernando, McArdle, Wendy L., Slagboom, P. Eline, Zeller, Tanja, Psaty, Bruce M., Uitterlinden, Andre G., de Geus, Eco J. C., Stott, David J., Binder, Harald, Hofman, Albert, Franco, Oscar H., Rotter, Jerome I., Ferrucci, Luigi, Spector, Tim D., Deary, Ian J., Maerz, Winfried, Greinacher, Andreas, Wild, Philipp S., Cucca, Francesco, Boomsma, Dorret I., Watkins, Hugh, Tang, Weihong, Ridker, Paul M., Jukema, Jan W., Scott, Rodney J., Mitchell, Paul, Hansen, Torben, O'Donnell, Christopher J., Smith, Nicholas L., Strachan, David P., Dehghan, Abbas, de Vries, Paul S., Sabater-Lleal, Maria, Chasman, Daniel I., Trompet, Stella, Ahluwalia, Tarunveer S., Teumer, Alexander, Kleber, Marcus E., Chen, Ming-Huei, Wang, Jie Jin, Attia, John R., Marioni, Riccardo E., Steri, Maristella, Weng, Lu-Chen, Pool, Rene, Grossmann, Vera, Brody, Jennifer A., Venturini, Cristina, Tanaka, Toshiko, Rose, Lynda M., Oldmeadow, Christopher, Mazur, Johanna, Basu, Saonli, Frånberg, Mattias, Yang, Qiong, Ligthart, Symen, Hottenga, Jouke J., Rumley, Ann, Mulas, Antonella, de Craen, Anton J. M., Grotevendt, Anne, Taylor, Kent D., Delgado, Graciela E., Kifley, Annette, Lopez, Lorna M., Berentzen, Tina L., Mangino, Massimo, Bandinelli, Stefania, Morrison, Alanna C., Hamsten, Anders, Tofler, Geoffrey, de Maat, Moniek P. M., Draisma, Harmen H. M., Lowe, Gordon D., Zoledziewska, Magdalena, Sattar, Naveed, Lackner, Karl J., Voelker, Uwe, McKnight, Barbara, Huang, Jie, Holliday, Elizabeth G., McEvoy, Mark A., Starr, John M., Hysi, Pirro G., Hernandez, Dena G., Guan, Weihua, Rivadeneira, Fernando, McArdle, Wendy L., Slagboom, P. Eline, Zeller, Tanja, Psaty, Bruce M., Uitterlinden, Andre G., de Geus, Eco J. C., Stott, David J., Binder, Harald, Hofman, Albert, Franco, Oscar H., Rotter, Jerome I., Ferrucci, Luigi, Spector, Tim D., Deary, Ian J., Maerz, Winfried, Greinacher, Andreas, Wild, Philipp S., Cucca, Francesco, Boomsma, Dorret I., Watkins, Hugh, Tang, Weihong, Ridker, Paul M., Jukema, Jan W., Scott, Rodney J., Mitchell, Paul, Hansen, Torben, O'Donnell, Christopher J., Smith, Nicholas L., Strachan, David P., and Dehghan, Abbas

Abstract

An increasing number of genome-wide association (GWA) studies are now using the higher resolution 1000 Genomes Project reference panel (1000G) for imputation, with the expectation that 1000G imputation will lead to the discovery of additional associated loci when compared to HapMap imputation. In order to assess the improvement of 1000G over HapMap imputation in identifying associated loci, we compared the results of GWA studies of circulating fibrinogen based on the two reference panels. Using both HapMap and 1000G imputation we performed a meta-analysis of 22 studies comprising the same 91,953 individuals. We identified six additional signals using 1000G imputation, while 29 loci were associated using both HapMap and 1000G imputation. One locus identified using HapMap imputation was not significant using 1000G imputation. The genome-wide significance threshold of 5x10(-8) is based on the number of independent statistical tests using HapMap imputation, and 1000G imputation may lead to further independent tests that should be corrected for. When using a stricter Bonferroni correction for the 1000G GWA study (P-value < 2.5x10(-8)), the number of loci significant only using HapMap imputation increased to 4 while the number of loci significant only using 1000G decreased to 5. In conclusion, 1000G imputation enabled the identification of 20% more loci than HapMap imputation, although the advantage of 1000G imputation became less clear when a stricter Bonferroni correction was used. More generally, our results provide insights that are applicable to the implementation of other dense reference panels that are under development.

Published
2017
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30. Comparison of HapMap and 1000 Genomes Reference Panels in a Large-Scale Genome-Wide Association Study

Author

Yao, Yong-Gang, de Vries, Paul S., Sabater-Lleal, Maria, Chasman, Daniel I., Trompet, Stella, Ahluwalia, Tarunveer S., Teumer, Alexander, Kleber, Marcus E., Chen, Ming-Huei, Wang, Jie Jin, Attia, John R., Marioni, Riccardo E., Steri, Maristella, Weng, Lu-Chen, Pool, Rene, Grossmann, Vera, Brody, Jennifer A., Venturini, Cristina, Tanaka, Toshiko, Rose, Lynda M., Oldmeadow, Christopher, Mazur, Johanna, Basu, Saonli, Frånberg, Mattias, Yang, Qiong, Ligthart, Symen, Hottenga, Jouke J., Rumley, Ann, Mulas, Antonella, de Craen, Anton J. M., Grotevendt, Anne, Taylor, Kent D., Delgado, Graciela E., Kifley, Annette, Lopez, Lorna M., Berentzen, Tina L., Mangino, Massimo, Bandinelli, Stefania, Morrison, Alanna C., Hamsten, Anders, Tofler, Geoffrey, de Maat, Moniek P. M., Draisma, Harmen H. M., Lowe, Gordon D., Zoledziewska, Magdalena, Sattar, Naveed, Lackner, Karl J., Völker, Uwe, McKnight, Barbara, Huang, Jie, Holliday, Elizabeth G., McEvoy, Mark A., Starr, John M., Hysi, Pirro G., Hernandez, Dena G., Guan, Weihua, Rivadeneira, Fernando, McArdle, Wendy L., Slagboom, P. Eline, Zeller, Tanja, Psaty, Bruce M., Uitterlinden, André G., de Geus, Eco J. C., Stott, David J., Binder, Harald, Hofman, Albert, Franco, Oscar H., Rotter, Jerome I., Ferrucci, Luigi, Spector, Tim D., Deary, Ian J., März, Winfried, Greinacher, Andreas, Wild, Philipp S., Cucca, Francesco, Boomsma, Dorret I., Watkins, Hugh, Tang, Weihong, Ridker, Paul M., Jukema, Jan W., Scott, Rodney J., Mitchell, Paul, Hansen, Torben, O'Donnell, Christopher J., Smith, Nicholas L., Strachan, David P., Dehghan, Abbas, Yao, Yong-Gang, de Vries, Paul S., Sabater-Lleal, Maria, Chasman, Daniel I., Trompet, Stella, Ahluwalia, Tarunveer S., Teumer, Alexander, Kleber, Marcus E., Chen, Ming-Huei, Wang, Jie Jin, Attia, John R., Marioni, Riccardo E., Steri, Maristella, Weng, Lu-Chen, Pool, Rene, Grossmann, Vera, Brody, Jennifer A., Venturini, Cristina, Tanaka, Toshiko, Rose, Lynda M., Oldmeadow, Christopher, Mazur, Johanna, Basu, Saonli, Frånberg, Mattias, Yang, Qiong, Ligthart, Symen, Hottenga, Jouke J., Rumley, Ann, Mulas, Antonella, de Craen, Anton J. M., Grotevendt, Anne, Taylor, Kent D., Delgado, Graciela E., Kifley, Annette, Lopez, Lorna M., Berentzen, Tina L., Mangino, Massimo, Bandinelli, Stefania, Morrison, Alanna C., Hamsten, Anders, Tofler, Geoffrey, de Maat, Moniek P. M., Draisma, Harmen H. M., Lowe, Gordon D., Zoledziewska, Magdalena, Sattar, Naveed, Lackner, Karl J., Völker, Uwe, McKnight, Barbara, Huang, Jie, Holliday, Elizabeth G., McEvoy, Mark A., Starr, John M., Hysi, Pirro G., Hernandez, Dena G., Guan, Weihua, Rivadeneira, Fernando, McArdle, Wendy L., Slagboom, P. Eline, Zeller, Tanja, Psaty, Bruce M., Uitterlinden, André G., de Geus, Eco J. C., Stott, David J., Binder, Harald, Hofman, Albert, Franco, Oscar H., Rotter, Jerome I., Ferrucci, Luigi, Spector, Tim D., Deary, Ian J., März, Winfried, Greinacher, Andreas, Wild, Philipp S., Cucca, Francesco, Boomsma, Dorret I., Watkins, Hugh, Tang, Weihong, Ridker, Paul M., Jukema, Jan W., Scott, Rodney J., Mitchell, Paul, Hansen, Torben, O'Donnell, Christopher J., Smith, Nicholas L., Strachan, David P., and Dehghan, Abbas

Abstract

An increasing number of genome-wide association (GWA) studies are now using the higher resolution 1000 Genomes Project reference panel (1000G) for imputation, with the expectation that 1000G imputation will lead to the discovery of additional associated loci when compared to HapMap imputation. In order to assess the improvement of 1000G over HapMap imputation in identifying associated loci, we compared the results of GWA studies of circulating fibrinogen based on the two reference panels. Using both HapMap and 1000G imputation we performed a meta-analysis of 22 studies comprising the same 91,953 individuals. We identified six additional signals using 1000G imputation, while 29 loci were associated using both HapMap and 1000G imputation. One locus identified using HapMap imputation was not significant using 1000G imputation. The genome-wide significance threshold of 5×10−8 is based on the number of independent statistical tests using HapMap imputation, and 1000G imputation may lead to further independent tests that should be corrected for. When using a stricter Bonferroni correction for the 1000G GWA study (P-value < 2.5×10−8), the number of loci significant only using HapMap imputation increased to 4 while the number of loci significant only using 1000G decreased to 5. In conclusion, 1000G imputation enabled the identification of 20% more loci than HapMap imputation, although the advantage of 1000G imputation became less clear when a stricter Bonferroni correction was used. More generally, our results provide insights that are applicable to the implementation of other dense reference panels that are under development.

Published
2017

32. Meta-analysis of gene–environment-wide association scans accounting for education level identifies additional loci for refractive error

Author

90812793, Fan, Qiao, Verhoeven, Virginie J. M., Wojciechowski, Robert, Barathi, Veluchamy A., Hysi, Pirro G., Guggenheim, Jeremy A., Höhn, René, Vitart, Veronique, Khawaja, Anthony P., Yamashiro, Kenji, Hosseini, S Mohsen, Lehtimäki, Terho, Lu, Yi, Haller, Toomas, Xie, Jing, Delcourt, Cécile, Pirastu, Mario, Wedenoja, Juho, Gharahkhani, Puya, Venturini, Cristina, Miyake, Masahiro, Hewitt, Alex W., Guo, Xiaobo, Mazur, Johanna, Huffman, Jenifer E., Williams, Katie M., Polasek, Ozren, Campbell, Harry, Rudan, Igor, Vatavuk, Zoran, Wilson, James F., Joshi, Peter K., McMahon, George, St Pourcain, Beate, Evans, David M., Simpson, Claire L., Schwantes-An, Tae-Hwi, Igo, Robert P., Mirshahi, Alireza, Cougnard-Gregoire, Audrey, Bellenguez, Céline, Blettner, Maria, Raitakari, Olli, Kähönen, Mika, Seppälä, Ilkka, Zeller, Tanja, Meitinger, Thomas, Ried, Janina S., Gieger, Christian, Portas, Laura, van Leeuwen, Elisabeth M., Amin, Najaf, Uitterlinden, André G., Rivadeneira, Fernando, Hofman, Albert, Vingerling, Johannes R., Wang, Ya Xing, Wang, Xu, Tai-Hui Boh, Eileen, Ikram, M. Kamran, Sabanayagam, Charumathi, Gupta, Preeti, Tan, Vincent, Zhou, Lei, Ho, Candice E. H., Lim, Wan’e, Beuerman, Roger W., Siantar, Rosalynn, Tai, E-Shyong, Vithana, Eranga, Mihailov, Evelin, Khor, Chiea-Chuen, Hayward, Caroline, Luben, Robert N., Foster, Paul J., Klein, Barbara E. K., Klein, Ronald, Wong, Hoi-Suen, Mitchell, Paul, Metspalu, Andres, Aung, Tin, Young, Terri L., He, Mingguang, Pärssinen, Olavi, van Duijn, Cornelia M., Jin Wang, Jie, Williams, Cathy, Jonas, Jost B., Teo, Yik-Ying, Mackey, David A., Oexle, Konrad, Yoshimura, Nagahisa, Paterson, Andrew D., Pfeiffer, Norbert, Wong, Tien-Yin, Baird, Paul N., Stambolian, Dwight, Wilson, Joan E. Bailey, Cheng, Ching-Yu, Hammond, Christopher J., Klaver, Caroline C. W., Saw, Seang-Mei, 90812793, Fan, Qiao, Verhoeven, Virginie J. M., Wojciechowski, Robert, Barathi, Veluchamy A., Hysi, Pirro G., Guggenheim, Jeremy A., Höhn, René, Vitart, Veronique, Khawaja, Anthony P., Yamashiro, Kenji, Hosseini, S Mohsen, Lehtimäki, Terho, Lu, Yi, Haller, Toomas, Xie, Jing, Delcourt, Cécile, Pirastu, Mario, Wedenoja, Juho, Gharahkhani, Puya, Venturini, Cristina, Miyake, Masahiro, Hewitt, Alex W., Guo, Xiaobo, Mazur, Johanna, Huffman, Jenifer E., Williams, Katie M., Polasek, Ozren, Campbell, Harry, Rudan, Igor, Vatavuk, Zoran, Wilson, James F., Joshi, Peter K., McMahon, George, St Pourcain, Beate, Evans, David M., Simpson, Claire L., Schwantes-An, Tae-Hwi, Igo, Robert P., Mirshahi, Alireza, Cougnard-Gregoire, Audrey, Bellenguez, Céline, Blettner, Maria, Raitakari, Olli, Kähönen, Mika, Seppälä, Ilkka, Zeller, Tanja, Meitinger, Thomas, Ried, Janina S., Gieger, Christian, Portas, Laura, van Leeuwen, Elisabeth M., Amin, Najaf, Uitterlinden, André G., Rivadeneira, Fernando, Hofman, Albert, Vingerling, Johannes R., Wang, Ya Xing, Wang, Xu, Tai-Hui Boh, Eileen, Ikram, M. Kamran, Sabanayagam, Charumathi, Gupta, Preeti, Tan, Vincent, Zhou, Lei, Ho, Candice E. H., Lim, Wan’e, Beuerman, Roger W., Siantar, Rosalynn, Tai, E-Shyong, Vithana, Eranga, Mihailov, Evelin, Khor, Chiea-Chuen, Hayward, Caroline, Luben, Robert N., Foster, Paul J., Klein, Barbara E. K., Klein, Ronald, Wong, Hoi-Suen, Mitchell, Paul, Metspalu, Andres, Aung, Tin, Young, Terri L., He, Mingguang, Pärssinen, Olavi, van Duijn, Cornelia M., Jin Wang, Jie, Williams, Cathy, Jonas, Jost B., Teo, Yik-Ying, Mackey, David A., Oexle, Konrad, Yoshimura, Nagahisa, Paterson, Andrew D., Pfeiffer, Norbert, Wong, Tien-Yin, Baird, Paul N., Stambolian, Dwight, Wilson, Joan E. Bailey, Cheng, Ching-Yu, Hammond, Christopher J., Klaver, Caroline C. W., and Saw, Seang-Mei

Abstract

Myopia is the most common human eye disorder and it results from complex genetic and environmental causes. The rapidly increasing prevalence of myopia poses a major public health challenge. Here, the CREAM consortium performs a joint meta-analysis to test single-nucleotide polymorphism (SNP) main effects and SNP × education interaction effects on refractive error in 40, 036 adults from 25 studies of European ancestry and 10, 315 adults from 9 studies of Asian ancestry. In European ancestry individuals, we identify six novel loci (FAM150B-ACP1, LINC00340, FBN1, DIS3L-MAP2K1, ARID2-SNAT1 and SLC14A2) associated with refractive error. In Asian populations, three genome-wide significant loci AREG, GABRR1 and PDE10A also exhibit strong interactions with education (P<8.5 × 10−5), whereas the interactions are less evident in Europeans. The discovery of these loci represents an important advance in understanding how gene and environment interactions contribute to the heterogeneity of myopia.

Published
2016

33. Systemic PaO2 oscillations cause mild brain injury in a pig model

Author

Klein, Klaus U, Johannes, Amelie, Brückner, Melanie, Thomas, Rainer, Matthews, Stephan, Frauenknecht, Katrin, Leukel, Petra, Mazur, Johanna, Poplawski, Alicia, Muellenbach, Ralf, Sommer, Clemens J, Thal, Serge C, Engelhard, Kristin, Klein, Klaus U, Johannes, Amelie, Brückner, Melanie, Thomas, Rainer, Matthews, Stephan, Frauenknecht, Katrin, Leukel, Petra, Mazur, Johanna, Poplawski, Alicia, Muellenbach, Ralf, Sommer, Clemens J, Thal, Serge C, and Engelhard, Kristin

Abstract

OBJECTIVE: Systemic PaO2 oscillations occur during cyclic recruitment and derecruitment of atelectasis in acute respiratory failure and might harm brain tissue integrity. DESIGN: Controlled animal study. SETTING: University research laboratory. SUBJECTS: Adult anesthetized pigs. INTERVENTIONS: Pigs were randomized to a control group (anesthesia and extracorporeal circulation for 20 hr with constant PaO2, n = 10) or an oscillation group (anesthesia and extracorporeal circulation for 20 hr with artificial PaO2 oscillations [3 cycles min⁻¹], n = 10). Five additional animals served as native group (n = 5). MEASUREMENTS AND MAIN RESULTS: Outcome following exposure to artificial PaO2 oscillations compared with constant PaO2 levels was measured using 1) immunohistochemistry, 2) real-time polymerase chain reaction for inflammatory markers, 3) receptor autoradiography, and 4) transcriptome analysis in the hippocampus. Our study shows that PaO2 oscillations are transmitted to brain tissue as detected by novel ultrarapid oxygen sensing technology. PaO2 oscillations cause significant decrease in NISSL-stained neurons (p < 0.05) and induce inflammation (p < 0.05) in the hippocampus and a shift of the balance of hippocampal neurotransmitter receptor densities toward inhibition (p < 0.05). A pathway analysis suggests that cerebral immune and acute-phase response may play a role in mediating PaO2 oscillation-induced brain injury. CONCLUSIONS: Artificial PaO2 oscillations cause mild brain injury mediated by inflammatory pathways. Although artificial PaO2 oscillations and endogenous PaO2 oscillations in lung-diseased patients have different origins, it is likely that they share the same noxious effect on the brain. Therefore, PaO2 oscillations might represent a newly detected pathway potentially contributing to the crosstalk between acute lung and remote brain injury.

Published
2016

35. Systemic PaO2 Oscillations Cause Mild Brain Injury in a Pig Model

Author

Klein, Klaus U., primary, Johannes, Amelie, additional, Brückner, Melanie, additional, Thomas, Rainer, additional, Matthews, Stephan, additional, Frauenknecht, Katrin, additional, Leukel, Petra, additional, Mazur, Johanna, additional, Poplawski, Alicia, additional, Muellenbach, Ralf, additional, Sommer, Clemens J., additional, Thal, Serge C., additional, and Engelhard, Kristin, additional

Published
2016
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36. Gwa'sala-'Nakwaxda'xw Nations Community Organizing: Stories and Lessons Learned (Report on A Collaborative Community Engagement Process)

Author

Mazur, Johanna

Abstract

The collaborative community-based research project presented in this report emerged out of a research partnership initiated by the Gwa’sala-’Nakwaxda’xw Nations on the north end of Vancouver Island, British Columbia, with the School of Community and Regional Planning at the University of British Columbia in Vancouver, Canada. This report discusses the community engagement process and research principles of this project, through my experience and worldview, with additional reflections shared by some of the co-researchers and participants through follow-up interviews. The project was about honouring, recording and learning from the ways the Gwa’sala- ’Nakwaxda’xw Nations are supporting each other and building community for their children and future generations. I collaborated with members of the Gwa’sala-’Nakwaxda’xw Nations, to create a booklet of stories about grassroots community organizing and collaborative planning, entitled Gwa’sala-’Nakwaxda’xw Community Organizing: Stories and Lessons Learned, designed as an appendix to the Gwa’sala-’Nakwaxda’xw Comprehensive Community Plan. As coresearchers, we hosted a series of focus groups for community members to share their experiences, values, inspirations and reflections connected to the planning, organizing, performing and volunteering they do for their community. The booklet of stories is a compilation of what people shared at the focus groups and photos we gathered to highlight people’s words. The stories are included in this report with permission from the Gwa’sala- ’Nakwaxda’xw Nations.

Published
2013
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37. Bayesian Inference of Gene Regulatory Networks : From Parameter Estimation to Experimental Design

Author

Mazur, Johanna

Subjects
510 Mathematics
Abstract

To learn the structure of gene regulatory networks is an interesting and important topic in systems biology. This structure could be used to specify key regulators and this knowledge may be used to develop new drugs which affect the expression of these regulators. However, the inference of gene regulatory networks, especially from time-series data is a challenging task. This is due to the limited amount of given data which additionally contain a lot of noise. These data cause from the technical point of view for the parameter estimation procedure problems like the non-identifiability and sloppiness of parameters. To address these difficulties, in these thesis new methods for both, the parameter estimation task and the experimental design for gene regulatory networks, are developed for a non-linear ordinary differential equations model, which use a Bayesian procedure and generate samples of the underlying distribution of the parameters. These distributions are of high interest, since they do not provide only one network structure but give all network structures that are consistent with the given data. And all of these structures can then be examined in more detail. The proposed method for Bayesian parameter estimation uses smoothing splines to circumvent the numerical integration of the underlying system of ordinary differential equations, which is usually used for parameter estimation procedures in systems of ordinary differential equations. An iterative Hybrid Monte Carlo and Metropolis-Hastings algorithm is used to sample the model parameters and the smoothing factor. This new method is applied to simulated data, which shows that it is able to reconstruct the topology of the underlying gene regulatory network with high accuracy. The approach was also applied to real experimental data, a synthetic designed 5-gene network (the DREAM 2 Challenge #3 data) and outperforms other methods. For the Bayesian experimental design step, a full Bayesian approach was used which does not use any parametric assumption of the posterior distribution, nor linearizes around a point estimate. To make the full Bayesian approach computationally manageable, maximum entropy sampling is used together with a population-based Markov chain Monte Carlo algorithm. The approach was applied to simulated and real experimental data, the DREAM 2 Challenge #3 data, and outperforms the usage of random experiments and a classical experimental design method.

Published
2012

40. A meta-analysis of 120 246 individuals identifies 18 new loci for fibrinogen concentration

Author

de Vries, Paul S., Chasman, Daniel I., Sabater-Lleal, Maria, Chen, Ming-Huei, Huffman, Jennifer E., Steri, Maristella, Tang, Weihong, Teumer, Alexander, Marioni, Riccardo E., Grossmann, Vera, Hottenga, Jouke J., Trompet, Stella, Müller-Nurasyid, Martina, Zhao, Jing Hua, Brody, Jennifer A., Kleber, Marcus E., Guo, Xiuqing, Wang, Jie Jin, Auer, Paul L., Attia, John R., Yanek, Lisa R., Ahluwalia, Tarunveer S., Lahti, Jari, Venturini, Cristina, Tanaka, Toshiko, Bielak, Lawrence F., Joshi, Peter K., Rocanin-Arjo, Ares, Kolcic, Ivana, Navarro, Pau, Rose, Lynda M., Oldmeadow, Christopher, Riess, Helene, Mazur, Johanna, Basu, Saonli, Goel, Anuj, Yang, Qiong, Ghanbari, Mohsen, Willemsen, Gonneke, Rumley, Ann, Fiorillo, Edoardo, de Craen, Anton J. M., Grotevendt, Anne, Scott, Robert, Taylor, Kent D., Delgado, Graciela E., Yao, Jie, Kifley, Annette, Kooperberg, Charles, Qayyum, Rehan, Lopez, Lorna M., Berentzen, Tina L., Räikkönen, Katri, Mangino, Massimo, Bandinelli, Stefania, Peyser, Patricia A., Wild, Sarah, Trégouët, David-Alexandre, Wright, Alan F., Marten, Jonathan, Zemunik, Tatijana, Morrison, Alanna C., Sennblad, Bengt, Tofler, Geoffrey, de Maat, Moniek P. M., de Geus, Eco J. C., Lowe, Gordon D., Zoledziewska, Magdalena, Sattar, Naveed, Binder, Harald, Völker, Uwe, Waldenberger, Melanie, Khaw, Kay-Tee, Mcknight, Barbara, Huang, Jie, Jenny, Nancy S., Holliday, Elizabeth G., Qi, Lihong, Mcevoy, Mark G., Becker, Diane M., Starr, John M., Sarin, Antti-Pekka, Hysi, Pirro G., Hernandez, Dena G., Jhun, Min A., Campbell, Harry, Hamsten, Anders, Rivadeneira, Fernando, Mcardle, Wendy L., Slagboom, P. Eline, Zeller, Tanja, Koenig, Wolfgang, Psaty, Bruce M., Haritunians, Talin, Liu, Jingmin, Palotie, Aarno, Uitterlinden, André G., Stott, David J., Hofman, Albert, Franco, Oscar H., Polasek, Ozren, Rudan, Igor, Morange, Pierre-Emmanuel, Wilson, James F., Kardia, Sharon L. R., Ferrucci, Luigi, Spector, Tim D., Eriksson, Johan G., Hansen, Torben, Deary, Ian J., Becker, Lewis C., Scott, Rodney J., Mitchell, Paul, März, Winfried, Wareham, Nick J., Peters, Annette, Greinacher, Andreas, Wild, Philipp S., Jukema, J. Wouter, Boomsma, Dorret I., Hayward, Caroline, Cucca, Francesco, Tracy, Russell, Watkins, Hugh, Reiner, Alex P., Folsom, Aaron R., Ridker, Paul M., O'Donnell, Christopher J., Smith, Nicholas L., Strachan, David P., Dehghan, Abbas, de Vries, Paul S., Chasman, Daniel I., Sabater-Lleal, Maria, Chen, Ming-Huei, Huffman, Jennifer E., Steri, Maristella, Tang, Weihong, Teumer, Alexander, Marioni, Riccardo E., Grossmann, Vera, Hottenga, Jouke J., Trompet, Stella, Müller-Nurasyid, Martina, Zhao, Jing Hua, Brody, Jennifer A., Kleber, Marcus E., Guo, Xiuqing, Wang, Jie Jin, Auer, Paul L., Attia, John R., Yanek, Lisa R., Ahluwalia, Tarunveer S., Lahti, Jari, Venturini, Cristina, Tanaka, Toshiko, Bielak, Lawrence F., Joshi, Peter K., Rocanin-Arjo, Ares, Kolcic, Ivana, Navarro, Pau, Rose, Lynda M., Oldmeadow, Christopher, Riess, Helene, Mazur, Johanna, Basu, Saonli, Goel, Anuj, Yang, Qiong, Ghanbari, Mohsen, Willemsen, Gonneke, Rumley, Ann, Fiorillo, Edoardo, de Craen, Anton J. M., Grotevendt, Anne, Scott, Robert, Taylor, Kent D., Delgado, Graciela E., Yao, Jie, Kifley, Annette, Kooperberg, Charles, Qayyum, Rehan, Lopez, Lorna M., Berentzen, Tina L., Räikkönen, Katri, Mangino, Massimo, Bandinelli, Stefania, Peyser, Patricia A., Wild, Sarah, Trégouët, David-Alexandre, Wright, Alan F., Marten, Jonathan, Zemunik, Tatijana, Morrison, Alanna C., Sennblad, Bengt, Tofler, Geoffrey, de Maat, Moniek P. M., de Geus, Eco J. C., Lowe, Gordon D., Zoledziewska, Magdalena, Sattar, Naveed, Binder, Harald, Völker, Uwe, Waldenberger, Melanie, Khaw, Kay-Tee, Mcknight, Barbara, Huang, Jie, Jenny, Nancy S., Holliday, Elizabeth G., Qi, Lihong, Mcevoy, Mark G., Becker, Diane M., Starr, John M., Sarin, Antti-Pekka, Hysi, Pirro G., Hernandez, Dena G., Jhun, Min A., Campbell, Harry, Hamsten, Anders, Rivadeneira, Fernando, Mcardle, Wendy L., Slagboom, P. Eline, Zeller, Tanja, Koenig, Wolfgang, Psaty, Bruce M., Haritunians, Talin, Liu, Jingmin, Palotie, Aarno, Uitterlinden, André G., Stott, David J., Hofman, Albert, Franco, Oscar H., Polasek, Ozren, Rudan, Igor, Morange, Pierre-Emmanuel, Wilson, James F., Kardia, Sharon L. R., Ferrucci, Luigi, Spector, Tim D., Eriksson, Johan G., Hansen, Torben, Deary, Ian J., Becker, Lewis C., Scott, Rodney J., Mitchell, Paul, März, Winfried, Wareham, Nick J., Peters, Annette, Greinacher, Andreas, Wild, Philipp S., Jukema, J. Wouter, Boomsma, Dorret I., Hayward, Caroline, Cucca, Francesco, Tracy, Russell, Watkins, Hugh, Reiner, Alex P., Folsom, Aaron R., Ridker, Paul M., O'Donnell, Christopher J., Smith, Nicholas L., Strachan, David P., and Dehghan, Abbas

Abstract

Genome-wide association studies have previously identified 23 genetic loci associated with circulating fibrinogen concentration. These studies used HapMap imputation and did not examine the X-chromosome. 1000 Genomes imputation provides better coverage of uncommon variants, and includes indels. We conducted a genome-wide association analysis of 34 studies imputed to the 1000 Genomes Project reference panel and including ∼120 000 participants of European ancestry (95 806 participants with data on the X-chromosome). Approximately 10.7 million single-nucleotide polymorphisms and 1.2 million indels were examined. We identified 41 genome-wide significant fibrinogen loci; of which, 18 were newly identified. There were no genome-wide significant signals on the X-chromosome. The lead variants of five significant loci were indels. We further identified six additional independent signals, including three rare variants, at two previously characterized loci: FGB and IRF1. Together the 41 loci explain 3% of the variance in plasma fibrinogen concentration.

Published
2015

41. A meta-analysis of 120 246 individuals identifies 18 new loci for fibrinogen concentration

Author

de Vries, Paul S., primary, Chasman, Daniel I., additional, Sabater-Lleal, Maria, additional, Chen, Ming-Huei, additional, Huffman, Jennifer E., additional, Steri, Maristella, additional, Tang, Weihong, additional, Teumer, Alexander, additional, Marioni, Riccardo E., additional, Grossmann, Vera, additional, Hottenga, Jouke J., additional, Trompet, Stella, additional, Müller-Nurasyid, Martina, additional, Zhao, Jing Hua, additional, Brody, Jennifer A., additional, Kleber, Marcus E., additional, Guo, Xiuqing, additional, Wang, Jie Jin, additional, Auer, Paul L., additional, Attia, John R., additional, Yanek, Lisa R., additional, Ahluwalia, Tarunveer S., additional, Lahti, Jari, additional, Venturini, Cristina, additional, Tanaka, Toshiko, additional, Bielak, Lawrence F., additional, Joshi, Peter K., additional, Rocanin-Arjo, Ares, additional, Kolcic, Ivana, additional, Navarro, Pau, additional, Rose, Lynda M., additional, Oldmeadow, Christopher, additional, Riess, Helene, additional, Mazur, Johanna, additional, Basu, Saonli, additional, Goel, Anuj, additional, Yang, Qiong, additional, Ghanbari, Mohsen, additional, Willemsen, Gonneke, additional, Rumley, Ann, additional, Fiorillo, Edoardo, additional, de Craen, Anton J. M., additional, Grotevendt, Anne, additional, Scott, Robert, additional, Taylor, Kent D., additional, Delgado, Graciela E., additional, Yao, Jie, additional, Kifley, Annette, additional, Kooperberg, Charles, additional, Qayyum, Rehan, additional, Lopez, Lorna M., additional, Berentzen, Tina L., additional, Räikkönen, Katri, additional, Mangino, Massimo, additional, Bandinelli, Stefania, additional, Peyser, Patricia A., additional, Wild, Sarah, additional, Trégouët, David-Alexandre, additional, Wright, Alan F., additional, Marten, Jonathan, additional, Zemunik, Tatijana, additional, Morrison, Alanna C., additional, Sennblad, Bengt, additional, Tofler, Geoffrey, additional, de Maat, Moniek P. M., additional, de Geus, Eco J. C., additional, Lowe, Gordon D., additional, Zoledziewska, Magdalena, additional, Sattar, Naveed, additional, Binder, Harald, additional, Völker, Uwe, additional, Waldenberger, Melanie, additional, Khaw, Kay-Tee, additional, Mcknight, Barbara, additional, Huang, Jie, additional, Jenny, Nancy S., additional, Holliday, Elizabeth G., additional, Qi, Lihong, additional, Mcevoy, Mark G., additional, Becker, Diane M., additional, Starr, John M., additional, Sarin, Antti-Pekka, additional, Hysi, Pirro G., additional, Hernandez, Dena G., additional, Jhun, Min A., additional, Campbell, Harry, additional, Hamsten, Anders, additional, Rivadeneira, Fernando, additional, Mcardle, Wendy L., additional, Slagboom, P. Eline, additional, Zeller, Tanja, additional, Koenig, Wolfgang, additional, Psaty, Bruce M., additional, Haritunians, Talin, additional, Liu, Jingmin, additional, Palotie, Aarno, additional, Uitterlinden, André G., additional, Stott, David J., additional, Hofman, Albert, additional, Franco, Oscar H., additional, Polasek, Ozren, additional, Rudan, Igor, additional, Morange, Pierre-Emmanuel, additional, Wilson, James F., additional, Kardia, Sharon L. R., additional, Ferrucci, Luigi, additional, Spector, Tim D., additional, Eriksson, Johan G., additional, Hansen, Torben, additional, Deary, Ian J., additional, Becker, Lewis C., additional, Scott, Rodney J., additional, Mitchell, Paul, additional, März, Winfried, additional, Wareham, Nick J., additional, Peters, Annette, additional, Greinacher, Andreas, additional, Wild, Philipp S., additional, Jukema, J. Wouter, additional, Boomsma, Dorret I., additional, Hayward, Caroline, additional, Cucca, Francesco, additional, Tracy, Russell, additional, Watkins, Hugh, additional, Reiner, Alex P., additional, Folsom, Aaron R., additional, Ridker, Paul M., additional, O'Donnell, Christopher J., additional, Smith, Nicholas L., additional, Strachan, David P., additional, and Dehghan, Abbas, additional

Published
2015
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43. Haplotype reference consortium panel: Practical implications of imputations with large reference panels.

Author

Iglesias, Adriana I., der Lee, Sven J., Bonnemaijer, Pieter W.M., Höhn, René, Nag, Abhishek, Gharahkhani, Puya, Khawaja, Anthony P., Broer, Linda, Foster, Paul J., Hammond, Christopher J., Hysi, Pirro G., Leeuwen, Elisabeth M., MacGregor, Stuart, Mackey, David A., Mazur, Johanna, Nickels, Stefan, Uitterlinden, André G., Klaver, Caroline C.W., Amin, Najaf, and Duijn, Cornelia M.

Abstract

Recently, the Haplotype Reference Consortium (HRC) released a large imputation panel that allows more accurate imputation of genetic variants. In this study, we compared a set of directly assayed common and rare variants from an exome array to imputed genotypes, that is, 1000 genomes project (1000GP) and HRC. We showed that imputation using the HRC panel improved the concordance between assayed and imputed genotypes at common, and especially, low-frequency variants. Furthermore, we performed a genome-wide association meta-analysis of vertical cup-disc ratio, a highly heritable endophenotype of glaucoma, in four cohorts using 1000GP and HRC imputations. We compared the results of the meta-analysis using 1000GP to the meta-analysis results using HRC. Overall, we found that using HRC imputation significantly improved P values ( P = 3.07 × 10−61), particularly for suggestive variants. Both meta-analyses were performed in the same sample size, yet we found eight genome-wide significant loci in the HRC-based meta-analysis versus seven genome-wide significant loci in the 1000GP-based meta-analysis. This study provides supporting evidence of the new avenues for gene discovery and fine mapping that the HRC imputation panel offers. [ABSTRACT FROM AUTHOR]

Published
2017
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44. Systematically evaluating interfaces for RNA-seq analysis from a life scientist perspective.

Author

Poplawski, Alicia, Marini, Federico, Hess, Moritz, Zeller, Tanja, Mazur, Johanna, and Binder, Harald

Subjects
NUCLEOTIDE sequence, GENE expression, LIFE sciences, DATA analysis, NUCLEIC acids
Abstract

RNA-sequencing (RNA-seq) has become an established way for measuring gene expression in model organisms and humans. While methods development for refining the corresponding data processing and analysis pipeline is ongoing, protocols for typical steps have been proposed and are widely used. Several user interfaces have been developed for making such analysis steps accessible to life scientists without extensive knowledge of command line tools. We performed a systematic search and evaluation of such interfaces to investigate to what extent these can indeed facilitate RNA-seq data analysis. We found a total of 29 open source interfaces, and six of the more widely used interfaces were evaluated in detail. Central criteria for evaluation were ease of configuration, documentation, usability, computational demand and reporting. No interface scored best in all of these criteria, indicating that the final choice will depend on the specific perspective of users and the corresponding weighting of criteria. Considerable technical hurdles had to be overcome in our evaluation. For many users, this will diminish potential benefits compared with command line tools, leaving room for future improvement of interfaces. [ABSTRACT FROM AUTHOR]

Published
2016
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46. A Systems Level Analysis Reveals Transcriptomic and Proteomic Complexity in Ixodes RicinusMidgut and Salivary Glands During Early Attachment and Feeding*

Author

Schwarz, Alexandra, Tenzer, Stefan, Hackenberg, Michael, Erhart, Jan, Gerhold-Ay, Aslihan, Mazur, Johanna, Kuharev, Jörg, Ribeiro, José M.C., and Kotsyfakis, Michail

Abstract

Although pathogens are usually transmitted within the first 24–48 h of attachment of the castor bean tick Ixodes ricinus, little is known about the tick's biological responses at these earliest phases of attachment. Tick midgut and salivary glands are the main tissues involved in tick blood feeding and pathogen transmission but the limited genomic information for I. ricinusdelays the application of high-throughput methods to study their physiology. We took advantage of the latest advances in the fields of Next Generation RNA-Sequencing and Label-free Quantitative Proteomics to deliver an unprecedented, quantitative description of the gene expression dynamics in the midgut and salivary glands of this disease vector upon attachment to the vertebrate host. A total of 373 of 1510 identified proteins had higher expression in the salivary glands, but only 110 had correspondingly high transcript levels in the same tissue. Furthermore, there was midgut-specific expression of 217 genes at both the transcriptome and proteome level. Tissue-dependent transcript, but not protein, accumulation was revealed for 552 of 885 genes. Moreover, we discovered the enrichment of tick salivary glands in proteins involved in gene transcription and translation, which agrees with the secretory role of this tissue; this finding also agrees with our finding of lower tick t-RNA representation in the salivary glands when compared with the midgut. The midgut, in turn, is enriched in metabolic components and proteins that support its mechanical integrity in order to accommodate and metabolize the ingested blood. Beyond understanding the physiological events that support hematophagy by arthropod ectoparasites, we discovered more than 1500 proteins located at the interface between ticks, the vertebrate host, and the tick-borne pathogens. Thus, our work significantly improves the knowledge of the genetics underlying the transmission lifecycle of this tick species, which is an essential step for developing alternative methods to better control tick-borne diseases.

Published
2014
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47. Genome-wide association meta-analysis of corneal curvature identifies novel loci and shared genetic influences across axial length and refractive error

Author

Fan, Qiao, Pozarickij, Alfred, Tan, Nicholas YQ, Guo, Xiaobo, Verhoeven, Virginie JM, Vitart, Veronique, Guggenheim, Jeremy A, Miyake, Masahiro, Tideman, J Willem L, Khawaja, Anthony P, Zhang, Liang, MacGregor, Stuart, Höhn, René, Chen, Peng, Biino, Ginevra, Wedenoja, Juho, Saffari, Seyed Ehsan, Tedja, Milly S, Xie, Jing, Lanca, Carla, Wang, Ya Xing, Sahebjada, Srujana, Mazur, Johanna, Mirshahi, Alireza, Martin, Nicholas G, Yazar, Seyhan, Pennell, Craig E, Yap, Maurice, Haarman, Annechien EG, Enthoven, Clair A, Polling, JanRoelof, Consortium For Refractive Error And Myopia (CREAM), UK Biobank Eye And Vision Consortium, Hewitt, Alex W, Jaddoe, Vincent WV, Van Duijn, Cornelia M, Hayward, Caroline, Polasek, Ozren, Tai, E-Shyong, Yoshikatsu, Hosoda, Hysi, Pirro G, Young, Terri L, Tsujikawa, Akitaka, Wang, Jie Jing, Mitchell, Paul, Pfeiffer, Norbert, Pärssinen, Olavi, Foster, Paul J, Fossarello, Maurizio, Yip, Shea Ping, Williams, Cathy, Hammond, Christopher J, Jonas, Jost B, He, Mingguang, Mackey, David A, Wong, Tien-Yin, Klaver, Caroline CW, Saw, Seang-Mei, Baird, Paul N, and Cheng, Ching-Yu

Subjects
genetic structures, Corneal Topography, Polymorphism, Single Nucleotide, Risk Assessment, eye diseases, White People, 3. Good health, Cornea, Axial Length, Eye, Refractometry, Phenotype, Asian People, Genetic Loci, Risk Factors, Databases, Genetic, Myopia, Humans, Gene Regulatory Networks, Genetic Predisposition to Disease, sense organs, 10. No inequality, Genome-Wide Association Study
Abstract

Corneal curvature, a highly heritable trait, is a key clinical endophenotype for myopia - a major cause of visual impairment and blindness in the world. Here we present a trans-ethnic meta-analysis of corneal curvature GWAS in 44,042 individuals of Caucasian and Asian with replication in 88,218 UK Biobank data. We identified 47 loci (of which 26 are novel), with population-specific signals as well as shared signals across ethnicities. Some identified variants showed precise scaling in corneal curvature and eye elongation (i.e. axial length) to maintain eyes in emmetropia (i.e. HDAC11/FBLN2 rs2630445, RBP3 rs11204213); others exhibited association with myopia with little pleiotropic effects on eye elongation. Implicated genes are involved in extracellular matrix organization, developmental process for body and eye, connective tissue cartilage and glycosylation protein activities. Our study provides insights into population-specific novel genes for corneal curvature, and their pleiotropic effect in regulating eye size or conferring susceptibility to myopia.

48. Meta-analysis of gene-environment-wide association scans accounting for education level identifies additional loci for refractive error

Author

Fan, Qiao, Verhoeven, Virginie J M, Wojciechowski, Robert, Barathi, Veluchamy A, Hysi, Pirro G, Guggenheim, Jeremy A, Höhn, René, Vitart, Veronique, Khawaja, Anthony P, Yamashiro, Kenji, Hosseini, S Mohsen, Lehtimäki, Terho, Lu, Yi, Haller, Toomas, Xie, Jing, Delcourt, Cécile, Pirastu, Mario, Wedenoja, Juho, Gharahkhani, Puya, Venturini, Cristina, Miyake, Masahiro, Hewitt, Alex W, Guo, Xiaobo, Mazur, Johanna, Huffman, Jenifer E, Williams, Katie M, Polasek, Ozren, Campbell, Harry, Rudan, Igor, Vatavuk, Zoran, Wilson, James F, Joshi, Peter K, McMahon, George, St Pourcain, Beate, Evans, David M, Simpson, Claire L, Schwantes-An, Tae-Hwi, Igo, Robert P, Mirshahi, Alireza, Cougnard-Gregoire, Audrey, Bellenguez, Céline, Blettner, Maria, Raitakari, Olli, Kähönen, Mika, Seppala, Ilkka, Zeller, Tanja, Meitinger, Thomas, Ried, Janina S, Gieger, Christian, Portas, Laura, Van Leeuwen, Elisabeth M, Amin, Najaf, Uitterlinden, André G, Rivadeneira, Fernando, Hofman, Albert, Vingerling, Johannes R, Wang, Ya Xing, Wang, Xu, Tai-Hui Boh, Eileen, Ikram, M Kamran, Sabanayagam, Charumathi, Gupta, Preeti, Tan, Vincent, Zhou, Lei, Ho, Candice E H, Lim, Wan'e, Beuerman, Roger W, Siantar, Rosalynn, Tai, E-Shyong, Vithana, Eranga, Mihailov, Evelin, Khor, Chiea-Chuen, Hayward, Caroline, Luben, Robert N, Foster, Paul J, Klein, Barbara E K, Klein, Ronald, Wong, Hoi-Suen, Mitchell, Paul, Metspalu, Andres, Aung, Tin, Young, Terri L, He, Mingguang, Pärssinen, Olavi, Van Duijn, Cornelia M, Jin Wang, Jie, Williams, Cathy, Jonas, Jost B, Teo, Yik-Ying, Mackey, David A, Oexle, Konrad, Yoshimura, Nagahisa, Paterson, Andrew D, Pfeiffer, Norbert, Wong, Tien-Yin, Baird, Paul N, Stambolian, Dwight, Wilson, Joan E Bailey, Cheng, Ching-Yu, Hammond, Christopher J, Klaver, Caroline C W, Saw, Seang-Mei, Rahi, Jugnoo S, Korobelnik, Jean-François, Kemp, John P, Timpson, Nicholas J, Smith, George Davey, Craig, Jamie E, Burdon, Kathryn P, Fogarty, Rhys D, Iyengar, Sudha K, Chew, Emily, Janmahasatian, Sarayut, Martin, Nicholas G, MacGregor, Stuart, Xu, Liang, Schache, Maria, Nangia, Vinay, Panda-Jonas, Songhomitra, Wright, Alan F, Fondran, Jeremy R, Lass, Jonathan H, Feng, Sheng, Zhao, Jing Hua, Khaw, Kay-Tee, Wareham, Nick J, Rantanen, Taina, Kaprio, Jaakko, Pang, Chi Pui, Chen, Li Jia, Tam, Pancy O, Jhanji, Vishal, Young, Alvin L, Döring, Angela, Raffel, Leslie J, Cotch, Mary-Frances, Li, Xiaohui, Yip, Shea Ping, Yap, Maurice K H, Biino, Ginevra, Vaccargiu, Simona, Fossarello, Maurizio, Fleck, Brian, Yazar, Seyhan, Tideman, Jan Willem L, Tedja, Milly, Deangelis, Margaret M, Morrison, Margaux, Farrer, Lindsay, Zhou, Xiangtian, Chen, Wei, Mizuki, Nobuhisa, Meguro, Akira, and Mäkelä, Kari Matti

Subjects
10. No inequality, 610 Medicine & health, 3. Good health
Abstract

Myopia is the most common human eye disorder and it results from complex genetic and environmental causes. The rapidly increasing prevalence of myopia poses a major public health challenge. Here, the CREAM consortium performs a joint meta-analysis to test single-nucleotide polymorphism (SNP) main effects and SNP × education interaction effects on refractive error in 40,036 adults from 25 studies of European ancestry and 10,315 adults from 9 studies of Asian ancestry. In European ancestry individuals, we identify six novel loci (FAM150B-ACP1, LINC00340, FBN1, DIS3L-MAP2K1, ARID2-SNAT1 and SLC14A2) associated with refractive error. In Asian populations, three genome-wide significant loci AREG, GABRR1 and PDE10A also exhibit strong interactions with education (P

49. Genome-wide association meta-analysis of corneal curvature identifies novel loci and shared genetic influences across axial length and refractive error.

Author

Fan Q, Pozarickij A, Tan NYQ, Guo X, Verhoeven VJM, Vitart V, Guggenheim JA, Miyake M, Tideman JWL, Khawaja AP, Zhang L, MacGregor S, Höhn R, Chen P, Biino G, Wedenoja J, Saffari SE, Tedja MS, Xie J, Lanca C, Wang YX, Sahebjada S, Mazur J, Mirshahi A, Martin NG, Yazar S, Pennell CE, Yap M, Haarman AEG, Enthoven CA, Polling J, Hewitt AW, Jaddoe VWV, van Duijn CM, Hayward C, Polasek O, Tai ES, Yoshikatsu H, Hysi PG, Young TL, Tsujikawa A, Wang JJ, Mitchell P, Pfeiffer N, Pärssinen O, Foster PJ, Fossarello M, Yip SP, Williams C, Hammond CJ, Jonas JB, He M, Mackey DA, Wong TY, Klaver CCW, Saw SM, Baird PN, and Cheng CY

Subjects
Asian People genetics, Databases, Genetic, Gene Regulatory Networks, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Myopia ethnology, Myopia pathology, Phenotype, Refractometry, Risk Assessment, Risk Factors, White People genetics, Axial Length, Eye pathology, Cornea pathology, Corneal Topography, Genetic Loci, Myopia genetics, Polymorphism, Single Nucleotide
Abstract

Corneal curvature, a highly heritable trait, is a key clinical endophenotype for myopia - a major cause of visual impairment and blindness in the world. Here we present a trans-ethnic meta-analysis of corneal curvature GWAS in 44,042 individuals of Caucasian and Asian with replication in 88,218 UK Biobank data. We identified 47 loci (of which 26 are novel), with population-specific signals as well as shared signals across ethnicities. Some identified variants showed precise scaling in corneal curvature and eye elongation (i.e. axial length) to maintain eyes in emmetropia (i.e. HDAC11/FBLN2 rs2630445, RBP3 rs11204213); others exhibited association with myopia with little pleiotropic effects on eye elongation. Implicated genes are involved in extracellular matrix organization, developmental process for body and eye, connective tissue cartilage and glycosylation protein activities. Our study provides insights into population-specific novel genes for corneal curvature, and their pleiotropic effect in regulating eye size or conferring susceptibility to myopia.

Published
2020
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50. Optimization of the Ussing chamber setup with excised rat intestinal segments for dissolution/permeation experiments of poorly soluble drugs.

Author

Forner K, Roos C, Dahlgren D, Kesisoglou F, Konerding MA, Mazur J, Lennernäs H, and Langguth P

Subjects
Animals, Caco-2 Cells chemistry, Humans, Intestines chemistry, Jejunum chemistry, Rats, Bile Acids and Salts chemistry, Caco-2 Cells physiology, Cell Membrane Permeability physiology, Intestines physiology, Jejunum physiology, Solubility
Abstract

Context: Prediction of the in vivo absorption of poorly soluble drugs may require simultaneous dissolution/permeation experiments. In vivo predictive media have been modified for permeation experiments with Caco-2 cells, but not for excised rat intestinal segments., Objective: The present study aimed at improving the setup of dissolution/permeation experiments with excised rat intestinal segments by assessing suitable donor and receiver media., Methods: The regional compatibility of rat intestine in Ussing chambers with modified Fasted and Fed State Simulated Intestinal Fluids (Fa/FeSSIF mod ) as donor media was evaluated via several parameters that reflect the viability of the excised intestinal segments. Receiver media that establish sink conditions were investigated for their foaming potential and toxicity. Dissolution/permeation experiments with the optimized conditions were then tested for two particle sizes of the BCS class II drug aprepitant., Results: Fa/FeSSIF mod were toxic for excised rat ileal sheets but not duodenal sheets, the compatibility with jejunal segments depended on the bile salt concentration. A non-foaming receiver medium containing bovine serum albumin (BSA) and Antifoam B was nontoxic. With these conditions, the permeation of nanosized aprepitant was higher than of the unmilled drug formulations., Discussion: The compatibility of Fa/FeSSIF mod depends on the excised intestinal region. The chosen conditions enable dissolution/permeation experiments with excised rat duodenal segments. The experiments correctly predicted the superior permeation of nanosized over unmilled aprepitant that is observed in vivo., Conclusion: The optimized setup uses FaSSIF mod as donor medium, excised rat duodenal sheets as permeation membrane and a receiver medium containing BSA and Antifoam B.

Published
2017
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