113 results on '"Yuan-Tsong Chen"'
Search Results
2. Disorders of Carbohydrate Metabolism
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Priya S. Kishnani and Yuan-Tsong Chen
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medicine.medical_specialty ,Glycogen ,business.industry ,medicine.medical_treatment ,Inborn errors of carbohydrate metabolism ,Lactase ,Biology ,Carbohydrate metabolism ,Pyruvate dehydrogenase complex ,medicine.disease ,Galactokinase ,Pyruvate carboxylase ,Uridine diphosphate ,chemistry.chemical_compound ,Endocrinology ,chemistry ,Biochemistry ,Internal medicine ,medicine ,business - Abstract
Inborn errors of carbohydrate metabolism covered in this chapter include disaccharidase deficiencies, disorders of monosaccharide metabolism, glycogen storage diseases, and gluconeogenic disorders. This chapter focuses mainly on clinical aspects, genetics and current treatments for these disorders. The defective digestion of dietary disaccharides starch, lactose and sucrose is due to deficiencies of congenital lactase, adult-type lactase, or sucrase-isomaltase. Disorders of monosaccharide metabolism include defects in transport (glucose-galactose malabsorption), enzymes of galactose metabolism (galactokinase, galactose-1-phosphate uridyl transferase, and uridine diphosphate galactose-4-epimerase deficiency), enzymes of fructose metabolism (liver fructose-1-phosphate aldolase), and dehydrogenases of pentose metabolism (fructose-6-phosphate and glucose-6-phosphate). To date, there are over 12 glycogenoses, or glycogen metabolism disorders, that have been cataloged. Glycogen storage diseases (GSD), a major category of glycogenoses, are categorized by the type of tissue involved: liver, muscle, and/or cardiac. Gluconeogenic disorders entail deficiencies of fructose-1,6-diphosphatase, pyruvate carboxylase, phosphoenolpyruvate carboxykinase, and pyruvate dehydrogenase complex.
- Published
- 2021
3. Genetic epidemiological study doesn't support GLA IVS4 + 919G > A variant is a significant mutation in Fabry disease
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Yuan-Tsong Chen, Fuu Jen Tsai, Ming-Shien Wen, Jer-Yuarn Wu, Chun-Ping Chang, Wuh-Liang Hwu, Nana Hsiang-Hua Wang, Hung-Lun Chiang, Yin-Hsiu Chien, and I-Wen Song
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Adult ,Male ,0301 basic medicine ,medicine.medical_specialty ,Heart Diseases ,Heart disease ,Endocrinology, Diabetes and Metabolism ,Taiwan ,Type 2 diabetes ,Biochemistry ,Cell Line ,Cohort Studies ,Coronary artery disease ,03 medical and health sciences ,Endocrinology ,Internal medicine ,Chlorocebus aethiops ,Genetics ,medicine ,Animals ,Humans ,cardiovascular diseases ,Myocardial infarction ,Molecular Biology ,Aged ,business.industry ,Infant, Newborn ,Atrial fibrillation ,Middle Aged ,medicine.disease ,Fabry disease ,Hypertensive heart disease ,Alternative Splicing ,HEK293 Cells ,030104 developmental biology ,alpha-Galactosidase ,Heart failure ,COS Cells ,Mutation ,MCF-7 Cells ,Fabry Disease ,Female ,K562 Cells ,business - Abstract
Background The GLA IVS4 + 919G > A which is linked to late-onset Fabry disease shows high frequency in Taiwan. Methods To determine whether IVS4 + 919G > A is a frequent cause of heart disease, we genotyped it in normal controls and other disease cohorts (type 2 diabetes, heart failure, ventricular tachycardia, atrial fibrillation and coronary artery disease). Normal controls and diabetes patients carrying the variant were evaluated for their cardiac condition. Minigene constructs were used to study GLA splicing patterns in different cell lines. Results GLA IVS4 + 919A was found in 4/1634 males (0.245%) and 2/1634 females (0.123%) in normal controls and in 4/2133 males (0.188%) and 7/1816 females (0.385%) in the type 2 diabetes cohort. Of all the 17 IVS4 + 919A carriers in these two groups, only two males reported heart-related disease (myocardial infarction and hypertensive heart disease). Furthermore, in the heart disease cohort (n = 649), only one male carried the variant. Minigene constructs showed that the AGS (stomach) cell line showed a distinct GLA splicing pattern. Conclusion Most subjects carrying GLA IVS4 + 919A did not show abnormal cardiac phenotypes. The near-absence of GLA IVS4 + 919A in heart disease cohort suggested that this variant is not a frequent cause of overt heart diseases in Taiwan and that the genotype-phenotype correlation and natural course of the disease need further investigation. We also showed that the GLA IVS4 + 919G > A nucleotide change did influence alternative splicing in a tissue-specific manner. Synopsis The GLA IVS4 + 919G > A variant is not a frequent cause of overt heart disease in Taiwan.
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- 2017
4. Pharmacogenetic dosing of warfarin in the Han-Chinese population: a randomized trial
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Jer-Yuarn Wu, Jiann-Shing Jeng, Chien-Hsiun Chen, Kuo-Chun Hung, Yeu-Jhy Chang, Ying Ting Chen, Hui-Ping Chuang, Tsong-Hai Lee, Kuan-Cheng Chang, Jin Jer Chen, Ming Ta Michael Lee, Yuan-Tsong Chen, Chao-Yung Wang, Chia-Wei Liou, Ying-Fu Chen, Chien-Hung Chang, and Ming-Shien Wen
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0301 basic medicine ,Adult ,Male ,medicine.medical_specialty ,Taiwan ,030204 cardiovascular system & hematology ,Pharmacology ,Loading dose ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Therapeutic index ,Randomized controlled trial ,Asian People ,law ,Internal medicine ,Genetics ,medicine ,Humans ,Single-Blind Method ,Dosing ,International Normalized Ratio ,Adverse effect ,Blood Coagulation ,Aged ,Aged, 80 and over ,Dose-Response Relationship, Drug ,business.industry ,Warfarin ,Anticoagulants ,Middle Aged ,Pharmacogenomic Testing ,030104 developmental biology ,Population Surveillance ,Molecular Medicine ,Female ,VKORC1 ,business ,Pharmacogenetics ,medicine.drug ,Follow-Up Studies - Abstract
Aim: This study aimed to determine clinical utility of genotype-guided dosing for warfarin in Han-Chinese. Methods: A total of 320 patients were randomly assigned International Warfarin Pharmacogenetic Consortium algorithm, Taiwan algorithm and optimal clinical care arms. The primary outcome of the study was the percentage of time in the therapeutic range during the first 90 days of treatment. Results: The percentage of time in the therapeutic range of the clinical care group in the first 2 weeks was significantly higher than the algorithm groups. This difference was no longer observed after 4 weeks. No difference in excessive anticoagulation (international normalized ratio ≥4.0) and adverse events was observed. Conclusion: Genotype-guided dosing did not provide significant benefit. Loading dose with frequent international normalized ratio monitoring could provide sufficient control of anticoagulation.
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- 2017
5. Performance of ALBI-PD Model and PALBI Grade in Sorafenib-failed Hepatocellular Carcinoma
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Chien Wei Su, Teh Ia Huo, Y.-H. Huang, Yee Chao, Ming-Chih Hou, P.-C. Lee, and Yuan-Tsong Chen
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Sorafenib ,Oncology ,medicine.medical_specialty ,Hepatology ,business.industry ,Internal medicine ,Hepatocellular carcinoma ,Medicine ,business ,medicine.disease ,medicine.drug - Published
- 2018
6. Knock-in human FGFR3 achondroplasia mutation as a mouse model for human skeletal dysplasia
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Ya-Ju Pai, Sheng-De Chen, I-Wen Song, Yi-Ching Lee, and Yuan-Tsong Chen
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0301 basic medicine ,medicine.medical_specialty ,Heterozygote ,Gene Dosage ,Mutation, Missense ,Dwarfism ,030105 genetics & heredity ,Biology ,Fibroblast growth factor ,medicine.disease_cause ,Article ,Achondroplasia ,03 medical and health sciences ,Mice ,Internal medicine ,Gene knockin ,medicine ,Missense mutation ,Animals ,Humans ,Receptor, Fibroblast Growth Factor, Type 3 ,Gene Knock-In Techniques ,Mutation ,Multidisciplinary ,Homozygote ,Heterozygote advantage ,Fibroblast growth factor receptor 3 ,medicine.disease ,Disease Models, Animal ,030104 developmental biology ,Endocrinology ,Mutant Proteins - Abstract
Achondroplasia (ACH), the most common genetic dwarfism in human, is caused by a gain-of function mutation in fibroblast growth factor receptor 3 (FGFR3). Currently, there is no effective treatment for ACH. The development of an appropriate human-relevant model is important for testing potential therapeutic interventions before human clinical trials. Here, we have generated an ACH mouse model in which the endogenous mouse Fgfr3 gene was replaced with human FGFR3G380R (FGFR3ACH) cDNA, the most common mutation in human ACH. Heterozygous (FGFR3ACH/+) and homozygous (FGFR3ACH/ACH) mice expressing human FGFR3G380R recapitulate the phenotypes observed in ACH patients, including growth retardation, disproportionate shortening of the limbs, round head, mid-face hypoplasia at birth, and kyphosis progression during postnatal development. We also observed premature fusion of the cranial sutures and low bone density in newborn FGFR3G380R mice. The severity of the disease phenotypes corresponds to the copy number of activated FGFR3G380R, and the phenotypes become more pronounced during postnatal skeletal development. This mouse model offers a tool for assessing potential therapeutic approaches for skeletal dysplasias related to over-activation of human FGFR3, and for further studies of the underlying molecular mechanisms.
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- 2016
7. Identification of susceptibility gene associated with female primary Sjögren's syndrome in Han Chinese by genome-wide association study
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Hsiang-Cheng Chen, Yuan-Tsong Chen, Chien-Hsiun Chen, Ming Ta Michael Lee, Jenn-Hwai Yang, Yi-Chun Chou, Chi-Ching Chang, Jer-Yuarn Wu, Chen-Hung Chen, I-Wen Song, Yuh Feng Lin, and Chung-Tei Chou
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musculoskeletal diseases ,0301 basic medicine ,Adult ,Male ,medicine.medical_specialty ,Genotype ,Genome-wide association study ,Apoptosis ,Human leukocyte antigen ,Acinar Cells ,Biology ,Polymorphism, Single Nucleotide ,Pathogenesis ,03 medical and health sciences ,Transcription Factors, TFII ,stomatognathic system ,Transforming Growth Factor beta ,Internal medicine ,Genetics ,medicine ,SNP ,Humans ,Genetic Predisposition to Disease ,Genetics (clinical) ,Autoimmune disease ,RNA-Binding Proteins ,medicine.disease ,eye diseases ,Human genetics ,stomatognathic diseases ,030104 developmental biology ,Endocrinology ,Sjogren's Syndrome ,Immunology ,Cohort ,Trans-Activators ,Female ,Genome-Wide Association Study - Abstract
Primary Sjogren's syndrome (PSS) is an autoimmune disease targeting exocrine glands. It ten times more dominantly affects women than men with an onset peak at menopause. The genetic factor predisposing women to PSS remains unclear. Therefore, we aimed to identify susceptibility loci for PSS in women. We performed genome-wide association study (GWAS) using 242 female PSS patients and 1444 female control in Han Chinese population residing in Taiwan. Replication was conducted in an independent cohort of 178 female PSS and 14,432 control subjects. We identified rs117026326 on GTF2I with GWAS significance (P = 1.10 × 10-15) and rs13079920 on RBMS3 with suggestive significance (P = 2.90 × 10-5) associating with PSS in women. The association of RBMS3 was further evidenced by imputation in which rs13072846 (P = 4.89 × 10-5) was identified and confirmed as female PSS associating SNP within the same LD with rs13079920. PSS pathogenesis involves both immune (effector) and exocrine (target) system. We suggested that while GTF2I is a previously reported associating gene which may function in immune system, RBMS3 is a novel susceptibility gene that predisposes women to PSS potentially through modulating acinar apoptosis and TGF-β signaling in target exocrine system.
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- 2016
8. Identification of PTCSC3 as a Novel Locus for Large‐Vessel Ischemic Stroke: A Genome‐Wide Association Study
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Tai-Ming Ko, Shih Ping Chen, Liang Suei Lu, Ming Shien Wen, Yi Min Liu, Chao-Yung Wang, Hui Wen Chen, Jer-Yuarn Wu, Ku Chou Chang, Chien-Hsiun Chen, Shu Yu Chou, Ming Ta Michael Lee, Hung Ting Liao, Yuan-Tsong Chen, Tsong Hai Lee, Jiann-Der Lee, Chia San Hsieh, Yeu Jhy Chang, Jen Tsung Yang, Kuo Lun Huang, Ting-Yu Chang, C.W. Wang, Chien Hung Chang, and Ying Ting Chen
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Genetic Markers ,Male ,0301 basic medicine ,Oncology ,China ,medicine.medical_specialty ,Pathology ,RNA, Untranslated ,Taiwan ,Genome-wide association study ,Polymorphism, Single Nucleotide ,Brain Ischemia ,polymorphism ,Brain ischemia ,Genetic, Association Studies ,03 medical and health sciences ,0302 clinical medicine ,Asian People ,Risk Factors ,Internal medicine ,medicine ,Genetic predisposition ,Humans ,Genetic Predisposition to Disease ,Stroke ,Aged ,Original Research ,genome‐wide association study ,Ischemic Stroke ,Cause of death ,business.industry ,Case-control study ,Middle Aged ,medicine.disease ,3. Good health ,Phenotype ,030104 developmental biology ,Genetic marker ,Case-Control Studies ,non‐coding RNA ,Female ,atherosclerosis ,Thyroid function ,Cardiology and Cardiovascular Medicine ,business ,030217 neurology & neurosurgery ,Genome-Wide Association Study - Abstract
Background Ischemic stroke is a major cause of death and disability in the world. A major ischemic stroke subtype, large‐vessel ischemic stroke (large artery atherosclerosis; LAA ), has been shown to have some genetic components in individuals of European ancestry. However, it is not clear whether the genetic predisposition to LAA stroke varies among ethnicities. We sought to identify genetic factors that contribute to LAA stroke in 2 independent samples of Han Chinese individuals. Methods and Results Novel genetic variants that predispose individuals to LAA stroke were identified using a genome‐wide association study ( GWAS ) of 444 individuals with LAA stroke and 1727 controls in a Han Chinese population residing in Taiwan. The study was replicated in an independent Han Chinese population comprising an additional 319 cases and 1802 controls. We identified 5 single‐nucleotide polymorphisms, including rs2415317 ( P =3.10×10 −8 ), rs934075 ( P =4.00×10 −9 ), rs944289 ( P =3.57×10 −8 ), rs2787417 ( P =1.76×10 −8 ), and rs1952706 ( P =2.92×10 −8 ), at one novel locus on chromosome 14q13.3 within PTCSC 3 (encoding papillary thyroid carcinoma susceptibility candidate 3) that were associated with LAA stroke at genome‐wide significance ( P −8 ). Conclusions Our data provide strong support for future studies on the role of PTCSC 3 in the pathogenesis of LAA stroke and the association between LAA stroke development and thyroid function. In addition, these findings provide insights into the genetic basis of LAA stroke and identify a novel pathway that might be applicable for future therapeutic intervention.
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- 2016
9. Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function
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Peter Kovacs, Alan F. Wright, Stephen Turner, Michèle M. Sale, Siim Sõber, Janoš Terzić, Elin Org, Richard S. Cooper, Alena Stančáková, Jerome I. Rotter, W. H. Linda Kao, Albert Hofman, Andrew B. Singleton, Florian Kronenberg, Jianjun Liu, Nicole L. Glazer, Christopher W. Knouff, Jennifer L. Bragg-Gresham, Juha Karjalainen, Li Ching Chang, Benjamin J. Wright, Jacqueline C.M. Witteman, Martin G. Larson, Klaus Stark, Richard J. Rodeheffer, Sharon L.R. Kardia, Douglas M. Ruderfer, Sheila Ulivi, Madhumathi Rao, Andrew A. Hicks, Eva Brand, Viviane Nicaud, Stephen G. Ball, Anna Köttgen, Germaine C. Verwoert, Anders Hamsten, Nick Shrine, Uwe Völker, Stefan Kloiber, Stephen Hancock, Emelia J. Benjamin, Bok Ghee Han, Kenneth Rice, Mark Woodward, Veronique Vitart, Karl Andersen, Nicholas J. Wareham, Robert Roberts, Maja Barbalić, David Couper, Yukinori Okada, André G. Uitterlinden, Sekar Kathiresan, Leo-Pekka Lyytikäinen, Pankaj Arora, Tatijana Zemunik, David S. Siscovick, Simonetta Guarrera, Dawn M. Waterworth, Tatjana Stojakovic, Braxton D. Mitchell, Devin Absher, Carmen A. Peralta, Mika Kivimäki, Xueling Sim, Norihiro Kato, Philippe Froguel, Keith L. Keene, Donna K. Arnett, Naoyuki Kamatani, Tazeen H. Jafar, Idris Guessous, Gunnar Jacobs, Michael M. Hoffmann, Kari Stefansson, Christian Hengstenberg, Tomonori Okamura, Inga Prokopenko, Christina Willenborg, Peter S. Braund, Rainer Rettig, Francesco U.S. Mattace-Raso, Vikal Tripathy, F. Gerald R. Fowkes, Laura R. Loehr, Harry Campbell, Margherita Cavalieri, Olle Melander, Hao Mei, I. Mateo Leach, Nicholette D. Palmer, Eva Albrecht, Naoharu Iwai, Stefan Martin Brand, Toshiko Tanaka, Jackie A. Cooper, Omri Gottesman, Manuela Uda, Angelo Scuteri, Aroon D. Hingorani, Cristiano Fava, Yusuke Nakamura, Jiang He, Min Jin Go, Serge Hercberg, Wendy L. McArdle, Philipp S. Wild, Florian Ernst, Paul Mitchell, Wolfgang Koenig, Caroline S. Fox, S. J.Cathy Fann, Janine F. Felix, Anna F. Dominiczak, Mike A. Nalls, Erik Ingelsson, Mario A. Morken, Susana Eyheramendy, Christopher Newton-Cheh, Igor Rudan, D. G. Vinay, Christopher P. Nelson, Ervin R. Fox, Xiuqing Guo, Jing Hua Zhao, Rick Twee-Hee Ong, Margaret M. Redfield, Oscar H. Franco, Yongmei Liu, Fulvio Ricceri, Mark A. Hlatky, Bernhard Paulweber, Mingyao Li, Themistocles L. Assimes, Karl Winkler, Inês Barroso, Sylvia E. Rosas, M Walker, Richard W Morris, Bo Hedblad, Hakon Hakonarson, Sonny Dandona, Peter H. Whincup, Martin Adam, Vilmundur Gudnason, Daniel Ackermann, Qiong Yang, Cuno S. P. M. Uiterwaal, Paul M. Ridker, George Davey Smith, Li Chen, C. Sinning, Terri L. Young, Jer-Yuarn Wu, Walter Palmas, Will Longstreth, Joe Devaney, Pavel Hamet, Xiaofeng Zhu, Fredrik Nyberg, Wilfried Renner, Anuj Goel, L. Adrienne Cupples, Nish Chaturvedi, Iftikhar J. Kullo, Nicholas D. Hastie, Aude Saint-Pierre, Panos Deloukas, Smita R. Kulkarni, Eric Boerwinkle, Wolfram Goessling, Gian Andri Thun, Eric J.G. Sijbrands, Shih-Jen Hwang, Carole Proust, Hirotsugu Ueshima, Kristian Hveem, Pierre Meneton, Joshua C. Denny, Olivier Devuyst, Kerri L. Wiggins, Ming-Huei Chen, Robert W. Lawrence, Robert L. Wilensky, Andre Franke, Nicole Soranzo, Simon Heath, Margot Haun, Karlhans Endlich, David Altshuler, Harald Grallert, Laurence Tiret, Luigi Ferrucci, Caroline Hayward, Sudha Seshadri, Bénédicte Stengel, Lynne E. Wagenknecht, John Attia, Andreas Ziegler, Renate B. Schnabel, Stefan Schreiber, Santosh Dahgam, Kurt Lohman, Christian M. Shaffer, Barbara Ludwig, Katalin Susztak, Chien-Hsiun Chen, Michele K. Evans, Paolo Vineis, Guo Li, Thomas J. Wang, Meena Kumari, Heather M. Stringham, Bruce M. Psaty, Norman Klopp, Halit Ongen, Ben A. Oostra, Stefan Coassin, Petra Bruse, Wei-Min Chen, Unnur Thorsteinsdottir, Charles N. Rotimi, Robert J. Carroll, Muredach P. Reilly, Niek Verweij, Dena G. Hernandez, Amy J. Swift, Barbara Kollerits, Hyung Lae Kim, Cristian Pattaro, Ivana Kolcic, Ronit Katz, John M. C. Connell, Dan E. Arking, Albert W. Dreisbach, Peter Vollenweider, C. S. Janipalli, Jian'an Luan, Erkki Vartiainen, James T. Willerson, John R. Thompson, Daniela Toniolo, Lyle J. Palmer, Alexander Teumer, Serkalem Demissie-Banjaw, Stella Trompet, James E. Hixson, Sue Shaw-Hawkins, Rossella Sorice, Bernhard R. Winkelmann, John Danesh, Anthony J. Balmforth, Toshio Ogihara, Jyotika K. Fernandes, Ulf Gyllensten, Ville Aalto, Åsa Johansson, Andres Metspalu, John F. Peden, Diana Kuh, Medea Imboden, Antonio Lupo, Su Chi Lim, Young-Jin Kim, Giovanni Malerba, Yurii S. Aulchenko, Satoshi Umemura, Ioanna Tzoulaki, Alan B. Weder, Helena Schmidt, Gerjan Navis, Susan R. Heckbert, Hans J. Rupprecht, Edward G. Lakatta, Christian Gieger, Najaf Amin, Paul Muntner, Lenore J. Launer, Ivana Persico, Hugh Watkins, Ian Ford, K. Radha Mani, Sylvia Stracke, Johanna Kuusisto, John Chalmers, Muhammad Islam, Lars Lind, Stefan R. Bornstein, Marjo-Riitta Järvelin, J. H. Young, Reiner Biffar, Santhi K. Ganesh, Kazuhiko Yamamoto, Annette Peters, Linda S. Adair, Tõnu Esko, Rebecca Hardy, Olga Jarinova, Antonietta Robino, Ruth McPherson, Benjamin F. Voight, Anne U. Jackson, Gang Shi, Stefania Bandinelli, Peter J. van der Most, John S. Gottdiener, Ying A. Wang, Mariza de Andrade, Joshua C. Bis, Leslie J. Raffel, Man Li, Jemma C. Hopewell, Bernhard O. Böhm, Aaron R. Folsom, Noël P. Burtt, S. Sidney, Diana Zelenika, Yuri Milaneschi, Pilar Galan, Iris M. Heid, Bernhard K. Krämer, Jean-Michel Gaspoz, Lynda M. Rose, Massimiliano Cocca, Jaap W. Deckers, Martin Farrall, Kent D. Taylor, Albert V. Smith, Candace Guiducci, Alan R. Shuldiner, Shiro Maeda, Liming Qu, Marilyn C. Cornelis, Xiaoling Wang, Daniel Shriner, Jutta Palmen, Yingchang Lu, Heyo K. Kroemer, Pio D'Adamo, Stephan J. L. Bakker, Tamara B. Harris, Myriam Rheinberger, Tetsuro Miki, Audrey Y. Chu, Ramachandran S. Vasan, Fuu Jen Tsai, Jan A. Staessen, Daniel I. Chasman, Jan Stritzke, Jasmin Divers, Meredith C. Foster, Jeanette M. Stafford, Maksim Struchalin, Arne Schillert, Jacques S. Beckmann, Mark E. Cooper, Jean-Charles Lambert, Mario Pirastu, Katja Butterbach, Carl G. P. Platou, Yan V. Sun, Marcus Fischer, Maciej Tomaszewski, Karl Werdan, Peng Chen, Daniel J. Rader, Thomas Münzel, Lowell F. Satler, Tom R. Gaunt, Brenda W.J.H. Penninx, William H. Matthai, John Whitfield, Rita P.S. Middelberg, Margus Viigimaa, Toshihiro Tanaka, Ida Yii Der Chen, Morris J. Brown, Valur Emilsson, J. Viikari, Wolfgang Lieb, Stephen E. Epstein, Harald Dobnig, Aravinda Chakravarti, Patrick Linsel-Nitschke, Stefan Pilz, Angela Doering, Sarah H. Wild, Patricia B. Munroe, Megan E. Rudock, Nicole Probst-Hensch, Danish Saleheen, Diederick E. Grobbee, Anke Tönjes, Narisu Narisu, Annika Rosengren, Masato Isono, Catherine Helmer, M. J.Kranthi Kumar, Alanna C. Morrison, Kay-Tee Khaw, Tanja Zeller, Jeffrey R. O'Connell, Christian Müller, Georg Homuth, Giriraj R. Chandak, Pankaj Sharma, Marcus Dörr, Veikko Salomaa, Paul F. O'Reilly, David Hadley, Hermann Brenner, Paolo Gasparini, Nanette R. Lee, Bamidele O. Tayo, Robert Clarke, Henri Wallaschofski, Marketa Sjögren, Abbas Dehghan, Melanie Waldenberger, Neil Risch, Vasyl Pihur, Jessica D. Faul, François Cambien, Christian Fuchsberger, Nicholas G. Martin, John C. Chambers, Zouhair Aherrahrou, Karl J. Lackner, Leif Groop, Matthias Olden, Wiek H. van Gilst, Mathias Gorski, Yvonne T. van der Schouw, Patrick Diemert, Christoph Bickel, Yik Ying Teo, Giorgio Pistis, Ruth J. F. Loos, Gudrun Veldre, Thorsten Reffelmann, Lude Franke, Karen L. Mohlke, Stefan Blankenberg, Massimo Mangino, Ian N. M. Day, Atsushi Takahashi, Alan B. Zonderman, Hua Tang, Reijo Laaksonen, Holly Kramer, Gary C. Curhan, Adrienne Tin, Talin Haritunians, Loic Yengo, Philip Howard, Arnika Kathleen Wagner, Anna Maria Corsi, Yen Pei C. Chang, Karin Halina Greiser, Jeanette Erdmann, Solveig Gretarsdottir, Sanjay Kinra, Alex Parker, Belen Ponte, Marina Ciullo, Michael Preuss, Tin Aung, Nicholas L. Smith, Michiaki Kubo, Richard N. Bergman, Alan S. Go, Patricia P. Chang, Gudmundur Thorgeirsson, Christa Meisinger, Gonçalo R. Abecasis, Maria Blettner, Jaana Laitinen, Daniel Taliun, Carlos Iribarren, Paavo Zitting, Thomas Lumley, Andreas Meinitzer, Wayne D. Rosamond, Daehee Kang, Johanne Tremblay, Stephan B. Felix, Colin A. McKenzie, Yuan-Tsong Chen, Lyudmyla Kedenko, Mladen Boban, Fadi J. Charchar, Adebowale Adeyemo, Brendan M. Buckley, Jennifer A. Smith, Reinhold Schmidt, Jaspal S. Kooner, Gavin Lucas, Paul Elliott, Dorairajan Prabhakaran, Tune H. Pers, Tunde Salako, Terrence Forrester, Paul Burton, Jeffrey R. Gulcher, Kelly A. Volcik, Richard M. Myers, Andreas Tomaschitz, H.-Erich Wichmann, Jie Yao, Giuseppe Matullo, Carsten A. Böger, Henry Völzke, Daniela Ruggiero, Federico Murgia, Yoshikuni Kita, Augustine Kong, Giovanni Gambaro, Cinzia Sala, Peter P. Pramstaller, James Scott, Maris Laan, Laura J. Scott, Alistair S. Hall, Sanaz Sedaghat, James F. Wilson, Joanne M. Murabito, Yi-An Ko, Honghuang Lin, Mark Seielstad, Leena Peltonen, Sven Bergmann, Thomas Meitinger, Matthias Nauck, María Soler Artigas, Thomas Illig, Nanette I. Steinle, Samer S. Najjar, Christina Loley, Debbie A Lawlor, Steven C. Hunt, Yali Li, Weihua Zhang, Jie Jin Wang, Daniele Cusi, Marco Orrù, Stephen P. Fortmann, Melissa Garcia, Barry I. Freedman, Joseph M. Lindsay, Juan P. Casas, Tomohiro Katsuya, Grant W. Montgomery, Hubert Scharnagl, Khanh-Dung H. Nguyen, Steven M. Schwartz, Afshin Parsa, Elizabeth G. Holliday, Murielle Bochud, Kiran Musunuru, Bruno H. Stricker, Lori L. Bonnycastle, Ilja M. Nolte, Timothy M. Frayling, Stefan Enroth, Michiel L. Bots, Mark J. Caulfield, Laura Portas, Vincent Chouraki, Carl D. Langefeld, Eran Halperin, Shufeng Chen, Philippa J. Talmud, Terho Lehtimäki, Steve E. Humphries, Gudmar Thorleifsson, Anika Grosshennig, Norbert Watzinger, Fumihiko Takeuchi, Pim van der Harst, Takayoshi Ohkubo, Nabila Bouatia-Naji, Erwin P. Bottinger, Roberto Elosua, Andrew Wong, Vladan Mijatovic, Maija K. Garnaas, Robert Zweiker, Joel N. Hirschhorn, Winfried März, Nilesh J. Samani, Inke R. König, Frank B. Hu, Marcus E. Kleber, Francis S. Collins, Elena Rochtchina, Ewa Zukowska-Szczechowska, Yong Li, Ayse Demirkan, Gina Hilton, G. Ehret, Thomas H. Mosley, Markus Perola, Alexandre F.R. Stewart, Josef Coresh, Olli T. Raitakari, Feng Zhang, Mark Lathrop, Michael Marmot, Yanbin Dong, Christopher J. O'Donnell, Kristin D. Marciante, Asif Rasheed, Mary F. Feitosa, Mary Susan Burnett, Rory Collins, J. Wouter Jukema, Nele Friedrich, Aida Karina Dieffenbach, Ying Wu, Yoon Shin Cho, Aaron Isaacs, Haidong Zhu, Marie Metzger, Myriam Alexander, Tanja B. Grammer, Tatiana Kuznetsova, Dabeeru C. Rao, Jayashri Aragam, Augusto D. Pichard, Jaakko Tuomilehto, Louise V. Wain, Elizabeth J. Atkinson, Tim D. Spector, Reedik Mägi, Tiit Nikopensius, Kenneth M. Kent, Guangju Zhai, Andrew D. Johnson, Menno Pruijm, David P. Strachan, Martin D. Tobin, Joban Sehmi, Janja Nahrstedt, E. Shyong Tai, Thor Aspelund, Jürgen Grässler, Hilma Holm, Matthew Denniff, Joshua W. Knowles, Tien Yin Wong, Erika Salvi, James F. Meschia, Dongfeng Gu, Ron Waksman, Stacey Gabriel, Judith A. Hoffman Bolton, Michael Boehnke, Johannes Haerting, Darina Czamara, Heribert Schunkert, Thomas Quertermous, Peter M. Nilsson, Jong-Young Lee, Yasuharu Tabara, Chittaranjan S. Yajnik, Daniel Levy, John Beilby, Fernando Rivadeneira, Claire Perret, Gudny Eiriksdottir, Jingzhong Ding, George A. Wells, Harold Snieder, Ayo P. Doumatey, Dag S. Thelle, Anja Medack, N. Charlotte Onland-Moret, Michael Stumvoll, David Ellinghaus, Ingrid B. Borecki, Tatsuhiko Tsunoda, Ian H. de Boer, M. Arfan Ikram, Andrew M. Taylor, Johannes H. Smit, Gary F. Mitchell, Anna-Liisa Hartikainen, Markku Laakso, Mark McEvoy, Andrew S. Plump, Toby Johnson, Cornelia M. van Duijn, Ozren Polasek, Wilmar Igl, Vincent Mooser, Rodney J. 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L., Lindsay, JM., Waksman, R., Knouff, CW., Waterworth, DM., Walker, MC., Epstein, SE., Rader, DJ., Nelson, CP., Wright, BJ., Balmforth, AJ., Ball, SG., Loehr, LR., Rosamond, WD., Benjamin, E., Haritunians, T., Couper, D., Murabito, J., Wang, YA., Stricker, BH., Chang, PP., Willerson, JT., Felix, SB., Watzinger, N., Aragam, J., Zweiker, R., Lind, L., Rodeheffer, RJ., Greiser, KH., Deckers, JW., Stritzke, J., Ingelsson, E., Kullo, I., Haerting, J., Reffelmann, T., Redfield, MM., Werdan, K., Mitchell, GF., Arnett, DK., Gottdiener, JS., Blettner, M., and Friedrich, N.
- Subjects
0301 basic medicine ,Nephrology ,Genetics and Molecular Biology (all) ,estimated glomerular filtration rate ,estimated glomerular filtration rate, chronic kidney disease, genetic determinants ,General Physics and Astronomy ,Kidney development ,Genome-wide association study ,Biochemistry ,Settore MED/14 - NEFROLOGIA ,Renal Insufficiency ,Chronic ,Genetics ,AGEN Consortium ,ddc:616 ,education.field_of_study ,Kidney ,Stage renal-disease ,Multidisciplinary ,Genome-wide association ,CHARGe-Heart Failure Group ,Gene Expression Regulation ,Genome-Wide Association Study ,Genotype ,Humans ,Renal Insufficiency, Chronic ,Genetic Predisposition to Disease ,Biochemistry, Genetics and Molecular Biology (all) ,Chemistry (all) ,Physics and Astronomy (all) ,Metaanalysis ,Renal Insufficiency, Chronic/genetics ,Biological sciences ,Serum creatinine ,medicine.anatomical_structure ,Efficient ,Ronyons -- Fisiologia ,Hypertension ,ICBP Consortium ,Transmembrane transporter activity ,genetic association, loci, kidney function ,CARDIOGRAM ,Human ,medicine.medical_specialty ,Science ,Population ,Renal function ,ECHOGen Consortium ,Replication ,Biology ,Environment ,Research Support ,General Biochemistry, Genetics and Molecular Biology ,N.I.H ,genetic determinants ,03 medical and health sciences ,GENOME-WIDE ASSOCIATION ,FALSE DISCOVERY RATES ,STAGE RENAL-DISEASE ,SERUM CREATININE ,METAANALYSIS ,VARIANTS ,INDIVIDUALS ,POPULATION ,RISK ,HYPERTENSION ,Kidney function ,Research Support, N.I.H., Extramural ,Internal medicine ,MD Multidisciplinary ,medicine ,Journal Article ,eGFRcrea ,eGFRcys ,ddc:610 ,Genetik ,Mortality ,education ,ddc:613 ,urogenital system ,Individuals ,Extramural ,General Chemistry ,ta3121 ,medicine.disease ,R1 ,030104 developmental biology ,570 Life sciences ,biology ,Genètica ,chronic kidney disease ,Kidney disease ,Meta-Analysis - Abstract
Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways. J.T. and P.H. are consultants for Servier. J.C. received research grants and honoraria from Servier. K.S. obtained research support from Boehringer Ingelheim. The remaining authors declared no competing financial interests.
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- 2016
10. Replication of genome-wide association signals of type 2 diabetes in Han Chinese in a prospective cohort
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Lee-Ming Chuang, J D Curb, Chano A. Hsiung, Ming Wei Lin, Yuan-Tsong Chen, Wei-Jei Lee, Pi-Hua Liu, Yen-Feng Chiu, Yi-Cheng Chang, Po-Chu Lee, Kuang Chung Shih, Wayne Huey-Herng Sheu, and Thomas Quertermous
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WWOX ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Insulin ,medicine.medical_treatment ,Single-nucleotide polymorphism ,Genome-wide association study ,Type 2 diabetes ,Biology ,medicine.disease ,PTPRD Gene ,Endocrinology ,Insulin resistance ,Diabetes mellitus ,Internal medicine ,medicine - Abstract
Summary Background A recent genome-wide association study for type 2 diabetes in Han Chinese identified several novel genetic variants. We investigated their associations with quantitative measures to explore the mechanism by which these variants influence glucose homoeostasis. We also examined whether these variants predict progression to diabetes in a large prospective family based Chinese cohort. Methods Five single nucleotide polymorphisms (SNPs) near the protein tyrosine phosphatase, receptor type, D (PTPRD), SRR, MAF/WWOX, and KCNQ1 genes were genotyped in 1138 subjects of Chinese origin from the Stanford Asia-Pacific Program for Hypertension and Insulin Resistance study. Results At baseline, the risk-conferring rs7192960 C allele near the MAF/WWOX genes was associated with lower homoeostasis model assessment of β-cell (HOMA-β) (P = 0·01) and second-phase insulin response in oral glucose tolerance test (OGTT) (P = 0·04). The risk-conferring rs2237897 C alleles in the KCNQ1 gene were associated with higher fasting glucose (P = 0·009), lower HOMA-β (P = 0·03), and lower first-phase insulin response in OGTT (P = 0·03). Over an average follow-up period of 5·43 years, participants with the risk-conferring rs17584499 TT genotype in the PTPRD gene were more likely to progress from nondiabetes to diabetes than were noncarriers (hazard ratio: 8·82, P = 4 × 10−5). The risk-conferring T allele in the PTPRD gene was associated with greater increase in homoeostasis model assessment of insulin resistance (HOMA-IR) (P = 0·04) over time. PTPRD gene expression in human adipose tissues was negatively associated with fasting insulin levels and HOMA-IR. Conclusion Genetic variants near the KCNQ1 and MAF/WWOX genes are associated with reduced insulin secretion. The PTPRD genetic variant appears to be associated with progression to diabetes in Han Chinese, most likely through increased insulin resistance.
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- 2012
11. A Genome-Wide Association Study Reveals a Quantitative Trait Locus of Adiponectin on CDH13 That Predicts Cardiometabolic Outcomes
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Tsung-Hsien Lin, Chih Tai Ting, Wei-Chuan Tsai, Hsin-Chou Yang, Yuan-Tsong Chen, Sheng Hsiung Sheu, Shing Jong Lin, Hung Yun Ho, Chia Min Chung, Hsin Bang Leu, Wen-Harn Pan, Jaw Wen Chen, and Jyh Hong Chen
- Subjects
Adult ,Blood Glucose ,Male ,medicine.medical_specialty ,Genotype ,Endocrinology, Diabetes and Metabolism ,Quantitative Trait Loci ,Single-nucleotide polymorphism ,Genome-wide association study ,030204 cardiovascular system & hematology ,Quantitative trait locus ,Biology ,Polymorphism, Single Nucleotide ,Brain Ischemia ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Genetics ,Internal Medicine ,medicine ,Humans ,SNP ,Genetic Predisposition to Disease ,030304 developmental biology ,Metabolic Syndrome ,0303 health sciences ,Adiponectin ,Odds ratio ,Cadherins ,medicine.disease ,3. Good health ,SNP genotyping ,Stroke ,Endocrinology ,Diabetes Mellitus, Type 2 ,Hypertension ,Female ,Metabolic syndrome ,Genome-Wide Association Study - Abstract
OBJECTIVE The plasma adiponectin level, a potential upstream and internal facet of metabolic and cardiovascular diseases, has a reasonably high heritability. Whether other novel genes influence the variation in adiponectin level and the roles of these genetic variants on subsequent clinical outcomes has not been thoroughly investigated. Therefore, we aimed not only to identify genetic variants modulating plasma adiponectin levels but also to investigate whether these variants are associated with adiponectin-related metabolic traits and cardiovascular diseases. RESEARCH DESIGN AND METHODS We conducted a genome-wide association study (GWAS) to identify quantitative trait loci (QTL) associated with high molecular weight forms of adiponectin levels by genotyping 382 young-onset hypertensive (YOH) subjects with Illumina HumanHap550 SNP chips. The culpable single nucleotide polymorphism (SNP) variants responsible for lowered adiponectin were then confirmed in another 559 YOH subjects, and the association of these SNP variants with the risk of metabolic syndrome (MS), type 2 diabetes mellitus (T2DM), and ischemic stroke was examined in an independent community–based prospective cohort, the CardioVascular Disease risk FACtors Two-township Study (CVDFACTS, n = 3,350). RESULTS The SNP (rs4783244) most significantly associated with adiponectin levels was located in intron 1 of the T-cadherin (CDH13) gene in the first stage (P = 7.57 × 10−9). We replicated and confirmed the association between rs4783244 and plasma adiponectin levels in an additional 559 YOH subjects (P = 5.70 × 10−17). This SNP was further associated with the risk of MS (odds ratio [OR] = 1.42, P = 0.027), T2DM in men (OR = 3.25, P = 0.026), and ischemic stroke (OR = 2.13, P = 0.002) in the CVDFACTS. CONCLUSIONS These findings indicated the role of T-cadherin in modulating adiponectin levels and the involvement of CDH13 or adiponectin in the development of cardiometabolic diseases.
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- 2011
12. Enhanced efficacy of enzyme replacement therapy in Pompe disease through mannose-6-phosphate receptor expression in skeletal muscle
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Dwight D. Koeberl, Jian Dai, Alison McVie-Wylie, Yuan-Tsong Chen, Songtao Li, Suhrad G. Banugaria, Deeksha Bali, Baodong Sun, and Xiaoyan Luo
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Male ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Motor Activity ,Biology ,Biochemistry ,Receptor, IGF Type 2 ,Article ,Mice ,chemistry.chemical_compound ,Endocrinology ,Internal medicine ,Glycogen storage disease type II ,Conditional gene knockout ,Genetics ,medicine ,Animals ,Clenbuterol ,Enzyme Replacement Therapy ,Muscle, Skeletal ,Receptor ,Molecular Biology ,Mice, Knockout ,Mannose 6-phosphate receptor ,Glycogen ,Glycogen Storage Disease Type II ,nutritional and metabolic diseases ,Skeletal muscle ,alpha-Glucosidases ,Enzyme replacement therapy ,Adrenergic beta-Agonists ,medicine.disease ,Disease Models, Animal ,medicine.anatomical_structure ,chemistry ,Acid alpha-glucosidase - Abstract
Enzyme replacement therapy (ERT) with acid α-glucosidase has become available for Pompe disease; however, the response of skeletal muscle, as opposed to the heart, has been attenuated. The poor response of skeletal muscle has been attributed to the low abundance of the cation-independent mannose-6-phosphate receptor (CI-MPR) in skeletal muscle compared to heart. To further understand the role of CI-MPR in Pompe disease, muscle-specific CI-MPR conditional knockout (KO) mice were crossed with GAA-KO (Pompe disease) mice. We evaluated the impact of CI-MPR-mediated uptake of GAA by evaluating ERT in CI-MPR-KO/GAA-KO (double KO) mice. The essential role of CI-MPR was emphasized by the lack of efficacy of ERT as demonstrated by markedly reduced biochemical correction of GAA deficiency and of glycogen accumulations in double KO mice, in comparison with the administration of the same therapeutic doses in GAA-KO mice. Clenbuterol, a selective β(2)-agonist, enhanced the CI-MPR expression in skeletal tissue and also increased efficacy from GAA therapy, thereby confirming the key role of CI-MPR with regard to enzyme replacement therapy in Pompe disease. Biochemical correction improved in both muscle and non-muscle tissues, indicating that therapy could be similarly enhanced in other lysosomal storage disorders. In summary, enhanced CI-MPR expression might improve the efficacy of enzyme replacement therapy in Pompe disease through enhancing receptor-mediated uptake of GAA.
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- 2011
13. Carbamazepine-Induced Toxic Effects and HLA-B*1502 Screening in Taiwan
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Yung-Chu Hsu, Hsiang-Yu Yu, Hung-Ting Liao, Hui-Ping Chuang, Chien-Hsiun Chen, Yu-Hsiang Su, Jer-Yuarn Wu, Shu-Yi Lin, Jing-Jane Tsai, Sheng-Feng Sung, Long-Sun Ro, Cheng-Hsien Lu, Chung-Ta Lu, Chih-Ta Tai, Yu-Hsuan Lin, Shey-Lin Wu, Yuan-Tsong Chen, Li-Chen Huang, Chen-Yang Shen, Peiyuan F. Hsieh, Ying Ju Chen, Luke I Chen, Sheng-Hsing Lan, Wen-Hung Chung, Juei-Jueng Lin, Pei-Joung Tsai, Chin-Song Lu, Cheung-Ter Ong, Chun-Che Chu, Shuen-Iu Hung, Pei Chen, Chi-Feng Chang, and Chih-Chao Yang
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medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,Incidence (epidemiology) ,medicine.medical_treatment ,General Medicine ,Carbamazepine ,Southeast asian ,medicine.disease ,Toxic epidermal necrolysis ,Anticonvulsant ,Internal medicine ,Immunology ,medicine ,Young adult ,business ,Pharmacogenetics ,medicine.drug ,Genetic testing - Abstract
Background Carbamazepine, an anticonvulsant and a mood-stabilizing drug, is the main cause of the Stevens–Johnson syndrome (SJS) and its related disease, toxic epidermal necrolysis (TEN), in Southeast Asian countries. Carbamazepine-induced SJS–TEN is strongly associated with the HLA-B*1502 allele. We sought to prevent carbamazepine-induced SJS–TEN by using HLA-B*1502 screening to prospectively identify subjects at genetic risk for the condition. Methods From 23 hospitals in Taiwan, we recruited 4877 candidate subjects who had not taken carbamazepine. We genotyped DNA purified from the subjects' peripheral blood to determine whether they carried the HLA-B*1502 allele. Those testing positive for HLA-B*1502 (7.7% of the total) were advised not to take carbamazepine and were given an alternative medication or advised to continue taking their prestudy medication; those testing negative (92.3%) were advised to take carbamazepine. We interviewed the subjects by telephone once a week for 2 months to monitor them ...
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- 2011
14. Glycogen-branching enzyme deficiency leads to abnormal cardiac development: novel insights into glycogen storage disease IV
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Yi-Ching Lee, Yuan-Tsong Chen, Chia Jung Chang, Deeksha Bali, and Yu-Ting Yan
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Heart Defects, Congenital ,Programmed cell death ,medicine.medical_specialty ,Hydrops Fetalis ,Amylopectin ,Genes, myc ,Fluorescent Antibody Technique ,Cell Cycle Proteins ,Biology ,Polymerase Chain Reaction ,Glycogen Storage Disease Type IV ,Mice ,chemistry.chemical_compound ,Heart Rate ,1,4-alpha-Glucan Branching Enzyme ,Hydrops fetalis ,Internal medicine ,Genetics ,medicine ,Animals ,Ventricular Function ,Cyclin D1 ,Myocytes, Cardiac ,Glycogen storage disease type IV ,Molecular Biology ,Genetics (clinical) ,Cell Proliferation ,Heart Failure ,Fetus ,Glycogen ,Heart ,Sequence Analysis, DNA ,General Medicine ,Cell cycle ,medicine.disease ,Glycogen Branching Enzyme Deficiency ,Endocrinology ,chemistry ,Heart failure ,Codon, Terminator ,Embryo Loss - Abstract
Glycogen storage disease type IV (GSD-IV) is an autosomal recessive disease caused by a deficiency in glycogen-branching enzyme (GBE1) activity that results in the accumulation of amylopectin-like polysaccharide, which presumably leads to osmotic swelling and cell death. This disease is extremely heterogeneous in terms of tissue involvement, age of onset and clinical manifestation. The most severe fetal form presents as hydrops fetalis; however, its pathogenetic mechanisms are largely unknown. In this study, mice carrying a stop codon mutation (E609X) in the Gbe1 gene were generated using a gene-driven mutagenesis approach. Homozygous mutants (Gbe(-/-) mice) recapitulated the clinical features of hydrops fetalis and the embryonic lethality of the severe fetal form of GSD-IV. However, contrary to conventional expectations, little amylopectin accumulation and no cell degeneration were found in Gbe(-/-) embryonic tissues. Glycogen accumulation was reduced in developing hearts of Gbe(-/-)embryos, and abnormal cardiac development, including hypertrabeculation and noncompaction of the ventricular wall, was observed. Further, Gbe1 ablation led to poor ventricular function in late gestation and ultimately caused heart failure, fetal hydrops and embryonic lethality. We also found that the cell-cycle regulators cyclin D1 and c-Myc were highly expressed in cardiomyocytes and likely contributed to cardiomyocyte proliferation and trabeculation/compaction of the ventricular wall. Our results reveal that early molecular events associated with Gbe1 deficiency contribute to abnormal cardiac development and fetal hydrops in the fetal form of GSD-IV.
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- 2010
15. Cross-reactive immunologic material status affects treatment outcomes in Pompe disease infants
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Amy S. Rosenberg, Hanna Mandel, Paula Goldenberg, Stephanie L. Dearmey, Daniel K. Benjamin, Dwight D. Koeberl, Yuan-Tsong Chen, Deeksha Bali, Priya S. Kishnani, James H. Heller, Jennifer S. Li, Sue Ann Smith, and Sarah P. Young
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Male ,Cardiac function curve ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Urinary system ,Enzyme-Linked Immunosorbent Assay ,Cross Reactions ,Biochemistry ,Gastroenterology ,Article ,Endocrinology ,Internal medicine ,Genetics ,medicine ,Lysosomal storage disease ,Humans ,Enzyme Replacement Therapy ,Muscle Strength ,Molecular Biology ,Alglucosidase alfa ,Retrospective Studies ,Glycogen Storage Disease Type II ,business.industry ,Infant ,Retrospective cohort study ,Enzyme replacement therapy ,medicine.disease ,Recombinant Proteins ,Surgery ,Clinical trial ,Treatment Outcome ,Immunoglobulin G ,alpha-Galactosidase ,Acid alpha-glucosidase ,Female ,business ,medicine.drug - Abstract
Deficiency of acid alpha glucosidase (GAA) causes Pompe disease, which is usually fatal if onset occurs in infancy. Patients synthesize a non-functional form of GAA or are unable to form native enzyme. Enzyme replacement therapy with recombinant human GAA (rhGAA) prolongs survival in infantile Pompe patients but may be less effective in cross-reactive immunologic material (CRIM)-negative patients. We retrospectively analyzed the influence of CRIM status on outcome in 21 CRIM-positive and 11 CRIM-negative infantile Pompe patients receiving rhGAA. Patients were from the clinical setting and from clinical trials of rhGAA, were 6 months of age, were not invasively ventilated, and were treated with IV rhGAA at a cumulative or total dose of 20 or 40 mg/kg/2 weeks. Outcome measures included survival, invasive ventilator-free survival, cardiac status, gross motor development, development of antibodies to rhGAA, and levels of urinary Glc(4). Following 52 weeks of treatment, 6/11 (54.5%) CRIM-negative and 1/21 (4.8%) CRIM-positive patients were deceased or invasively ventilated (p
- Published
- 2010
16. Emerging therapies for glycogen storage disease type I
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Priya S. Kishnani, Yuan-Tsong Chen, Deeksha Bali, and Dwight D. Koeberl
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congenital, hereditary, and neonatal diseases and abnormalities ,Glycogen storage disease type I ,medicine.medical_specialty ,Anemia ,Endocrinology, Diabetes and Metabolism ,Genetic enhancement ,nutritional and metabolic diseases ,Genetic Therapy ,Glycogen Storage Disease Type I ,Neutropenia ,Biology ,Bioinformatics ,medicine.disease ,Models, Biological ,Endocrinology ,Internal medicine ,medicine ,Humans ,Altered metabolism ,Organ system ,Homeostasis - Abstract
Glycogen storage disease type I (GSD I) is caused by deficiency of the glucose-6-phosphatase catalytic subunit in type Ia or of glucose-6-phosphate transporter in type Ib. The cellular bases for disruptions of homeostasis have been increasingly understood in GSD I, including those for anemia, renal failure and neutropenia. Advances in the understanding of cellular abnormalities in GSD I have provided rationales for new therapy, and recent developments in gene therapy have led to potential curative treatments for GSD I. These advances will benefit patients with GSD I in the future, improving both quality of life and survival, as well as illuminating the molecular effects of altered metabolism upon multiple organ systems.
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- 2009
17. A large kindred of early-onset osteoarthritis of the knee and hip: excluding the link to COL2A1 gene
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Liang-Kuang Chen, Yuan-Tsong Chen, Ming-Ta Michael Lee, Hui-Ping Chuang, Shu-Chi Mu, Jer-Yuarn Wu, and Hwa Chang Liu
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Adult ,Male ,medicine.medical_specialty ,Genotype ,Knee Joint ,Single-nucleotide polymorphism ,Locus (genetics) ,Biology ,Polymorphism, Single Nucleotide ,Osteoarthritis, Hip ,Rheumatology ,Genetic linkage ,Internal medicine ,Osteoarthritis ,medicine ,Humans ,Pharmacology (medical) ,Age of Onset ,Collagen Type II ,Gene ,Aged ,Genes, Dominant ,Genetics ,Chromosome Mapping ,Sequence Analysis, DNA ,Osteoarthritis, Knee ,Pedigree ,Radiography ,Phenotype ,Endocrinology ,Arm span ,Microsatellite ,Female ,Hip Joint ,Age of onset - Abstract
Objectives To characterize a large extended family with early-onset OA of the knee and investigate its associations with the COL2A1 gene. Methods Phenotype assessments were conducted in a six-generation family to identify individuals affected with OA. Short tandem repeat polymorphic (STRP) markers and DNA sequencing were performed to investigate the involvement of the COL2A1 gene in this family. Results The kindred affected with OA showed autosomal dominant inheritance. The mean age of onset was 37.3 +/- 19.2, 29.8 +/- 13.7 and 12.0 +/- 7.2 years for generations IV, V and VI, respectively, and 25 +/- 16.1 years for males and 34.3 +/- 15.5 years for females. The height of the affected males was shorter than the unaffected males (155.9 +/- 11.4 vs 164.5 +/- 16.0 cm, P = 0.010). Arm span in the affected males was also significantly shorter than the unaffected males (158.4 +/- 12.5 vs 165.3 +/- 16.7 cm, P = 0.027). However, both height and arm span were not reduced in the affected female OA patients. STRP markers surrounding COL2A1 locus did not show linkage of the COL2A1 locus with the OA. Sequencing of COL2A1 gene revealed three single nucleotide polymorphisms but no mutation was found in the affected patients. Conclusions The COL2A1 was not a susceptibility gene responsible for the OA phenotype in a large extended kindred with familial early-onset OA. The availability of DNA samples will allow genome-wide linkage study to identify the susceptibility locus.
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- 2009
18. AAV Vector-mediated Reversal of Hypoglycemia in Canine and Murine Glycogen Storage Disease Type Ia
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Daniel M. Kozink, Daniel K. Benjamin, Talmage T. Brown, Songtao Li, Yuan-Tsong Chen, Amanda Demaster, Valerie M. Vaughn, Baodong Sun, Carlos R. F. Pinto, Steven L. Hillman, Andrew Bird, Dwight D. Koeberl, Meghan A. Kruse, Priya S. Kishnani, and Mark W. Jackson
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medicine.medical_specialty ,viruses ,Genetic enhancement ,Transgene ,Genetic Vectors ,Glycogen Storage Disease Type I ,Biology ,Hypoglycemia ,Virus ,Glycogen storage disease type Ia ,Mice ,Dogs ,Internal medicine ,Drug Discovery ,Genetics ,medicine ,Animals ,Humans ,Vector (molecular biology) ,Molecular Biology ,Tropism ,Mice, Knockout ,Pharmacology ,nutritional and metabolic diseases ,Genetic Therapy ,Dependovirus ,medicine.disease ,Virology ,Liver Glycogen ,Disease Models, Animal ,Endocrinology ,Glucose-6-Phosphatase ,Molecular Medicine ,Hepatocyte growth factor ,medicine.drug - Abstract
Glycogen storage disease type Ia (GSD-Ia) profoundly impairs glucose release by the liver due to glucose-6-phosphatase (G6Pase) deficiency. An adeno-associated virus (AAV) containing a small human G6Pase transgene was pseudotyped with AAV8 (AAV2/8) to optimize liver tropism. Survival was prolonged in 2-week-old G6Pase (-/-) mice by 600-fold fewer AAV2/8 vector particles (vp), in comparison to previous experiments involving this model (2 x 10(9) vp; 3 x 10(11) vp/kg). When the vector was pseudotyped with AAV1, survival was prolonged only at a higher dose (3 x 10(13) vp/kg). The AAV2/8 vector uniquely prevented hypoglycemia during fasting and fully corrected liver G6Pase deficiency in GSD-Ia mice and dogs. The AAV2/8 vector has prolonged survival in three GSD-Ia dogs to11 months, which validated this strategy in the large animal model for GSD-Ia. Urinary biomarkers, including lactate and 3-hydroxybutyrate, were corrected by G6Pase expression solely in the liver. Glycogen accumulation in the liver was reduced almost to the normal level in vector-treated GSD-Ia mice and dogs, as was the hepatocyte growth factor (HGF) in GSD-Ia mice. These preclinical data demonstrated the efficacy of correcting hepatic G6Pase deficiency, and support the further preclinical development of AAV vector-mediated gene therapy for GSD-Ia.
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- 2008
19. Brain Abscess in Glycogen Storage Disease Type Ib
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Yuan-Tsong Chen, Hae K. Park, and Stephen G. Kahler
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Male ,medicine.medical_specialty ,Pathology ,business.industry ,Brain Abscess ,General Medicine ,Disease ,Glycogen Storage Disease Type I ,Staphylococcal Infections ,Neutropenia ,medicine.disease ,Endocrinology ,Internal medicine ,Metabolic control analysis ,Pediatrics, Perinatology and Child Health ,Glycogen Storage Disease Type Ib ,medicine ,Humans ,Neutrophil dysfunction ,Child ,Tomography, X-Ray Computed ,Abscess ,Complication ,business ,Brain abscess - Abstract
Neutropenia, neutrophil dysfunction, and recurrent infections are important manifestations of glycogen storage disease type Ib. We report here a child who has had adequate metabolic control, but developed brain abscess, an infection not previously described in this disease. This case provides further evidence that the neutrophil anomaly is related to the basic enzyme defect, not secondary to the metabolic derangement.
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- 2008
20. Efficacy of Helper-dependent Adenovirus Vector-mediated Gene Therapy in Murine Glycogen Storage Disease Type Ia
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Dwight D. Koeberl, Kazuhiro Oka, Lawrence Chan, Andrew Bird, Baodong Sun, and Yuan-Tsong Chen
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medicine.medical_specialty ,Genetic enhancement ,Genetic Vectors ,Glycogen Storage Disease Type I ,Hypoglycemia ,Biology ,Glycogen storage disease type Ia ,Adenoviridae ,Viral vector ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Drug Discovery ,medicine ,Genetics ,Animals ,Vector (molecular biology) ,Molecular Biology ,030304 developmental biology ,Mice, Knockout ,Pharmacology ,0303 health sciences ,Growth retardation ,Genetic Therapy ,Metabolism ,medicine.disease ,3. Good health ,Endocrinology ,Liver ,Glucose-6-Phosphatase ,Molecular Medicine ,Glycogen ,030217 neurology & neurosurgery - Abstract
Genetic deficiency of glucose-6-phosphatase (G6Pase) underlies glycogen storage disease type Ia (GSD-Ia, also known as von Gierke disease; MIM 232200), an autosomal recessive disorder of metabolism associated with life-threatening hypoglycemia and growth retardation. We tested whether helper-dependent adenovirus (HDAd)-mediated hepatic delivery of G6Pase would lead to prolonged survival and sustained correction of the metabolic abnormalities in G6Pase knockout (KO) mice, a model for a severe form of GSD-Ia. An HDAd vector encoding G6Pase was administered intravenously (2 or 5 x 10(12)vector particles/kg) to 2-week-old (w.o.) G6Pase-KO mice. Following HDAd vector administration survival was prolonged to a median of 7 months, in contrast to untreated affected mice that did not survive past 3 weeks of age. G6Pase levels increased more than tenfold between 3 days and 28 weeks after HDAd injection (P0.03). The weights of untreated 2 w.o. G6Pase-KO mice were approximately half those of their unaffected littermates, and treatment stimulated their growth to the size of wild-type mice. Severe hypoglycemia and hypercholesterolemia, which are hallmarks of GSD-Ia both in humans and in mice, were also restored to normalcy by the treatment. Glycogen accumulation in the liver was markedly reduced. The efficacy of HDAd-G6Pase treatment in reversing the physiological and biochemical abnormalities associated with GSD-Ia in affected G6Pase-KO mice justifies further preclinical evaluation in murine and canine models of GSD-Ia.
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- 2007
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21. Surrogate estimates of insulin sensitivity in subjects with hypertension
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Yii-Der Ida Chen, Chii-Min Hwu, Lee-Ming Chuang, Beatriz L. Rodriguez, John S. Grove, Yi-Jen Hung, J D Curb, Chin-Fu Hsiao, Low-Tone Ho, and Yuan-Tsong Chen
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Adult ,Blood Glucose ,Male ,medicine.medical_specialty ,endocrine system diseases ,medicine.medical_treatment ,Sensitivity and Specificity ,Correlation ,Insulin resistance ,Asian People ,Predictive Value of Tests ,Internal medicine ,Diabetes Mellitus ,Internal Medicine ,medicine ,Humans ,Insulin ,Partial correlation ,Analysis of Variance ,business.industry ,Quantitative insulin sensitivity check index ,nutritional and metabolic diseases ,Middle Aged ,Glucose clamp technique ,Explained variation ,medicine.disease ,Endocrinology ,Hypertension ,Glucose Clamp Technique ,Female ,Analysis of variance ,Insulin Resistance ,business ,hormones, hormone substitutes, and hormone antagonists - Abstract
The purpose of the study is to compare surrogate estimates of insulin sensitivity with a directly measured insulin sensitivity index, steady-state plasma glucose (SSPG) from insulin suppression test (IST), in subjects with hypertension. Two hundred and twenty-eight hypertensive patients who received IST for SSPG were included for analysis. Estimates from fasting measurements alone, homeostasis model assessment for insulin resistance (HOMA-IR) and quantitative insulin sensitivity check index (QUICKI)), and indices from fasting and/or 2 h samples (ISI(0,120) and ISI(TX)) were calculated. In addition to Pearson and partial correlations, variance-component models were used to test the relationship between surrogate estimates of insulin sensitivity and SSPG. A large proportion of variance owing to covariates in the variance-component models indicated the goodness of model fit, irrespective of the independence among variables. SSPG was positively correlated with logarithmic transformation (Log) (HOMA-IR) and negatively correlated with QUICKI, Log (ISI(0,120)) and ISI(TX) (all P
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- 2007
22. Dysregulation of C/EBPα by mutant Huntingtin causes the urea cycle deficiency in Huntington's disease
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Ming Chang Chiang, Yi-Chih Wu, Jer-Yuarn Wu, Dau-Ming Niu, Yuan-Tsong Chen, Yi-Hsin Lee, Hao-Hung Chang, Chiung-Mei Chen, Bing-Wen Soong, Yih-Ru Wu, Chin-San Liu, Yijuang Chern, and Hui-Mei Chen
- Subjects
Male ,medicine.medical_specialty ,Huntingtin ,Down-Regulation ,Nerve Tissue Proteins ,Motor Activity ,Mice ,chemistry.chemical_compound ,Hsp27 ,Huntington's disease ,Internal medicine ,CCAAT-Enhancer-Binding Protein-alpha ,Genetics ,Citrulline ,medicine ,Huntingtin Protein ,Animals ,Humans ,Urea ,Promoter Regions, Genetic ,Protein Structure, Quaternary ,Molecular Biology ,Transcription factor ,Genetics (clinical) ,biology ,Brain-Derived Neurotrophic Factor ,Nuclear Proteins ,Hyperammonemia ,General Medicine ,Middle Aged ,medicine.disease ,Diet ,Huntington Disease ,Endocrinology ,Liver ,chemistry ,Urea cycle ,Disease Progression ,biology.protein ,Female ,Mutant Proteins ,Protein Binding - Abstract
Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by a CAG trinucleotide expansion in the Huntingtin (Htt) gene. Using two mouse models of HD, we demonstrate that the urea cycle deficiency characterized by hyperammonemia, high blood citrulline and suppression of urea cycle enzymes is a prominent feature of HD. The resultant ammonia toxicity might exacerbate the neurological deficits of HD. Suppression of C/EBPalpha, a crucial transcription factor for the transcription of urea cycle enzymes, appears to mediate the urea cycle deficiency in HD. We found that in the presence of mutant Htt, C/EBPalpha loses its ability to interact with an important cofactor (CREB-binding protein). Moreover, mutant Htt recruited C/EBPalpha into aggregates, as well as suppressed expression of the C/EBPalpha gene. Consumption of protein-restricted diets not only led to the restoration of C/EBPalpha's activity, and repair of the urea cycle deficiency and hyperammonemia, but also ameliorated the formation of Htt aggregates, the motor deterioration, the suppression of striatal brain-derived neurotrophic factor and the normalization of three protein chaperones (Hsp27, Hsp70 and Hsp90). Treatments aimed at repairing the urea cycle deficiency may provide a new strategy for dealing with HD.
- Published
- 2007
23. Use of HLA-B*58:01 genotyping to prevent allopurinol induced severe cutaneous adverse reactions in Taiwan: national prospective cohort study
- Author
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Chun Lin Huang, Ya-Hui Yang, Chia-Li Yu, Kuang Hui Yu, Chung-Ming Huang, Chen-Yang Shen, Pi-Jung Hsiao, Tai-Ming Ko, Chia Tse Weng, Yuan-Tsong Chen, Song Chou Hsieh, Hsueh Wei Yen, Shih Yang Chen, Yi-Ming Chen, Mei-Chuan Kuo, Jer-Chia Tsai, Ming Ta Michael Lee, Der-Yuan Chen, Jeng-Hsien Yen, Chang-Youh Tsai, Chrong-Reen Wang, Hung Ting Liao, C.W. Wang, Yi-Chun Chou, Shue Fen Luo, Teh Ling Liou, Meng Yu Weng, Tsan Teng Ou, Chih Shung Wong, Chen Ching Wu, Chih Sheng Chu, Jer-Yuarn Wu, Kuo Shu Chen, Guang Dar Yin, Chia Shuo Chang, Kai Hung Cheng, Jia Jung Lee, Pei Chen, Wen Ter Lai, Chen Hung Chen, Hui Ping Chuang, Wen Chan Tsai, Ming Fei Liu, Shih Yuan Hung, Chien Hsiun Chen, and Tsung-Hsien Lin
- Subjects
Male ,medicine.medical_specialty ,Heterozygote ,Genotype ,Allopurinol ,Taiwan ,Scars ,Gout Suppressants ,Internal medicine ,medicine ,Humans ,Genetic Testing ,Prospective Studies ,Prospective cohort study ,Genotyping ,business.industry ,Incidence (epidemiology) ,Pruritus ,Research ,General Medicine ,Exanthema ,Middle Aged ,Rash ,HLA-B ,Confidence interval ,Surgery ,HLA-B Antigens ,Chronic Disease ,Female ,Drug Eruptions ,medicine.symptom ,business ,medicine.drug - Abstract
Objective To evaluate the use of prospective screening for the HLA-B*58:01 allele to identify Taiwanese individuals at risk of severe cutaneous adverse reactions (SCARs) induced by allopurinol treatment. Design National prospective cohort study. Setting 15 medical centres in different regions of Taiwan, from July 2009 to August 2014. Participants 2926 people who had an indication for allopurinol treatment but had not taken allopurinol previously. Participants were excluded if they had undergone a bone marrow transplant, were not of Han Chinese descent, and had a history of allopurinol induced hypersensitivity. DNA purified from 2910 participants’ peripheral blood was used to assess the presence of HLA-B*58:01. Main outcome measures Incidence of allopurinol induced SCARs with and without screening. Results Participants who tested positive for HLA-B*58:01 (19.6%, n=571) were advised to avoid allopurinol, and were referred to an alternate drug treatment or advised to continue with their prestudy treatment. Participants who tested negative (80.4%, n=2339) were given allopurinol. Participants were interviewed once a week for two months to monitor symptoms. The historical incidence of allopurinol induced SCARs, estimated by the National Health Insurance research database of Taiwan, was used for comparison. Mild, transient rash without blisters developed in 97 (3%) participants during follow-up. None of the participants was admitted to hospital owing to adverse drug reactions. SCARs did not develop in any of the participants receiving allopurinol who screened negative for HLA-B*58:01. By contrast, seven cases of SCARs were expected, based on the estimated historical incidence of allopurinol induced SCARs nationwide (0.30% per year, 95% confidence interval 0.28% to 0.31%; P=0.0026; two side one sample binomial test). Conclusions Prospective screening of the HLA-B*58:01 allele, coupled with an alternative drug treatment for carriers, significantly decreased the incidence of allopurinol induced SCARs in Taiwanese medical centres.
- Published
- 2015
24. Precision Medicine for Kawasaki Disease
- Author
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Yuan-Tsong Chen, Jer-Yuarn Wu, and Tai-Ming Ko Ko
- Subjects
medicine.medical_specialty ,biology ,business.industry ,medicine.disease ,Precision medicine ,medicine.anatomical_structure ,Internal medicine ,Epidemiology ,biology.protein ,Etiology ,Cardiology ,Medicine ,Kawasaki disease ,Antibody ,business ,Vasculitis ,Systemic vasculitis ,Artery - Abstract
Kawasaki disease (KD) is a multisystem inflammatory illness of infants and young children that could result in acute vasculitis. Death due to this systemic vasculitis syndrome most frequently results from thrombosed coronary artery aneurysms and coronary arteritis. Without treatment, 25% of children with KD develop coronary artery abnormalities. Current therapy for KD consists of intravenous immunoglobulin within the first 10 days of fever onset; this treatment reduces the prevalence of coronary artery abnormalities to 5%. Advances in genetic and proteomic analysis have sparked a worldwide effort to identify genes and potential biomarkers associated with KD. In this review, we highlight important research advances that have been made in the epidemiology, etiology, genetic polymorphisms, diagnosis, and therapy of KD.
- Published
- 2015
25. Comparison of maltose and acarbose as inhibitors of maltase-glucoamylase activity in assaying acid α-glucosidase activity in dried blood spots for the diagnosis of infantile Pompe disease
- Author
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Haoyue Zhang, Joan Keutzer, Yuan-Tsong Chen, Deeksha Bali, Sarah P. Young, Cortney Carr, Helmut Kallwass, David S. Millington, Jian Dai, and Priya S. Kishnani
- Subjects
Adult ,Heterozygote ,medicine.medical_specialty ,Glycoside Hydrolase Inhibitors ,chemistry.chemical_compound ,Internal medicine ,medicine ,Humans ,Enzyme Inhibitors ,Maltose ,Genetics (clinical) ,Acarbose ,chemistry.chemical_classification ,biology ,Spots ,Glycogen Storage Disease Type II ,Infant, Newborn ,alpha-Glucosidases ,Clinical Enzyme Tests ,Hydrogen-Ion Concentration ,Enzyme assay ,Dried blood spot ,Enzyme ,Endocrinology ,chemistry ,Alpha-glucosidase ,biology.protein ,medicine.drug - Abstract
Purpose: The study’s purpose was to compare acarbose and maltose as inhibitors of maltase-glucoamylase activity for determining acid α-glucosidase activity in dried blood spot specimens for early identification of patients with infantile Pompe disease, a severe form of acid α-glucosidase deficiency. Methods: Acid α-glucosidase activities in dried blood spot extracts were determined fluorometrically using the artificial substrate 4-methylumbelliferyl-α-D-pyranoside. Acarbose or maltose was used to inhibit maltase-glucoamylase, an enzyme present in polymorphonuclear neutrophils that contributes to the total α-glucosidase activity at acidic pH. Results: Complete discrimination between patients with proven infantile Pompe disease (n = 20), obligate heterozygotes (n = 16), and controls (n = 150) was achieved using 8 μmol/L acarbose as the inhibitor. Higher acarbose concentration (80 μmol/L) did not improve the assay. By using 4 mM maltose as the inhibitor, heterozygotes and patients were not completely separated. The results using acarbose compared well with those using the skin fibroblast assay in the same group of patients with proven infantile Pompe disease. Conclusion: Acid α-glucosidase activity measurements in dried blood spot extracts can reliably detect infantile Pompe disease in patients. The convenience of collecting and shipping dried blood specimens plus rapid turnaround time makes this assay an attractive alternative to established methods.
- Published
- 2006
26. Cyclic Alopecia and Abnormal Epidermal Cornification in Zdhhc13-Deficient Mice Reveal the Importance of Palmitoylation in Hair and Skin Differentiation
- Author
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Amir Haddad, Kai-Ming Liu, I-Wen Song, Yi-Ju Chen, Jer-Yuarn Wu, Li-Ying Chen, Yuan-Tsong Chen, Yu-Ju Chen, Jeffrey J.Y. Yen, and Li-Fen Shen
- Subjects
medicine.medical_specialty ,Transgene ,Skin Absorption ,Blotting, Western ,Mice, Transgenic ,Dermatology ,Biology ,Biochemistry ,Methylation ,Sensitivity and Specificity ,Serine ,Cornified envelope ,Mice ,Palmitoylation ,Hair cycle ,Internal medicine ,medicine ,Animals ,Protein Precursors ,Molecular Biology ,Cuticle (hair) ,Epidermis (botany) ,integumentary system ,Membrane Proteins ,Alopecia ,Cell Biology ,medicine.disease ,Immunohistochemistry ,Mice, Inbred C57BL ,Hair loss ,Endocrinology ,Animals, Newborn ,Gene Expression Regulation ,Skin Abnormalities ,Acyltransferases ,Hair - Abstract
Many biochemical pathways involved in hair and skin development have not been investigated. Here, we reported on the lesions and investigated the mechanism underlying hair and skin abnormalities in Zdhhc13(skc4) mice with a deficiency in DHHC13, a palmitoyl-acyl transferase encoded by Zdhhc13. Homozygous affected mice showed ragged and dilapidated cuticle of the hair shaft (CUH, a hair anchoring structure), poor hair anchoring ability, and premature hair loss at early telogen phase of the hair cycle, resulting in cyclic alopecia. Furthermore, the homozygous affected mice exhibited hyperproliferation of the epidermis, disturbed cornification, fragile cornified envelope (CE, a skin barrier structure), and impaired skin barrier function. Biochemical investigations revealed that cornifelin, which contains five palmitoylation sites at cysteine residues (C58, C59, C60, C95, and C101), was a specific substrate of DHHC13 and that it was absent in the CUH and CE structures of the affected mice. Furthermore, cornifelin levels were markedly reduced when two palmitoylated cysteines were replaced with serine (C95S and C101S). Taken together, our results suggest that DHHC13 is important for hair anchoring and skin barrier function and that cornifelin deficiency contributes to cyclic alopecia and skin abnormalities in Zdhhc13(skc4) mice.
- Published
- 2014
27. Amylopectinosis disease isolated to the heart with normal glycogen branching enzyme activity and gene sequence
- Author
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Michael R. Narkewicz, Sing Chung Li, Bibhuti B. Das, Gary W. Mierau, D. Dunbar Ivy, Ronald J. Sokol, M. R. Matthews, Yuan-Tsong Chen, and Deeksha Bali
- Subjects
medicine.medical_specialty ,Amylopectin ,Cardiomyopathy ,Glycogen debranching enzyme ,Electrocardiography ,Glycogen Storage Disease Type IV ,Ventricular Dysfunction, Left ,chemistry.chemical_compound ,1,4-alpha-Glucan Branching Enzyme ,Internal medicine ,medicine ,Glycogen branching enzyme ,Humans ,Myocyte ,Transplantation ,Glycogen ,biology ,business.industry ,Infant ,Skeletal muscle ,Fibroblasts ,medicine.disease ,Endocrinology ,medicine.anatomical_structure ,chemistry ,Pediatrics, Perinatology and Child Health ,biology.protein ,Female ,Cardiomyopathies ,business ,Phosphofructokinase - Abstract
We report a 17-month-old female patient with a rare cause of cardiomyopathy secondary to accumulation of amylopectin-like material (fibrillar glycogen) isolated to the heart. Evidence of amylopectinosis isolated to cardiac myocytes in this patient was demonstrated by histology and electron microscopy. Glycogen content, glycogen branching enzyme (GBE) activity, as well as phosphofructokinase enzyme activities measured in liver, skeletal muscle, fibroblasts and ex-transplanted heart tissue were all in the normal to lower normal ranges. Normal skeletal muscle and liver tissue histology and GBE activity, normal GBE activity in skin fibroblasts, plus normal GBE gene sequence in this patient exclude the classical branching enzyme deficiency (type IV GSD). We believe that this is an as yet uncharacterized and novel phenotype of GSD associated with cardiomyopathy, in which there is an imbalance in the regulation of glycogen metabolism limited to the heart.
- Published
- 2005
28. Glycogen storage in multiple muscles of old GSD-II mice can be rapidly cleared after a single intravenous injection with a modified adenoviral vector expressing hGAA
- Author
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Felicia Migone, Andrea Amalfitano, Delila Serra, E. Y. Ding, Fang Xu, Yuan-Tsong Chen, and Ayn Schneider
- Subjects
congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Time Factors ,Transgene ,Blotting, Western ,Genetic Vectors ,Mice, Transgenic ,Biology ,medicine.disease_cause ,Adenoviridae ,Viral vector ,Mice ,chemistry.chemical_compound ,Internal medicine ,Drug Discovery ,Glycogen storage disease type II ,Genetics ,medicine ,Lysosomal storage disease ,Animals ,Molecular Biology ,Genetics (clinical) ,Glycogen ,Glycogen Storage Disease Type II ,Muscles ,Histological Techniques ,Age Factors ,nutritional and metabolic diseases ,Skeletal muscle ,alpha-Glucosidases ,Genetic Therapy ,medicine.disease ,Endocrinology ,medicine.anatomical_structure ,chemistry ,Acid alpha-glucosidase ,Molecular Medicine ,Glucan 1,4-alpha-Glucosidase - Abstract
Background Glycogen storage disease II (GSD-II) is an autosomal recessive lysosomal storage disease, due to acid-alpha-glucosidase (GAA) deficiency. The disease is characterized by massive glycogen accumulation in the cardiac and skeletal muscles. There is early onset (infantile, also known as Pompe disease) as well as late onset (juvenile and adult) forms of GSD-II. Few studies have been published to date that have explored the consequences of delivering a potential therapy to either late onset GSD-II subjects, and/or early onset patients with long-established muscle pathology. One recent report utilizing GAA-KO mice transgenically expressing human GAA (hGAA) suggested that long-established disease in both cardiac and skeletal muscle is likely to prove resistant to therapies. To investigate the potential for disease reversibility in old GSD-II mice, we studied their responsiveness to exogenous hGAA exposure via a gene therapy approach that we have previously shown to be efficacious in young GAA-KO mice. Methods An [E1-, polymerase-] adenoviral vector encoding hGAA was intravenously injected into two groups of aged GAA-KO mice; GAA expression and tissue glycogen reduction were evaluated. Results After vector injection, we found that extremely high amounts of hepatically secreted hGAA could be produced, and subsequently taken up by multiple muscle tissues in the old GAA-KO mice by 17 days post-injection (dpi). As a result, all muscle groups tested in the old GAA-KO mice showed significant glycogen reductions by 17 dpi, relative to that of age-matched, but mock-injected GAA-KO mice. For example, glycogen reduction in heart was 84%, in quadriceps 46%, and in diaphragm 73%. Our data also showed that the uptake and the subsequent intracellular processing of virally expressed hGAA were not impaired in older muscles. Conclusions Overall, the previously reported ‘resistance’ of old GAA-KO muscles to exogenous hGAA replacement approaches can be rapidly overcome after a single intravenous injection with a modified adenoviral vector expressing hGAA. Copyright © 2004 John Wiley & Sons, Ltd.
- Published
- 2005
29. Efficacy of an Adeno-associated Virus 8-Pseudotyped Vector in Glycogen Storage Disease Type II
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Andrew Bird, Yuan-Tsong Chen, Dwight D. Koeberl, Haoyue Zhang, Baodong Sun, Andrea Amalfitano, Luis M. Franco, Ayn Schneider, and Sarah P. Young
- Subjects
Male ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,viruses ,Genetic enhancement ,Genetic Vectors ,Motor Activity ,Biology ,medicine.disease_cause ,Virus ,Cell Line ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,Drug Discovery ,Glycogen storage disease type II ,Genetics ,medicine ,Animals ,Humans ,Vector (molecular biology) ,Molecular Biology ,Adeno-associated virus ,030304 developmental biology ,Mice, Knockout ,Pharmacology ,Sex Characteristics ,0303 health sciences ,Glycogen ,Glycogen Storage Disease Type II ,nutritional and metabolic diseases ,Skeletal muscle ,alpha-Glucosidases ,Genetic Therapy ,Dependovirus ,medicine.disease ,3. Good health ,Glucose ,medicine.anatomical_structure ,Endocrinology ,Gene Expression Regulation ,chemistry ,030220 oncology & carcinogenesis ,Molecular Medicine ,Female ,Glucan 1,4-alpha-Glucosidase ,Maltase - Abstract
Glycogen storage disease type II (GSD-II; Pompe disease) causes death in infancy from cardiorespiratory failure. The underlying deficiency of acid alpha-glucosidase (GAA; acid maltase) can be corrected by liver-targeted gene therapy in GSD-II, if secretion of GAA is accompanied by receptor-mediated uptake in cardiac and skeletal muscle. An adeno-associated virus (AAV) vector encoding human (h) GAA was pseudotyped as AAV8 (AAV2/8) and injected intravenously into immunodeficient GSD-II mice. High levels of hGAA were maintained in plasma for 24 weeks following AAV2/8 vector administration. A marked increase in vector copy number in the liver was demonstrated for the AAV2/8 vector compared to the analogous AAV2/2 vector. GAA deficiency in the heart and skeletal muscle was corrected with the AAV2/8 vector in male GSD-II mice, consistent with receptor-mediated uptake of hGAA. Male GSD-II mice demonstrated complete correction of glycogen storage in heart and diaphragm with the AAV2/8 vector, while female GSD-II mice had correction only in the heart. A biomarker for GSD-II was reduced in both sexes following AAV2/8 vector administration. Therefore, GAA production with an AAV2/8 vector in a depot organ, the liver, generated evidence for efficacious gene therapy in a mouse model for GSD-II.
- Published
- 2005
30. Alglucosidase alfa enzyme replacement therapy as a therapeutic approach for glycogen storage disease type III
- Author
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Adviye A. Tolun, Stephanie Austin, Beth L. Thurberg, Baodong Sun, Yuan-Tsong Chen, William E. Kraus, Deeksha Bali, Keri Fredrickson, and Priya S. Kishnani
- Subjects
Adult ,Male ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Pharmacology ,Biology ,Glycogen storage disease type III ,Biochemistry ,law.invention ,Glycogen Storage Disease Type III ,chemistry.chemical_compound ,Endocrinology ,law ,In vivo ,Internal medicine ,Genetics ,medicine ,Humans ,Myocyte ,Enzyme Replacement Therapy ,Muscle, Skeletal ,Molecular Biology ,Alglucosidase alfa ,Glycogen ,nutritional and metabolic diseases ,Skeletal muscle ,alpha-Glucosidases ,Enzyme replacement therapy ,Middle Aged ,medicine.disease ,Treatment Outcome ,medicine.anatomical_structure ,chemistry ,Recombinant DNA ,Female ,medicine.drug - Abstract
We investigated the feasibility of using recombinant human acid-α glucosidase (rhGAA, Alglucosidase alfa), an FDA approved therapy for Pompe disease, as a treatment approach for glycogen storage disease type III (GSD III). An in vitro disease model was established by isolating primary myoblasts from skeletal muscle biopsies of patients with GSD IIIa. We demonstrated that rhGAA significantly reduced glycogen levels in the two GSD IIIa patients' muscle cells (by 17% and 48%, respectively) suggesting that rhGAA could be a novel therapy for GSD III. This conclusion needs to be confirmed in other in vivo models.
- Published
- 2013
31. Nephrotic Syndrome Complicating α-Glucosidase Replacement Therapy for Pompe Disease
- Author
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John A. Phillips, Priya S. Kishnani, Andrea Amalfitano, George E. Tiller, Deyanira Corzo, Susan M. Richards, Yuan-Tsong Chen, Tracy E. Hunley, Martha Dudek, and Agnes B. Fogo
- Subjects
Male ,medicine.medical_specialty ,Nephrotic Syndrome ,Kidney ,Gastroenterology ,Antibodies ,Immune tolerance ,Immune system ,Membranous nephropathy ,Internal medicine ,Glycogen storage disease type II ,Immune Tolerance ,Humans ,Medicine ,Alglucosidase alfa ,Glycogen Storage Disease Type II ,business.industry ,alpha-Glucosidases ,Enzyme replacement therapy ,medicine.disease ,medicine.anatomical_structure ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,Immunology ,business ,Nephrotic syndrome ,medicine.drug - Abstract
We report a patient with Pompe disease who developed reversible nephrotic syndrome during prolonged, high-dose, experimental, enzyme replacement therapy with recombinant human acid α-glucosidase (rhGAA). Because of the development of antibodies to rhGAA and concomitant clinical decline, escalating doses of rhGAA were administered as part of an experimental immune tolerance regimen. Histologic evaluation of kidney tissue revealed glomerular deposition of immune complexes containing rhGAA itself, in a pattern of membranous nephropathy. To our knowledge, this is the first reported case of nephrotic syndrome occurring during enzyme replacement therapy. The nephrotic syndrome gradually resolved after the rhGAA dose was decreased, indicating that decreasing the antigenic load can ameliorate glomerular immune complex deposition associated with enzyme replacement in a highly sensitized patient.
- Published
- 2004
32. Glycogen debranching enzyme is associated with rat skeletal muscle sarcoplasmic reticulum
- Author
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S. J. Lees, J. H. Williams, and Yuan-Tsong Chen
- Subjects
medicine.medical_specialty ,Physiology ,Blotting, Western ,Stimulation ,Glycogen debranching enzyme ,Rats, Sprague-Dawley ,Glycogen debranching enzyme activity ,Glycogen phosphorylase ,chemistry.chemical_compound ,Physical Conditioning, Animal ,Internal medicine ,Glycogen branching enzyme ,medicine ,Animals ,Muscle, Skeletal ,Gel electrophoresis ,biology ,Glycogen ,Glycogen Phosphorylase ,Skeletal muscle ,Glycogen Debranching Enzyme System ,Sciatic Nerve ,Electric Stimulation ,Rats ,Sarcoplasmic Reticulum ,Endocrinology ,medicine.anatomical_structure ,chemistry ,biology.protein ,Electrophoresis, Polyacrylamide Gel ,Female - Abstract
AIMS: Gel electrophoresis revealed a band of molecular weight approximately 160 000 Da associated with the skeletal muscle sarcoplasmic reticulum (SR) vesicle preparations. This investigation sought to examine glycogen debranching enzyme associated with skeletal muscle SR. METHODS: Sarcoplasmic reticulum samples were also taken from muscle whose glycogen content had been reduced either via stimulation of the sciatic nerve or alpha-amylase treatment of muscle homogenates. RESULTS: The stimulation protocol reduced whole muscle glycogen by 86% (7.4 +/- 0.4 vs. 1.0 +/- 0.3 microg mg(-1) wet mass, P < or = 0.05). Glycogen associated with the SR was reduced by 82% in the stimulation protocol (533 +/- 82 vs. 96 +/- 7 microg mg(-1) protein) and by 94% in alpha-amylase treatment (493 +/- 11 vs. 29 +/- 2 microg mg(-1) protein), respectively. Gel electrophoresis and Western blots revealed that the content of glycogen debranching enzyme was reduced by approximately 53% as a result of muscle stimulation and by approximately 46% in alpha-amylase treatment (P < or = 0.05). In addition, glycogen debranching enzyme activity was reduced by 61% in stimulated samples compared with control (20.3 +/- 1.0 vs. 8.0 +/- 1.2 nmol mg(-1) min(-1), respectively), a value consistent with reductions observed from gel electrophoresis and Western blots. CONCLUSION: These results confirm that similar to glycogen phosphorylase, glycogen debranching enzyme is associated with the skeletal muscle SR and is dissociated under exercise conditions.
- Published
- 2004
33. Hypertension and Impaired Glycine Handling in Mice Lacking the Orphan Transporter XT2
- Author
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Yuan-Tsong Chen, Hui Quan, Marc G. Caron, Robert Stevens, Thomas M. Coffman, Krairerk Athirakul, William C. Wetsel, and Gonzalo E. Torres
- Subjects
Neurotransmitter transporter ,medicine.medical_specialty ,DNA, Complementary ,Glycine ,Blood Pressure ,Kidney ,Plasma Membrane Neurotransmitter Transport Proteins ,Excretion ,Mice ,Internal medicine ,Mammalian Genetic Models with Minimal or Complex Phenotypes ,medicine ,Animals ,Amino Acids ,Molecular Biology ,Dopamine transporter ,Mice, Knockout ,Base Sequence ,biology ,Reabsorption ,Membrane Transport Proteins ,Transporter ,Cell Biology ,Mice, Inbred C57BL ,Blood pressure ,medicine.anatomical_structure ,Endocrinology ,Gene Targeting ,Hypertension ,biology.protein ,Carrier Proteins ,Cotransporter - Abstract
A family of orphan transporters has been discovered that are structurally related to the Na(+)-Cl(-)-dependent neurotransmitter transporters, including the dopamine transporter. One member of this family, the mouse XT2 gene, is predominantly expressed in the kidney and has 95% homology to rat ROSIT (renal osmotic stress-induced Na(+)-Cl(-) organic solute cotransporter). To study the physiological functions of this transporter, we generated XT2-knockout mice by gene targeting. XT2(-/-) mice develop and survive normally with no apparent abnormalities. To attempt to identify potential substrates for XT2, we screened urine from XT2-knockout mice by high-pressure liquid chromatography and mass spectrometry and found significantly elevated concentrations of glycine. To study glycine handling, XT2(+/+) and XT2(-/-) mice were injected with radiolabeled glycine, and urine samples were collected to monitor glycine excretion. After 2 h, XT2(-/-) mice were found to excrete almost twice as much glycine as the XT2(+/+) controls (P = 0.03). To determine whether the absence of the XT2 transporter affected sodium and fluid homeostasis, we measured systolic blood pressure by computerized tail-cuff manometry. Systolic blood pressure was significantly higher in XT2(-/-) mice (127 +/- 3 mmHg) than in wild-type controls (114 +/- 2 mmHg; P0.001). This difference in systolic blood pressure was maintained on high and low salt feeding. To examine whether the alteration in blood pressure and the defect in glycine handling were related, we measured systolic blood pressure in the XT2(-/-) mice during dietary glycine supplementation. Glycine loading caused systolic blood pressure to fall in the XT2(-/-) mice from 127 +/- 3 to 115 +/- 3 mmHg (P0.001), a level virtually identical to that of the wild-type controls. These data suggest that the XT2 orphan transporter is involved in glycine reabsorption and that the absence of this transporter is sufficient to cause hypertension.
- Published
- 2004
34. ALBI Grade Determines Post-Progression Survivals after Sorafenib Treatment Failure in Advanced Hepatocellular Carcinoma Patients: A Model for Second-Line Trial Selection
- Author
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Chien Wei Su, P.-C. Lee, Yuan-Tsong Chen, Y.-H. Huang, Han Chieh Lin, and Yee Chao
- Subjects
Oncology ,medicine.medical_specialty ,Second line ,Hepatology ,business.industry ,Internal medicine ,Hepatocellular carcinoma ,medicine ,Sorafenib treatment ,medicine.disease ,business ,Selection (genetic algorithm) - Published
- 2016
35. Genetic epistasis of adiponectin and PPAR?2 genotypes in modulation of insulin sensitivity: a family-based association study
- Author
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John S. Grove, S.-S. Kuo, Chao A. Hsiung, Lee-Ming Chuang, Thomas Quertermous, Yii-Der Ida Chen, Yuan-Tsong Chen, Chih-Tsueng He, J. D. Curb, Wei-Shiung Yang, and Low-Tone Ho
- Subjects
China ,medicine.medical_specialty ,Genotype ,Endocrinology, Diabetes and Metabolism ,Mutation, Missense ,Receptors, Cytoplasmic and Nuclear ,Biology ,medicine.disease_cause ,Polymorphism, Single Nucleotide ,Asian People ,Gene Frequency ,Japan ,Gene interaction ,Internal medicine ,Internal Medicine ,medicine ,Humans ,Insulin ,Family ,Allele frequency ,Gene ,Genetics ,Mutation ,Adiponectin ,Proteins ,Epistasis, Genetic ,Exons ,Glucose Tolerance Test ,Phenotype ,Endocrinology ,Amino Acid Substitution ,Area Under Curve ,Hypertension ,Intercellular Signaling Peptides and Proteins ,Epistasis ,Insulin Resistance ,Transcription Factors - Abstract
Genetic interactions in modulating the phenotypes of a complex trait, such as insulin sensitivity, were usually taken for granted. However, this has not been commonly shown. Previous studies have suggested that both PPARgamma2 and adiponectin genes could influence insulin sensitivity. Therefore it is likely that they could modulate insulin sensitivity through gene to gene interactions.We genotyped 1793 subjects of Chinese and Japanese descendents from 601 hypertensive families recruited in Sapphire study for a T94G in the adiponectin gene exon 2 and the PPARgamma2 Pro12Ala polymorphisms. Serum insulin concentrations and insulin resistance index (HOMA(IR)) were used as the markers of insulin sensitivity.We found that the T allele of adiponectin gene was associated with a higher Ins60 and higher area under curve of insulin (AUCi) in OGTT utilizing all subjects in a mixed model that corrected for family effects. Important interactions between adiponectin and PPARgamma2 genotypes were found in fasting insulin concentrations (Ins0), insulin concentrations at 2-h (Ins120) in OGTT and insulin resistance index (HOMA(IR)). The main effects of the PPARgamma2 genotypes were in the plasma glucose concentrations in OGTT. In contrast, the main effects of adiponectin genotypes were in every insulin variable, including Ins0, Ins60, Ins120, AUCi and HOMA(IR). The subjects carrying the adiponectin G allele and the PPARgamma2 Ala12 allele seemed to be more insulin sensitive.These results showed that adiponectin is a genetic factor associated with insulin sensitivity. Interactions with PPARgamma2 genotypes modified this association.
- Published
- 2003
36. Long-term correction of glycogen storage disease type II with a hybrid Ad-AAV vector
- Author
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Yuan-Tsong Chen, Andrea Amalfitano, Baodong Sun, Dwight D. Koeberl, and Andrew Bird
- Subjects
medicine.medical_specialty ,Time Factors ,Genetic enhancement ,Blotting, Western ,Genetic Vectors ,Enzyme-Linked Immunosorbent Assay ,Hindlimb ,Biology ,Virus ,Adenoviridae ,Cell Line ,chemistry.chemical_compound ,Transduction (genetics) ,Mice ,Internal medicine ,Glycogen storage disease type II ,Drug Discovery ,medicine ,Genetics ,Animals ,Humans ,Tissue Distribution ,Northern blot ,Muscle, Skeletal ,Molecular Biology ,Mice, Knockout ,Pharmacology ,Glycogen ,Glycogen Storage Disease Type II ,Reverse Transcriptase Polymerase Chain Reaction ,Myocardium ,Skeletal muscle ,Dependovirus ,medicine.disease ,Blotting, Northern ,Endocrinology ,medicine.anatomical_structure ,Biochemistry ,chemistry ,Liver ,Molecular Medicine ,HeLa Cells ,Plasmids - Abstract
We administered an adenovirus-adeno-associated virus (Ad-AAV) vector encoding human acid α-glucosidase (hGAA) to acid α-glucosidase-knockout (GAA-KO) mice on day 3 of life by gastrocnemius injection. In contrast to previous results for muscle-targeted Ad vector in adult GAA-KO mice, the muscles of the hindlimb showed reduced glycogen content and persistent hGAA for as long as 6 months after neonatal Ad-AAV vector administration. Not only the injected gastrocnemius muscles, but also the hamstrings and quadriceps muscles produced therapeutic levels of hGAA as a result of widespread transduction with the Ad-AAV vector; moreover, hGAA activity was 50-fold elevated as compared to normal mice. Vector RNA was detected in the hindlimb muscles, the hearts, and the livers by northern blot analysis and/or by RT-PCR for as long as 6 months. The low levels of hGAA detected in the heart were attributable to transduction with the Ad-AAV vector, not to secretion of hGAA by the injected muscle and uptake by the heart. Finally, although an antibody response to hGAA was present, it did not prevent the correction of glycogen storage in the skeletal muscle of GAA-KO mice.
- Published
- 2003
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37. Tissue-Specific Inactivation of Murine M6P/IGF2R
- Author
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Andrew A. Wylie, David J. Pulford, Alison McVie-Wylie, Yuan-Tsong Chen, Randy L. Jirtle, Terry C. Orton, Catherine M. Nolan, Heather K. Evans, and Robert A. Waterland
- Subjects
medicine.medical_specialty ,T cell ,Insulin-like growth factor 2 receptor ,Kidney metabolism ,Gene targeting ,Biology ,Pathology and Forensic Medicine ,Cell biology ,medicine.anatomical_structure ,Endocrinology ,Growth factor receptor ,Internal medicine ,Insulin-like growth factor 2 ,Conditional gene knockout ,Knockout mouse ,medicine ,biology.protein - Abstract
The mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R) encodes a multifunctional protein involved in lysosomal enzyme trafficking, fetal organogenesis, tumor suppression, and T cell- mediated immunity. M6P/IGF2R is an imprinted gene in mice with expression only from the maternal allele. Complete knockout of this gene causes neonatal lethality, thus preventing analysis of its multifunctional role postnatally. To help elucidate the biological functions of M6P/IGF2R in adulthood, we generated both complete and tissue-specific M6P/IGF2R knockout mice using the Cre/loxP system. We confirm that complete M6P/IGF2R knockout results in fetal overgrowth and neonatal lethality. In contrast, tissue-specific inactivation of this gene in either the liver or skeletal and cardiac muscle gives rise to viable animals with no obvious phenotype. The successful creation of viable tissue-specific M6P/IGF2R knockout mouse models will now allow for detailed analysis of receptor function in a number of cellular processes including brain development, carcinogenesis, lysosomal trafficking, and T cell-mediated immunity.
- Published
- 2003
38. Multiple muscles in the AMD quail can be ?cross-corrected? of pathologic glycogen accumulation after intravenous injection of an [E1-, polymerase-] adenovirus vector encoding human acid-?-glucosidase
- Author
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Felicia Migone, Yuan-Tsong Chen, Delila Serra, E. Y. Ding, Andrea Amalfitano, D. Pressley, M. Mizutani, T. Kikuchi, T. Lawson, and Alison McVie-Wylie
- Subjects
medicine.medical_specialty ,Time Factors ,Blotting, Western ,Genetic Vectors ,Immunoblotting ,Quail ,Adenoviridae ,chemistry.chemical_compound ,Internal medicine ,Lysosome ,biology.animal ,Drug Discovery ,Gene expression ,Genetics ,medicine ,Animals ,Humans ,Myocyte ,Tissue Distribution ,Secretion ,Muscle, Skeletal ,Molecular Biology ,Genetics (clinical) ,Muscle Cells ,Glycogen ,biology ,Muscles ,Gene Transfer Techniques ,Skeletal muscle ,alpha-Glucosidases ,Genetic Therapy ,Disease Models, Animal ,medicine.anatomical_structure ,Endocrinology ,Liver ,chemistry ,Acid alpha-glucosidase ,Molecular Medicine ,Glucan 1,4-alpha-Glucosidase ,Lysosomes - Abstract
Background Previously, in murine models of acid maltase deficiency (AMD), we demonstrated that intravenous administration of an improved adenovirus (Ad) vector encoding human acid alpha glucosidase (hGAA) resulted in liver transduction, followed by high-level hepatocyte-mediated secretion of hGAA into the plasma space. The hGAA secreted by the liver was taken up and targeted to muscle cell lysosomes. The levels of hGAA achieved by this approach resulted in clearance of lysosomal glycogen accumulations; in some muscle tissues the effect was prolonged (>6 months). We next wished to demonstrate whether this approach could be generalized across divergent species. To accomplish this goal, we determined whether a similar approach would also result in efficacy, but in a quail model of AMD. Methods An [E1-, E2b-]Ad vector encoding hGAA was intravenously injected into AMD quails. At several time points thereafter, plasma, liver, and multiple muscle tissues were assayed for evidence of hGAA gene expression, liver-mediated hGAA secretion, uptake of hGAA by skeletal muscles, and evidence of glycogen correction in AMD skeletal muscles. These results were compared with those obtained from mock-injected AMD or wild-type quails. Results Intravenous [E1-, E2b-]Ad/hGAA vector injection resulted in high-level liver transduction and hepatic secretion of precursor forms of hGAA. The hepatically secreted hGAA was found to not only be efficiently taken up by cardiac and skeletal muscles, but was also proteolytically cleaved and processed equivalently to the quail-GAA protein detected in wild-type quails. The observations suggest that the signals regulating muscle cell uptake (but not proteolytic cleavage) of lysosomal enzymes are conserved and recognized across divergent species of vertebrates. Importantly, once localized to skeletal muscle lysosomes, the hGAA was able to effectively clear the glycogen accumulations present in AMD quail muscles. Conclusions Adenovirus-mediated transduction of the hGAA gene, followed by hepatic secretion, uptake, and cross-correction of the pathologic glycogen accumulation noted in multiple muscles of both the AMD mouse and AMD quail, adds support to the notion that gene transfer strategies (Ad-mediated or other agents) targeting liver tissues with the hGAA gene are likely to be highly efficacious in humans affected by AMD. Copyright © 2002 John Wiley & Sons, Ltd.
- Published
- 2003
39. Delivery of glucose-6-phosphatase in a canine model for glycogen storage disease, type Ia, with adeno-associated virus (AAV) vectors
- Author
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Yuan-Tsong Chen, Priya S. Kishnani, Denise Peterson, Talmage T. Brown, Daniel K. Benjamin, T Juopperi, Mark W. Jackson, R. M. Beaty, Anne Boney, Dwight D. Koeberl, and Andrew Bird
- Subjects
Blood Glucose ,medicine.medical_specialty ,Time Factors ,Genetic enhancement ,Genetic Vectors ,Glycogen Storage Disease Type I ,Biology ,medicine.disease_cause ,Virus ,chemistry.chemical_compound ,Dogs ,Transduction, Genetic ,Internal medicine ,Genetics ,medicine ,Animals ,Glycogen storage disease ,Lactic Acid ,Vector (molecular biology) ,Molecular Biology ,Adeno-associated virus ,Triglycerides ,Glycogen ,Genetic transfer ,Genetic Therapy ,Dependovirus ,medicine.disease ,Adenoviridae ,Cholesterol ,Endocrinology ,Liver ,chemistry ,Models, Animal ,Glucose-6-Phosphatase ,Molecular Medicine - Abstract
Therapy in glycogen storage disease type Ia (GSD Ia), an inherited disorder of carbohydrate metabolism, relies on nutritional support that postpones but fails to prevent long-term complications of GSD Ia. In the canine model for GSD Ia, we evaluated the potential of intravenously delivered adeno-associated virus (AAV) vectors for gene therapy. In three affected canines, liver glycogen was reduced following hepatic expression of canine glucose-6-phosphatase (G6Pase). Two months after AAV vector administration, one affected dog had normalization of fasting glucose, cholesterol, triglycerides, and lactic acid. Concatamerized AAV vector DNA was confirmed by Southern blot analysis of liver DNA isolated from treated dogs, as head-to-tail, head-to-head, and tail-to-tail concatamers. Six weeks after vector administration, the level of vector DNA signal in each dog varied from one to five copies per cell, consistent with variation in the efficiency of transduction within the liver. AAV vector administration in the canine model for GSD Ia resulted in sustained G6Pase expression and improvement in liver histology and in biochemical parameters.
- Published
- 2002
40. Validation of novel eligibility criteria by integrating ALBI grade and progression pattern for sorafenib-failed hepatocellular carcinoma
- Author
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Fa-Yauh Lee, Yuan-Tsong Chen, P.-C. Lee, Yee Chao, Han Chieh Lin, Mei Hsuan Lee, Y.-H. Huang, Ming-Chih Hou, C.-P. Li, Teh Ia Huo, and Chien Wei Su
- Subjects
Sorafenib ,Oncology ,medicine.medical_specialty ,Pathology ,Hepatology ,business.industry ,Hepatocellular carcinoma ,Internal medicine ,medicine ,medicine.disease ,business ,medicine.drug - Published
- 2017
41. Determinants of the over-anticoagulation response during warfarin initiation therapy in Asian patients based on population pharmacokinetic-pharmacodynamic analyses
- Author
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Minami Ohara, Chen-Hui Luo, Aki Arima, Yuan-Tsong Chen, Hui-Ping Chuang, Harumi Takahashi, Kiyoshi Mihara, Tsong-Hai Lee, Akiko Onozuka, Mari Shiomi, Ming Ta Michael Lee, Takashi Morita, Rui Nagai, and Ming-Shien Wen
- Subjects
Male ,Multivariate analysis ,CYP4F2 ,lcsh:Medicine ,Logistic regression ,Gastroenterology ,Cytochrome P-450 Enzyme System ,Medicine and Health Sciences ,heterocyclic compounds ,lcsh:Science ,Body surface area ,education.field_of_study ,Multidisciplinary ,Hematology ,Middle Aged ,Treatment Outcome ,Female ,VKORC1 ,medicine.drug ,Research Article ,medicine.medical_specialty ,Population ,Asian People ,Internal medicine ,Vitamin K Epoxide Reductases ,medicine ,Humans ,Pharmacokinetics ,cardiovascular diseases ,Cytochrome P450 Family 4 ,education ,CYP2C9 ,Blood Coagulation ,Aged ,Cytochrome P-450 CYP2C9 ,Pharmacology ,Polymorphism, Genetic ,Dose-Response Relationship, Drug ,Coagulation Disorders ,business.industry ,lcsh:R ,Warfarin ,Anticoagulants ,Surgery ,Logistic Models ,Pharmacodynamics ,Pharmacogenetics ,Mutation ,lcsh:Q ,Clinical Medicine ,business - Abstract
UNLABELLED:To clarify pharmacokinetic-pharmacodynamic (PK-PD) factors associated with the over-anticoagulation response in Asians during warfarin induction therapy, population PK-PD analyses were conducted in an attempt to predict the time-courses of the plasma S-warfarin concentration, Cp(S), and coagulation and anti-coagulation (INR) responses. In 99 Chinese patients we analyzed the relationships between dose and Cp(S) to estimate the clearance of S-warfarin, CL(S), and that between Cp(S) and the normal prothrombin concentration (NPT) as a coagulation marker for estimation of IC50. We also analyzed the non-linear relationship between NPT inhibition and the increase in INR to derive the non-linear index λ. Population analyses accurately predicted the time-courses of Cp(S), NPT and INR. Multivariate analysis showed that CYP2C9*3 mutation and body surface area were predictors of CL(S), that VKORC1 and CYP4F2 polymorphisms were predictors of IC50, and that baseline NPT was a predictor of λ. CL(S) and λ were significantly lower in patients with INR≥4 than in those with INR
- Published
- 2014
42. Mouse model of glycogen storage disease type III
- Author
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Jer-Yuarn Wu, Kai-Ming Liu, and Yuan-Tsong Chen
- Subjects
Male ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Immunoblotting ,Aspartate transaminase ,Biology ,Glycogen storage disease type III ,Biochemistry ,Glycogen debranching enzyme ,chemistry.chemical_compound ,Glycogen phosphorylase ,Glycogen Storage Disease Type III ,Mice ,Endocrinology ,Internal medicine ,Genetics ,medicine ,Glycogen storage disease ,Animals ,Humans ,Muscle Strength ,Molecular Biology ,Mice, Knockout ,Glycogen ,Glycogen Debranching Enzyme System ,Fasting ,medicine.disease ,Disease Models, Animal ,chemistry ,Alanine transaminase ,Liver ,Organ Specificity ,biology.protein ,Creatine kinase ,Female - Abstract
Glycogen storage disease type IIIa (GSD IIIa) is caused by a deficiency of the glycogen debranching enzyme (GDE), which is encoded by the Agl gene. GDE deficiency leads to the pathogenic accumulation of phosphorylase limit dextrin (PLD), an abnormal glycogen, in the liver, heart, and skeletal muscle. To further investigate the pathological mechanisms behind this disease and develop novel therapies to treat this disease, we generated a GDE-deficient mouse model by removing exons after exon 5 in the Agl gene. GDE reduction was confirmed by western blot and enzymatic activity assay. Histology revealed massive glycogen accumulation in the liver, muscle, and heart of the homozygous affected mice. Interestingly, we did not find any differences in the general appearance, growth rate, and life span between the wild-type, heterozygous, and homozygous affected mice with ad libitum feeding, except reduced motor activity after 50weeks of age, and muscle weakness in both the forelimb and hind legs of homozygous affected mice by using the grip strength test at 62weeks of age. However, repeated fasting resulted in decreased survival of the knockout mice. Hepatomegaly and progressive liver fibrosis were also found in the homozygous affected mice. Blood chemistry revealed that alanine transaminase (ALT), aspartate transaminase (AST) and alkaline phosphatase (ALP) activities were significantly higher in the homozygous affected mice than in both wild-type and heterozygous mice and the activity of these enzymes further increased with fasting. Creatine phosphokinase (CPK) activity was normal in young and adult homozygous affected mice. However, the activity was significantly elevated after fasting. Hypoglycemia appeared only at a young age (3weeks) and hyperlipidemia was not observed in our model. In conclusion, with the exception of normal lipidemia, these mice recapitulate human GSD IIIa; moreover, we found that repeated fasting was detrimental to these mice. This mouse model will be useful for future investigation regarding the pathophysiology and treatment strategy of human GSD III.
- Published
- 2014
43. Recombinant human acid α-glucosidase enzyme therapy for infantile glycogen storage disease type II: Results of a phase I/II clinical trial
- Author
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Yuan-Tsong Chen, A.Resai Bengur, John Phillips, Russell E. Ware, Andrea Amalfitano, Joanne Mackey, Joseph M. Majure, Richard P. Morse, Wendy A. Smith, Edward H. Bossen, Priya S. Kishnani, Jennifer A. Sullivan, George E. Hoganson, Alison McVie-Wylie, G. Bradley Schaefer, Deborah L. Veerling, Joel Charrow, and Laura E. Case
- Subjects
Cardiac function curve ,medicine.medical_specialty ,Skeletal muscle ,Enzyme replacement therapy ,Biology ,Muscle disorder ,medicine.disease ,Molecular biology ,Gastroenterology ,medicine.anatomical_structure ,Internal medicine ,Glycogen storage disease type II ,Acid alpha-glucosidase ,medicine ,Adverse effect ,Alglucosidase alfa ,Genetics (clinical) ,medicine.drug - Abstract
Purpose: Infantile glycogen storage disease type II (GSD-II) is a fatal genetic muscle disorder caused by deficiency of acid α-glucosidase (GAA). The purpose of this study was to investigate the safety and efficacy of recombinant human GAA (rhGAA) enzyme therapy for this fatal disorder. Methods: The study was designed as a phase I/II, open-label, single-dose study of rhGAA infused intravenously twice weekly in three infants with infantile GSD-II. rhGAA used in this study was purified from genetically engineered Chinese hamster ovary (CHO) cells overproducing GAA. Adverse effects and efficacy of rhGAA upon cardiac, pulmonary, neurologic, and motor functions were evaluated during 1 year of the trial period. The primary end point assessed was heart failure–free survival at 1 year of age. This was based on historical control data that virtually all patients died of cardiac failure by 1 year of age. Results: The results of more than 250 infusions showed that rhGAA was generally well tolerated. Steady decreases in heart size and maintenance of normal cardiac function for more than 1 year were observed in all three infants. These infants have well passed the critical age of 1 year (currently 16, 18, and 22 months old) and continue to have normal cardiac function. Improvements of skeletal muscle functions were also noted; one patient showed marked improvement and currently has normal muscle tone and strength as well as normal neurologic and Denver developmental evaluations. Muscle biopsies confirmed that dramatic reductions in glycogen accumulation had occurred after rhGAA treatment in this patient. Conclusions: This phase I/II first study of recombinant human GAA derived from CHO cells showed that rhGAA is capable of improving cardiac and skeletal muscle functions in infantile GSD-II patients. Further study will be needed to assess the overall potential of this therapy.
- Published
- 2001
44. Variant GADL1 and response to lithium therapy in bipolar I disorder
- Author
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Chien-Hsiun, Chen, Chau-Shoun, Lee, Ming-Ta Michael, Lee, Wen-Chen, Ouyang, Chiao-Chicy, Chen, Mian-Yoon, Chong, Jer-Yuarn, Wu, Happy Kuy-Lok, Tan, Yi-Ching, Lee, Liang-Jen, Chuo, Nan-Ying, Chiu, Hin-Yeung, Tsang, Ta-Jen, Chang, For-Wey, Lung, Chen-Huan, Chiu, Cheng-Ho, Chang, Ying-Sheue, Chen, Yuh-Ming, Hou, Cheng-Chung, Chen, Te-Jen, Lai, Chun-Liang, Tung, Chung-Ying, Chen, Hsien-Yuan, Lane, Tung-Ping, Su, Jung, Feng, Jin-Jia, Lin, Ching-Jui, Chang, Po-Ren, Teng, Chia-Yih, Liu, Chih-Ken, Chen, I-Chao, Liu, Jiahn-Jyh, Chen, Ti, Lu, Chun-Chieh, Fan, Ching-Kuan, Wu, Chang-Fang, Li, Kathy Hsiao-Tsz, Wang, Lawrence Shih-Hsin, Wu, Hsin-Ling, Peng, Chun-Ping, Chang, Liang-Suei, Lu, Yuan-Tsong, Chen, Andrew Tai-Ann, Cheng, and Ming-Kuen, Chou
- Subjects
Oncology ,Adult ,Male ,medicine.medical_specialty ,China ,Bipolar I disorder ,Bipolar Disorder ,Lithium (medication) ,Genotype ,Carboxy-Lyases ,Single-nucleotide polymorphism ,Lithium ,Polymorphism, Single Nucleotide ,Linkage Disequilibrium ,Maintenance Chemotherapy ,Exon ,Young Adult ,Asian People ,Lithium therapy ,Antimanic Agents ,Internal medicine ,medicine ,Humans ,Psychiatry ,Depression (differential diagnoses) ,Aged ,Aged, 80 and over ,business.industry ,General Medicine ,Middle Aged ,medicine.disease ,Phenotype ,Genomewide association ,Female ,medicine.symptom ,business ,Mania ,medicine.drug ,Genome-Wide Association Study - Abstract
Lithium has been a first-line choice for maintenance treatment of bipolar disorders to prevent relapse of mania and depression, but many patients do not have a response to lithium treatment.We selected subgroups from a sample of 1761 patients of Han Chinese descent with bipolar I disorder who were recruited by the Taiwan Bipolar Consortium. We assessed their response to lithium treatment using the Alda scale and performed a genomewide association study on samples from one subgroup of 294 patients with bipolar I disorder who were receiving lithium treatment. We then tested the single-nucleotide polymorphisms (SNPs) that showed the strongest association with a response to lithium for association in a replication sample of 100 patients and tested them further in a follow-up sample of 24 patients. We sequenced the exons, exon-intron boundaries, and part of the promoter of the gene encoding glutamate decarboxylase-like protein 1 (GADL1) in 94 patients who had a response to lithium and in 94 patients who did not have a response in the genomewide association sample.Two SNPs in high linkage disequilibrium, rs17026688 and rs17026651, that are located in the introns of GADL1 showed the strongest associations in the genomewide association study (P=5.50×10(-37) and P=2.52×10(-37), respectively) and in the replication sample of 100 patients (P=9.19×10(-15) for each SNP). These two SNPs had a sensitivity of 93% for predicting a response to lithium and differentiated between patients with a good response and those with a poor response in the follow-up cohort. Resequencing of GADL1 revealed a novel variant, IVS8+48delG, which lies in intron 8 of the gene, is in complete linkage disequilibrium with rs17026688 and is predicted to affect splicing.Genetic variations in GADL1 are associated with the response to lithium maintenance treatment for bipolar I disorder in patients of Han Chinese descent. (Funded by Academia Sinica and others.).
- Published
- 2013
45. Genome-wide association study in NSAID-induced acute urticaria/angioedema in Spanish and Han Chinese populations
- Author
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Inmaculada Doña, Chou Yc, Lin Sc, Natalia Blanca-López, Paloma Campo, Liou Lb, Chien Hsiun Chen, Cristobalina Mayorga, Jer-Yuarn Wu, Carmen Rondon, Javier Fernández, Gabriela Canto, Plaza-Serón Mdel C, Yuan-Tsong Chen, M.J. Torres, Lee Mt, Hui-Ping Chuang, Rosa-Maria Guéant-Rodriguez, Jean-Louis Guéant, Jose Julio Laguna, Miguel Blanca, Jose A. Cornejo-Garcia, Allergy Service [Carlos Haya Hospital], Hospital Regional Universitario Carlos Haya, Chang Gung Memorial Hospital and University, Allergy Service [Hospital Universitario Infanta Leonor], Hospital Universitario Infanta Leonor [Madrid], Academia Sinica, Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Cathay General Hospital [Taipei], Allergy Unit [Cruz Roja-Madrid], Hospital Central de la Cruz Roja San Jose y Santa Adela, Allergy Section [Alicante], Universidad de Alicante, RIKEN Center for Integrative Medical Sciences [Yokohama] (RIKEN IMS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), and China Medical University Taichung
- Subjects
Adult ,Male ,Han chinese ,medicine.medical_specialty ,Genotype ,Urticaria ,[SDV]Life Sciences [q-bio] ,acute urticaria/angioedema ,Genome-wide association study ,Drug Hypersensitivity ,03 medical and health sciences ,0302 clinical medicine ,Asian People ,mast cells NSAIDs ,Internal medicine ,Genetics ,Cyclic AMP ,Medicine ,Humans ,Angioedema ,030304 developmental biology ,Pharmacology ,0303 health sciences ,Acute urticaria ,business.industry ,Anti-Inflammatory Agents, Non-Steroidal ,Hispanic or Latino ,Middle Aged ,3. Good health ,030228 respiratory system ,Case-Control Studies ,Molecular Medicine ,Calcium ,Female ,medicine.symptom ,Tumor Suppressor Protein p53 ,business ,P53 signaling ,Genome-Wide Association Study - Abstract
Aim: Acute urticaria/angioedema (AUA) induced by cross-intolerance to NSAIDs is the most frequent clinical entity in hypersensitivity reactions to drugs. In this work, we conducted a genome-wide association study in Spanish and Han Chinese patients suffering from NSAID-induced AUA. Materials & methods: A whole-genome scan was performed on a total of 232 cases (112 Spanish and 120 Han Chinese) with NSAID-induced AUA and 225 unrelated controls (124 Spanish and 101 Han Chinese). Results: Although no polymorphism reached genome-wide significance, we obtained suggestive associations for three clusters in the Spanish group (RIMS1, BICC1 and RAD51L 1) and one region in the Han Chinese population (ABI3BP). Five regions showed suggestive associations after meta-analysis: HLF, RAD51L1, COL24A1, GalNAc-T13 and FBXL7. A majority of these genes are related to Ca2+, cAMP and/or P53 signaling pathways. Conclusion: The associations described were different from those related to the metabolism of arachidonic acid and could provide new mechanisms underlying NSAID-induced AUA. Original submitted 7 June 2013; Revision submitted 19 August 2013
- Published
- 2013
46. Acylcarnitines in fibroblasts of patients with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency and other fatty acid oxidation disorders
- Author
-
Michael D. Feezor, Michael J. Bennett, Steven L. Hillman, Dietrich Matern, M. Qumsiyeh, J. L. K. Van Hove, David S. Millington, Stephen G. Kahler, Yuan-Tsong Chen, and Jianjun Shen
- Subjects
medicine.medical_specialty ,Metabolite ,Mitochondrion ,Biology ,Microbodies ,chemistry.chemical_compound ,Carnitine ,Internal medicine ,Genetics ,medicine ,Humans ,Myopathy ,Beta oxidation ,Cells, Cultured ,Genetics (clinical) ,chemistry.chemical_classification ,Fatty Acids ,3-Hydroxyacyl CoA Dehydrogenases ,Fibroblasts ,3-Hydroxyacyl-CoA Dehydrogenase ,Endocrinology ,Enzyme ,chemistry ,Biochemistry ,lipids (amino acids, peptides, and proteins) ,medicine.symptom ,Oxidation-Reduction ,Long-Chain-3-Hydroxyacyl-CoA Dehydrogenase ,medicine.drug - Abstract
Mitochondrial fatty acid oxidation disorders cause hypoglycaemia, hepatic dysfunction, myopathy, cardiomyopathy and encephalopathy. Despite their recognition for more than 15 years, diagnosis and treatment remain difficult. To help design rational diagnostic and therapeutic strategies, we studied the pathophysiology of accumulating metabolites in a whole-cell system. Acylcarnitines were quantified in cells and media of cultured fibroblasts after incubation with L-carnitine and fatty acids. Following incubation with palmitate, long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD)-deficient fibroblasts compared with controls showed elevation of hydroxypalmitoyl- and palmitoyl-carnitine and reduction of C10- and shorter acylcarnitines, and following incubation with linoleate an increase in C14:2-, C18:2- and hydroxy-C18:2- acylcarnitines and reduction in C10:1-acylcarnitines. Hydroxyacylcarnitines remained more intracellular compared to corresponding saturated acylcarnitines. Incubation with decanoate and octanoate showed absence of hydroxylated acylcarnitines and correction of secondary metabolic disturbances, suggesting that optimal treatment should include medium-chain triglycerides of these chain lengths. Fibroblasts of patients with other fatty acid oxidation disorders showed distinct elevations of disease-specific acylcarnitines. This acylcarnitine analysis allows the diagnosis of LCHAD deficiency and its differentiation from other fatty acid oxidation disorders, which can pose difficulties in vivo. The strategy has allowed in-depth analysis with different substrates, providing suggestions for the rational design of treatment trials.
- Published
- 2000
47. Nutritional deficiencies in a patient with glycogen storage disease type Ib
- Author
-
Anne Boney, Yuan-Tsong Chen, and Priya S. Kishnani
- Subjects
Male ,medicine.medical_specialty ,Pediatrics ,Adolescent ,Diet therapy ,Folic Acid Deficiency ,Glycogen Storage Disease Type I ,Weight loss ,Internal medicine ,Glycogen Storage Disease Type Ib ,Genetics ,medicine ,Humans ,Genetics (clinical) ,Glycogen storage disease type I ,business.industry ,Dietary management ,Vitamin B 12 Deficiency ,Iron Deficiencies ,Micronutrient ,medicine.disease ,Nutrition Disorders ,Malnutrition ,Parenteral nutrition ,Endocrinology ,medicine.symptom ,business ,Follow-Up Studies - Abstract
The current mainstay of treatment in glycogen storage disease type I (GSD I) is dietary management that includes providing a frequent source of glucose to prevent hypoglycaemia. To ensure compliance, routine follow-up by a health care team, including a dietitian, experienced in the treatment of GSD is necessary. We describe an adolescent patient with GSD Ib in good metabolic control who was admitted with a 3-month history of weakness, depression, vomiting, decreased appetite and a 11.4-kg weight loss. He had a recent onset of unsteady gait, inability to write, and sore mouth. After an extensive work-up, the patient was found to have vitamin B12, folate, iron and other nutritional deficiencies, which explained his symptoms. The patient improved within 72 h of initiation of total parenteral nutrition and therapeutic doses of deficient micronutrients, with a complete recovery in 2 months. Dietary restrictions, dependence on non-food products (e.g. cornstarch in GSD I), and social and developmental issues place individuals with metabolic disorders at a high risk for developing an array of nutritional deficiencies. This case highlights the importance of both close follow-up of the metabolic control and close monitoring of growth and nutritional intake in individuals with inborn errors of metabolism. This case also illustrates the importance of daily supplementation with appropriate multivitamins, calcium and other minerals needed to meet the Recommended Dietary Allowances (RDAs) in these patients.
- Published
- 1999
48. Systemic correction of the muscle disorder glycogen storage disease type II after hepatic targeting of a modified adenovirus vector encoding human acid-α-glucosidase
- Author
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Alison McVie-Wylie, Thomas L. Dawson, Paul H. Plotz, Andrea Amalfitano, Nina Raben, Yuan-Tsong Chen, and Hailiang Hu
- Subjects
medicine.medical_specialty ,Genetic enhancement ,Genetic Vectors ,Cytomegalovirus ,Biology ,Muscle disorder ,medicine.disease_cause ,Adenoviridae ,Viral vector ,Mice ,chemistry.chemical_compound ,Muscular Diseases ,Internal medicine ,Glycogen storage disease type II ,Lysosomal storage disease ,medicine ,Animals ,Humans ,Muscle, Skeletal ,Promoter Regions, Genetic ,Myopathy ,Mice, Knockout ,Multidisciplinary ,Glycogen ,Glycogen Storage Disease Type II ,alpha-Glucosidases ,Genetic Therapy ,Biological Sciences ,medicine.disease ,Genes, pol ,Mice, Inbred C57BL ,Endocrinology ,Liver ,chemistry ,medicine.symptom - Abstract
This report demonstrates that a single intravenous administration of a gene therapy vector can potentially result in the correction of all affected muscles in a mouse model of a human genetic muscle disease. These results were achieved by capitalizing both on the positive attributes of modified adenovirus-based vectoring systems and receptor-mediated lysosomal targeting of enzymes. The muscle disease treated, glycogen storage disease type II, is a lysosomal storage disorder that manifests as a progressive myopathy, secondary to massive glycogen accumulations in the skeletal and/or cardiac muscles of affected individuals. We demonstrated that a single intravenous administration of a modified Ad vector encoding human acid α-glucosidase (GAA) resulted in efficient hepatic transduction and secretion of high levels of the precursor GAA proenzyme into the plasma of treated animals. Subsequently, systemic distribution and uptake of the proenzyme into the skeletal and cardiac muscles of the GAA-knockout mouse was confirmed. As a result, systemic decreases (and correction) of the glycogen accumulations in a variety of muscle tissues was demonstrated. This model can potentially be expanded to include the treatment of other lysosomal enzyme disorders. Lessons learned from systemic genetic therapy of muscle disorders also should have implications for other muscle diseases, such as the muscular dystrophies.
- Published
- 1999
49. Clinical and metabolic correction of pompe disease by enzyme therapy in acid maltase-deficient quail
- Author
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Mark F. Pennybacker, J. L. K. Van Hove, M. Mizutani, Nobutsune Ichihara, H. W. Yang, Tateki Kikuchi, and Yuan-Tsong Chen
- Subjects
Male ,medicine.medical_specialty ,Recombinant Fusion Proteins ,CHO Cells ,Coturnix ,Muscle disorder ,Biology ,chemistry.chemical_compound ,Cricetinae ,Internal medicine ,biology.animal ,Glycogen storage disease type II ,medicine ,Animals ,Humans ,Tissue Distribution ,Myopathy ,Glycogen ,Bird Diseases ,Glycogen Storage Disease Type II ,Muscles ,Body Weight ,alpha-Glucosidases ,General Medicine ,biology.organism_classification ,medicine.disease ,Quail ,Endocrinology ,chemistry ,Acid alpha-glucosidase ,Glucan 1,4-alpha-Glucosidase ,medicine.symptom ,Maltase ,Research Article - Abstract
Pompe disease is a fatal genetic muscle disorder caused by a deficiency of acid alpha-glucosidase (GAA), a glycogen degrading lysosomal enzyme. GAA-deficient (AMD) Japanese quails exhibit progressive myopathy and cannot lift their wings, fly, or right themselves from the supine position (flip test). Six 4-wk-old acid maltase-deficient quails, with the clinical symptoms listed, were intravenously injected with 14 or 4.2 mg/kg of precursor form of recombinant human GAA or buffer alone every 2-3 d for 18 d (seven injections). On day 18, both high dose-treated birds (14 mg/kg) scored positive flip tests and flapped their wings, and one bird flew up more than 100 cm. GAA activity increased in most of the tissues examined. In heart and liver, glycogen levels dropped to normal and histopathology was normal. In pectoralis muscle, morphology was essentially normal, except for increased glycogen granules. In sharp contrast, sham-treated quail muscle had markedly increased glycogen granules, multi-vesicular autophagosomes, and inter- and intrafascicular fatty infiltrations. Low dose-treated birds (4.2 mg/kg) improved less biochemically and histopathologically than high dose birds, indicating a dose-dependent response. Additional experiment with intermediate doses and extended treatment (four birds, 5.7-9 mg/kg for 45 d) halted the progression of the disease. Our data is the first to show that an exogenous protein can target to muscle and produce muscle improvement. These data also suggest enzyme replacement with recombinant human GAA is a promising therapy for human Pompe disease.
- Published
- 1998
50. Double mutant fibrillin-1 (FBN1) allele in a patient with neonatal Marfan syndrome
- Author
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Stephen G. Kahler, Yuan-Tsong Chen, Maurice Godfrey, Priya S. Kishnani, Martha Decker-Phillips, and Mei Wang
- Subjects
musculoskeletal diseases ,Marfan syndrome ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Systemic disease ,Fibrillin-1 ,DNA Mutational Analysis ,Biology ,Fibrillins ,medicine.disease_cause ,Polymerase Chain Reaction ,Marfan Syndrome ,Exon ,Internal medicine ,Genetics ,medicine ,Humans ,cardiovascular diseases ,Allele ,Transversion ,Alleles ,Genetics (clinical) ,Extracellular Matrix Proteins ,Mutation ,Tricuspid valve ,Microfilament Proteins ,Infant ,Exons ,medicine.disease ,Endocrinology ,medicine.anatomical_structure ,Female ,Fibrillin ,Research Article - Abstract
It is now well established that defects in fibrillin-1 (FBN1) cause the variable and pleiotropic features of Marfan syndrome (MFS) and, at the most severe end of its clinical spectrum, neonatal Marfan syndrome (nMFS). Patients with nMFS have mitral and tricuspid valve involvement and aortic root dilatation, and die of congestive heart failure, often in the first year of life. Although mutations in classical MFS have been observed along the entire length of the FBN1 mRNA, mutations in nMFS appear to cluster in a relatively small region of FBN1, approximately between exons 24 and 34. Here we describe the appearance of two FBN1 mutations in a single allele of an infant with nMFS. The changes were within six bases of each other in exon 26. One was a T3212G transversion resulting in an I1071S amino acid substitution and the second was an A3219T transversion resulting in an E1073D amino acid substitution. This is the first reported double mutant allele in FBN1.
- Published
- 1996
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