DOCSLIB.ORG

Tissue-Specific Alteration of Metabolic Pathways Influences Glycemic Regulation

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Tissue-Specific Alteration of Metabolic Pathways Influences Glycemic Regulation bioRxiv preprint doi: https://doi.org/10.1101/790618; this version posted October 3, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. Tissue-Specific Alteration of Metabolic Pathways Influences Glycemic Regulation 1,2 3 4 5,6,7 Natasha H. J. Ng *, Sara M. Willems *, Juan Fernandez , Rebecca S. Fine , Eleanor Wheeler8,3, Jennifer Wessel9,10, Hidetoshi Kitajima4, Gaelle Marenne8, Jana K. Rundle1, Xueling Sim11,12, Hanieh Yeghootkar13, Nicola L. Beer1, Anne Raimondo1, Andrei I. Tarasov1, Soren K. Thomsen1,14, Martijn van de Bunt4,1, Shuai Wang15, Sai Chen12, Yuning Chen15, Yii-Der Ida Chen16, Hugoline G. de Haan17, Niels Grarup18, Ruifang Li-Gao17, Tibor V. Varga19, Jennifer L Asimit8,20, Shuang Feng21, Rona J. Strawbridge22,23, Erica L. Kleinbrink24, Tarunveer S. Ahluwalia25,26, Ping An27, Emil V. Appel18, Dan E Arking28, Juha Auvinen29,30, Lawrence F. Bielak31, Nathan A. Bihlmeyer28, Jette Bork-Jensen18, Jennifer A. Brody32,33, Archie Campbell34, Audrey Y Chu35, Gail Davies36,37, Ayse Demirkan38, James S. Floyd32,33, Franco Giulianini35, Xiuqing Guo16, Stefan Gustafsson39, Benoit Hastoy1, Anne U. Jackson12, Johanna Jakobsdottir40, Marjo-Riitta Jarvelin41,29,42, Richard A. Jensen32,33, Stavroula Kanoni43, Sirkka Keinanen- Kiukaanniemi44,45, Jin Li46, Man Li47,48, Kurt Lohman49, Yingchang Lu50,51, Jian'an Luan3, Alisa K. Manning52,53, Jonathan Marten54, Carola Marzi55,56, Karina Meidtner57,56, Dennis O. Mook- Kanamori17,58, Taulant Muka59,38, Giorgio Pistis60,61, Bram Prins8, Kenneth M. Rice32,62, Neil Robertson4, Serena Sanna60,63, Yuan Shi64, Albert Vernon Smith40,65, Jennifer A. Smith31,66, Lorraine Southam8,4,67, Heather M. Stringham12, Salman M. Tajuddin68, Vinicius Tragante69, Sander W. van der Laan70,71, Helen R. Warren43,72, Jie Yao16, Andrianos M. Yiorkas73,74, Weihua 75,76 31 77 78 78,79 Zhang , Wei Zhao , Emma Ahlqvist , Mariaelisa Graff , Heather M. Highland , Anne E. Justice78, Ken Sin Lo80, Eirini Marouli43, Carolina Medina-Gomez38,81, Saima Afaq41, Wesam A Alhejily43,82, Najaf Amin38, Folkert W. Asselbergs69,83,84 , Lori L. Bonnycastle85, Michiel L. Bots86, Ivan Brandslund87, Ji Chen8, Cramer Christensen88, John Danesh89, Renée de Mutsert17, Abbas Dehghan38,90,91, Tapani Ebeling92, Paul Elliott41,93,94, EPIC-InterAct Consortium, Aliki-Eleni Farmaki95,96, Jessica D. Faul66, Paul W. Franks19,97,6, Steve Franks98, Andreas Fritsche99,56, Anette P. Gjesing18, Mark O. Goodarzi100, Vilmundur Gudnason40,65, Göran Hallmans101, Tamara B. Harris40, Karl-Heinz Herzig102,103, Marie-France Hivert104,105, Jan-Håkan Jansson106, Min A Jhun31,107, Torben Jørgensen108,109,110, Marit E. Jørgensen26,111, Pekka Jousilahti112, Eero Kajantie113,112,114,115, Maria Karaleftheri116, Sharon L.R. Kardia31, Leena Kinnunen112, Heikki A. Koistinen112,117,118, Pirjo Komulainen119, Peter Kovacs120,121, Johanna Kuusisto122, Markku Laakso122, Leslie A. Lange123, Lenore J112. Launer40, Jung-Jin Lee124, Aaron Leong125, Jaana Lindström112, Jocelyn E. Manning Fox126,127, Satu Männistö112, Nisa M Maruthur128,129,48, Leena Moilanen130, Antonella Mulas60,131, Mike A. Nalls132,133, Matthew Neville1, James S. Pankow134, Alison Pattie37, Eva R.B. Petersen135, Hannu Puolijoki136, Asif Rasheed137, Paul Redmond37, Frida Renström19,101, Michael Roden138,139,56, Danish Saleheen124,137, Juha Saltevo140, Kai Savonen119,141, Sylvain Sebert44,42, Tea Skaaby108, Kerrin S Small142, Alena Stančáková122, Jakob Stokholm25, Konstantin Strauch143, E-Shyong Tai144,11,145, Kent D. Taylor16, Betina H. Thuesen108, Anke Tönjes121, Emmanouil Tsafantakis146, Tiinamaija Tuomi147,148,149, Jaakko Tuomilehto112,150,151,152, Understanding Society Scientific Group, Matti Uusitupa153, Marja Vääräsmäki154,155, Ilonca Vaartjes86, Magdalena Zoledziewska60, Goncalo Abecasis61, Beverley Balkau156, Hans Bisgaard25, Alexandra I. Blakemore74,73, Matthias Blüher120,121, Heiner Boeing157, Eric Boerwinkle158, Klaus Bønnelykke25, Erwin P. Bottinger50, bioRxiv preprint doi: https://doi.org/10.1101/790618; this version posted October 3, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. Mark J. Caulfield43,72, John C Chambers41,76,159, Daniel I Chasman35,160,161, Ching-Yu 64,162,163 1 85 48,129 60,131 Cheng , Anne Clark , Francis S. Collins , Josef Coresh , Francesco Cucca , Gert J. de Borst164, Ian J. Deary36,37, George Dedoussis95, Panos Deloukas43,165, Hester M. den Ruijter70, Josée Dupuis15,166, Michele K. Evans68, Ele Ferrannini167, Oscar H Franco38,59, Harald Grallert55,56, Leif Groop168,149, Torben Hansen18,169, Andrew T. Hattersley170, Caroline Hayward54, Joel N. Hirschhorn171,6,7, Arfan Ikram38, Erik Ingelsson46,39,172,173, Fredrik Karpe1,174, Kay-Tee Kaw175, Wieland Kiess176, Jaspal S Kooner177,76,159, Antje Körner176, Timo Lakka178,119,141, Claudia Langenberg3, Lars Lind179, Cecilia M Lindgren4,180, Allan Linneberg108,181, Leonard Lipovich24,182, Ching-Ti Liu15, Jun Liu38, Yongmei Liu183, Ruth J.F. Loos50,184, Patrick E. MacDonald126,127, Karen L. Mohlke185, Andrew D Morris186, Patricia B. Munroe43,72, Alison Murray187, Sandosh Padmanabhan188, Colin N A Palmer189, Gerard Pasterkamp70,71, Oluf Pedersen18, Patricia A. Peyser31, Ozren Polasek190, David Porteous34, Michael A. Province27, Bruce M Psaty32,33,191,192, Rainer Rauramaa119, Paul M Ridker35,160,193, Olov Rolandsson194, 1,174 17 186 112 Patrik Rorsman , Frits R. Rosendaal , Igor Rudan , Veikko Salomaa , Matthias B. Schulze57,56, Robert Sladek195,196, Blair H Smith189, Timothy D Spector142, John M. Starr197,36, Michael Stumvoll121, Cornelia M van Duijn38, Mark Walker198, Nick J. Wareham3, David R. Weir66, James G. Wilson199, Tien Yin Wong64,162,163, Eleftheria Zeggini8,67, Alan B. Zonderman68, Jerome I. Rotter16, Andrew P. Morris200,4, Michael Boehnke12, Jose Florez201,202, Mark I McCarthy4,1,174, James B Meigs125,202, Anubha Mahajan4, Robert A. Scott3, Anna L Gloyn1,4,174*+, Inês Barroso8,3*+ *Authors contributed equally +Corresponding authors: Anna L Gloyn - [email protected] Inês Barroso- [email protected] 1. Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK, OX3 7LE. 2. Stem Cells and Diabetes Laboratory, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore 138673, Singapore 3. MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK. 4. Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK, OX3 7BN 5. Department of Genetics, Harvard Medical School, Boston, MA, 02115 6. Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, MA 02115 7. Broad Institute of MIT and Harvard, Cambridge, MA, 02142 8. Department of Human Genetics, Wellcome Sanger Institute, Genome Campus, Hinxton, Cambridge, CB10 1SA, UK 9. Departments of Epidemiology & Medicine, Schools of Public Health & Medicine, Indiana University, Indiaiapolis, IN 46202 10. Diabetes Translational Research Center, Indiana University School of Medicine, Indianapolis, IN 46202 bioRxiv preprint doi: https://doi.org/10.1101/790618; this version posted October 3, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 11. Saw Swee Hock School of Public Health, National University Health System, National University of Singapore, Singapore 117549, Singapore. 12. Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI 48109, USA 13. Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, EX2 5DW, UK 14. Present address: Vertex Pharmaceuticals Europe Ltd, Milton Park, Abingdon, OX14 4RW, UK 15. Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA. 16. Institute for Translational Genomics and Population Sciences, Departments of Pediatrics and Medicine, LABiomed at Harbor-UCLA Medical Center, Torrance, CA, USA 17. Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, 2333 ZA, the Netherlands 18. Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark 19. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Malmö, SE-205 02, Sweden 20. MRC Biostatistics Unit, Cambridge Biomedical Campus, Cambridge Institute of Public Health, Forvie Site, Robinson Way, Cambridge CB2 0SR, UK. 21. Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan, USA 22. UKRI Innovation Fellow at HDR UK,Mental Health and Wellbeing, Institute of Health and Wellbeing, College of Medical, Veterinary and Life Sciences, University of Glasgow, Room 113, 1 Lilybank Gardens ,Glasgow, G12 8RZ 23. Cardiovascular Medicine Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm,171 76, Sweden 24. Center for Molecular Medicine and Genetics, Wayne State University,
Load more

Recommended publications
  • The Genetics of Nontraditional Glycemic Biomarkers of Type 2 Diabetes
    THE GENETICS OF NONTRADITIONAL GLYCEMIC BIOMARKERS OF TYPE 2 DIABETES by Stephanie J. Loomis, MPH A dissertation submitted to The Johns Hopkins University in conformity with the requirements for the degree of Doctor of Philosophy Baltimore, Maryland May, 2018 © 2018 Stephanie J. Loomis All rights reserved Abstract Type 2 diabetes is a major public health problem that affects over 10% of the US adult population. It is associated with substantially increased risks of mortality and serious clinical outcomes such as heart disease, stroke, kidney disease and retinopathy. Diabetes is defined by hyperglycemia, or elevated glucose concentrations in the blood, which are commonly measured by fasting glucose and hemoglobin A1c (HbA1c), but these have limitations. As a result, nontraditional glycemic biomarkers, fructosamine, glycated albumin and 1,5-anhydroglucitol (1,5-AG) are gaining interest. While it is established that genetics play a role in type 2 diabetes, fasting glucose, and HbA1c, the genetics of fructosamine, glycated albumin, and 1,5-AG have not been well explored. This dissertation sought to determine the amount of variation in each biomarker due to genetics through heritability estimation, and to determine the specific genetic variants associated with each biomarker though genome wide association study (GWAS) analysis, multivariate phenotype analysis, and exome sequencing analysis. Heritability estimates showed a substantial portion of fructosamine, glycated albumin and 1,5-AG variation was due to genetics, which is likely comprised of both common and rare variants. GWAS identified common variants associated with fructosamine and glycated albumin including a known diabetes variant and a likely nonglycemic variant. Exome sequencing did not identify variants associated with fructosamine and glycated albumin, but multivariate phenotype analysis identified a potentially interesting region in a gene that alters bilirubin levels that may affect fructosamine in a nonglycemic manner.
    [Show full text]
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
    [Show full text]
  • SUPPLEMENTARY DATA Principal Investigators and Acknowledgment
    SUPPLEMENTARY DATA Principal Investigators and Acknowledgment Hispanic Community Health Study/Study of Latinos (HSHC/SOL) Robert Kaplan, Sylvia Wassertheil-Smoller (Bronx); Martha L. Daviglus, Aida L. Giachello (Chicago); Neil Schneiderman, David Lee, Leopoldo Raij, John Ryan (Miami); Greg Talavera, John Elder, Matthew Allison, Michael Criqui (San Deigo). The authors thank the staff and participants of HCHS/SOL for their important contributions. A complete list of staff and investigators has been provided by Sorlie P., et al. in Ann Epidemiol. 2010 ;20:642-649 and is also available on the study website http://www.cscc.unc.edu/hchs/. The baseline examination of the Hispanic Community Health Study/Study of Latinos was carried out as a collaborative study supported by contracts from the National Heart, Lung, and Blood Institute (NHLBI) to the University of North Carolina (N01-HC65233), University of Miami (N01-HC65234), Albert Einstein College of Medicine (N01-HC65235), Northwestern University (N01-HC65236), and San Diego State University (N01-HC65237). The following Institutes/Centers/Offices contributed to the HCHS/SOL first funding period through a transfer of funds to the NHLBI: National Institute on Minority Health and Health Disparities, the National Institute of Deafness and Other Communications Disorders, the National Institute of Dental and Craniofacial Research, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Neurological Disorders and Stroke, and the NIH Office of Dietary Supplements. The Genetic Analysis Center at the University of Washington was supported by NHLBI and NIDCR contracts (HHSN268201300005C AM03 and MOD03). Genotyping efforts were supported by NHLBI HSN 26220/20054C, NCATS CTSI grant UL1TR000123, and NIDDK Diabetes Research Center (DRC) grant DK063491.
    [Show full text]
  • Supplementary Table S4. FGA Co-Expressed Gene List in LUAD
    Supplementary Table S4. FGA co-expressed gene list in LUAD tumors Symbol R Locus Description FGG 0.919 4q28 fibrinogen gamma chain FGL1 0.635 8p22 fibrinogen-like 1 SLC7A2 0.536 8p22 solute carrier family 7 (cationic amino acid transporter, y+ system), member 2 DUSP4 0.521 8p12-p11 dual specificity phosphatase 4 HAL 0.51 12q22-q24.1histidine ammonia-lyase PDE4D 0.499 5q12 phosphodiesterase 4D, cAMP-specific FURIN 0.497 15q26.1 furin (paired basic amino acid cleaving enzyme) CPS1 0.49 2q35 carbamoyl-phosphate synthase 1, mitochondrial TESC 0.478 12q24.22 tescalcin INHA 0.465 2q35 inhibin, alpha S100P 0.461 4p16 S100 calcium binding protein P VPS37A 0.447 8p22 vacuolar protein sorting 37 homolog A (S. cerevisiae) SLC16A14 0.447 2q36.3 solute carrier family 16, member 14 PPARGC1A 0.443 4p15.1 peroxisome proliferator-activated receptor gamma, coactivator 1 alpha SIK1 0.435 21q22.3 salt-inducible kinase 1 IRS2 0.434 13q34 insulin receptor substrate 2 RND1 0.433 12q12 Rho family GTPase 1 HGD 0.433 3q13.33 homogentisate 1,2-dioxygenase PTP4A1 0.432 6q12 protein tyrosine phosphatase type IVA, member 1 C8orf4 0.428 8p11.2 chromosome 8 open reading frame 4 DDC 0.427 7p12.2 dopa decarboxylase (aromatic L-amino acid decarboxylase) TACC2 0.427 10q26 transforming, acidic coiled-coil containing protein 2 MUC13 0.422 3q21.2 mucin 13, cell surface associated C5 0.412 9q33-q34 complement component 5 NR4A2 0.412 2q22-q23 nuclear receptor subfamily 4, group A, member 2 EYS 0.411 6q12 eyes shut homolog (Drosophila) GPX2 0.406 14q24.1 glutathione peroxidase
    [Show full text]
  • Identification of Potential Key Genes and Pathway Linked with Sporadic Creutzfeldt-Jakob Disease Based on Integrated Bioinformatics Analyses
    medRxiv preprint doi: https://doi.org/10.1101/2020.12.21.20248688; this version posted December 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. Identification of potential key genes and pathway linked with sporadic Creutzfeldt-Jakob disease based on integrated bioinformatics analyses Basavaraj Vastrad1, Chanabasayya Vastrad*2 , Iranna Kotturshetti 1. Department of Biochemistry, Basaveshwar College of Pharmacy, Gadag, Karnataka 582103, India. 2. Biostatistics and Bioinformatics, Chanabasava Nilaya, Bharthinagar, Dharwad 580001, Karanataka, India. 3. Department of Ayurveda, Rajiv Gandhi Education Society`s Ayurvedic Medical College, Ron, Karnataka 562209, India. * Chanabasayya Vastrad [email protected] Ph: +919480073398 Chanabasava Nilaya, Bharthinagar, Dharwad 580001 , Karanataka, India NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. medRxiv preprint doi: https://doi.org/10.1101/2020.12.21.20248688; this version posted December 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. Abstract Sporadic Creutzfeldt-Jakob disease (sCJD) is neurodegenerative disease also called prion disease linked with poor prognosis. The aim of the current study was to illuminate the underlying molecular mechanisms of sCJD. The mRNA microarray dataset GSE124571 was downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were screened.
    [Show full text]
  • A Clinical and Molecular Review of Ubiquitous Glucose-6-Phosphatase Deficiency Caused by G6PC3 Mutations Siddharth Banka1,2* and William G Newman1,2
    Banka and Newman Orphanet Journal of Rare Diseases 2013, 8:84 http://www.ojrd.com/content/8/1/84 REVIEW Open Access A clinical and molecular review of ubiquitous glucose-6-phosphatase deficiency caused by G6PC3 mutations Siddharth Banka1,2* and William G Newman1,2 Abstract The G6PC3 gene encodes the ubiquitously expressed glucose-6-phosphatase enzyme (G-6-Pase β or G-6-Pase 3 or G6PC3). Bi-allelic G6PC3 mutations cause a multi-system autosomal recessive disorder of G6PC3 deficiency (also called severe congenital neutropenia type 4, MIM 612541). To date, at least 57 patients with G6PC3 deficiency have been described in the literature. G6PC3 deficiency is characterized by severe congenital neutropenia, recurrent bacterial infections, intermittent thrombocytopenia in many patients, a prominent superficial venous pattern and a high incidence of congenital cardiac defects and uro-genital anomalies. The phenotypic spectrum of the condition is wide and includes rare manifestations such as maturation arrest of the myeloid lineage, a normocellular bone marrow, myelokathexis, lymphopaenia, thymic hypoplasia, inflammatory bowel disease, primary pulmonary hypertension, endocrine abnormalities, growth retardation, minor facial dysmorphism, skeletal and integument anomalies amongst others. Dursun syndrome is part of this extended spectrum. G6PC3 deficiency can also result in isolated non-syndromic severe neutropenia. G6PC3 mutations in result in reduced enzyme activity, endoplasmic reticulum stress response, increased rates of apoptosis of affected cells and dysfunction of neutrophil activity. In this review we demonstrate that loss of function in missense G6PC3 mutations likely results from decreased enzyme stability. The condition can be diagnosed by sequencing the G6PC3 gene. A number of G6PC3 founder mutations are known in various populations and a possible genotype-phenotype relationship also exists.
    [Show full text]
  • Specificity of a Polyclonal Fecal Elastase ELISA for CELA3
    RESEARCH ARTICLE Specificity of a Polyclonal Fecal Elastase ELISA for CELA3 Frank Ulrich Weiss, Christoph Budde, Markus M. Lerch* University Medicine Greifswald, Department of Medicine A, Ferdinand Sauerbruch-Str., D-17475 Greifswald, Germany * [email protected] a11111 Abstract Introduction Elastase is a proteolytic pancreatic enzyme that passes through the gastrointestinal tract undergoing only limited degradation. ELISA tests to determine stool elastase concentra- tions have therefore been developed for the diagnosis of exocrine pancreatic insufficiency. OPEN ACCESS Five different isoforms of pancreatic elastase (CELA1, CELA2A, CELA2B, CELA3A, Citation: Weiss FU, Budde C, Lerch MM (2016) CELA3B) are encoded in the human genome. We have investigated three different poly- Specificity of a Polyclonal Fecal Elastase ELISA for CELA3. PLoS ONE 11(7): e0159363. doi:10.1371/ clonal antisera that are used in a commercial fecal elastase ELISA to determine their speci- journal.pone.0159363 ficity for different pancreatic elastase isoforms. Editor: Keping Xie, The University of Texas MD Anderson Cancer Center, UNITED STATES Material and Methods Received: October 9, 2015 Different polyclonal rabbit antisera against human elastase peptides (BIOSERV Diagnos- Accepted: July 2, 2016 tics GmbH, Germany) were tested by Western blot analysis of human pancreatic juice, in HEK-293 cells expressing Elastase constructs, and in the protein content of porcine pancre- Published: July 26, 2016 atin, used for treatment of exocrine pancreatic insufficiency. Copyright: © 2016 Weiss et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits Results unrestricted use, distribution, and reproduction in any In human pancreatic juice the polyclonal antisera detected proteins at the corresponding medium, provided the original author and source are size of human pancreatic elastase isoforms (~29kDa).
    [Show full text]
  • G6PC Gene Glucose-6-Phosphatase Catalytic Subunit
    G6PC gene glucose-6-phosphatase catalytic subunit Normal Function The G6PC gene provides instructions for making an enzyme called glucose 6- phosphatase. This enzyme is found on the membrane of the endoplasmic reticulum, which is a structure inside cells that is involved in protein processing and transport. Glucose 6-phosphatase works together with the glucose 6-phosphate translocase protein (produced from the SLC37A4 gene) to break down a type of sugar molecule called glucose 6-phosphate. The breakdown of this molecule produces the simple sugar glucose, which is the primary source of energy for most cells in the body. The glucose 6- phosphatase enzyme is expressed (active) in the liver, kidneys, and intestines, and is the main regulator of glucose production in the liver. Health Conditions Related to Genetic Changes Glycogen storage disease type I At least 85 mutations in the G6PC gene have been found to cause glycogen storage disease type Ia (GSDIa). Most of these mutations change single protein building blocks ( amino acids) in the glucose 6-phosphatase enzyme. Some specific mutations are seen more frequently in certain ethnic or racial groups. Mutations in the G6PC gene impair the function of the glucose 6-phosphatase enzyme. When this enzyme is not functioning normally, glucose 6-phosphate is not broken down and glucose is not produced. Glucose 6-phosphate that is not broken down to glucose is converted to fat and glycogen, a complex sugar that is stored within cells. Too much fat and glycogen stored within a cell can be toxic. This buildup damages organs and tissues throughout the body, particularly the liver and kidneys, leading to the signs and symptoms of GSDIa.
    [Show full text]
  • Dysregulation of Post-Transcriptional Modification by Copy Number
    Yoshikawa et al. Translational Psychiatry (2021) 11:331 https://doi.org/10.1038/s41398-021-01460-1 Translational Psychiatry ARTICLE Open Access Dysregulation of post-transcriptional modification by copy number variable microRNAs in schizophrenia with enhanced glycation stress Akane Yoshikawa1,2,ItaruKushima 3,4, Mitsuhiro Miyashita 1,5,6,KazuyaToriumi 1, Kazuhiro Suzuki 1,5, Yasue Horiuchi 1, Hideya Kawaji 7, Shunya Takizawa8,NorioOzaki 3, Masanari Itokawa1 and Makoto Arai 1 Abstract Previously, we identified a subpopulation of schizophrenia (SCZ) showing increased levels of plasma pentosidine, a marker of glycation and oxidative stress. However, its causative genetic factors remain largely unknown. Recently, it has been suggested that dysregulated posttranslational modification by copy number variable microRNAs (CNV-miRNAs) may contribute to the etiology of SCZ. Here, an integrative genome-wide CNV-miRNA analysis was performed to investigate the etiology of SCZ with accumulated plasma pentosidine (PEN-SCZ). The number of CNV-miRNAs and the gene ontology (GO) in the context of miRNAs within CNVs were compared between PEN-SCZ and non-PEN-SCZ groups. Gene set enrichment analysis of miRNA target genes was further performed to evaluate the pathways affected in PEN-SCZ. We show that miRNAs were significantly enriched within CNVs in the PEN-SCZ versus non-PEN-SCZ groups (p = 0.032). Of note, as per GO analysis, the dysregulated neurodevelopmental events in the two groups may have different origins. Additionally, gene set enrichment analysis of miRNA target genes revealed that miRNAs involved in glycation/oxidative stress and synaptic neurotransmission, especially glutamate/GABA receptor signaling, fi 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; were possibly affected in PEN-SCZ.
    [Show full text]
  • Functional Genomic Annotation of Genetic Risk Loci Highlights Inflammation and Epithelial Biology Networks in CKD
    BASIC RESEARCH www.jasn.org Functional Genomic Annotation of Genetic Risk Loci Highlights Inflammation and Epithelial Biology Networks in CKD Nora Ledo, Yi-An Ko, Ae-Seo Deok Park, Hyun-Mi Kang, Sang-Youb Han, Peter Choi, and Katalin Susztak Renal Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania ABSTRACT Genome-wide association studies (GWASs) have identified multiple loci associated with the risk of CKD. Almost all risk variants are localized to the noncoding region of the genome; therefore, the role of these variants in CKD development is largely unknown. We hypothesized that polymorphisms alter transcription factor binding, thereby influencing the expression of nearby genes. Here, we examined the regulation of transcripts in the vicinity of CKD-associated polymorphisms in control and diseased human kidney samples and used systems biology approaches to identify potentially causal genes for prioritization. We interro- gated the expression and regulation of 226 transcripts in the vicinity of 44 single nucleotide polymorphisms using RNA sequencing and gene expression arrays from 95 microdissected control and diseased tubule samples and 51 glomerular samples. Gene expression analysis from 41 tubule samples served for external validation. 92 transcripts in the tubule compartment and 34 transcripts in glomeruli showed statistically significant correlation with eGFR. Many novel genes, including ACSM2A/2B, FAM47E, and PLXDC1, were identified. We observed that the expression of multiple genes in the vicinity of any single CKD risk allele correlated with renal function, potentially indicating that genetic variants influence multiple transcripts. Network analysis of GFR-correlating transcripts highlighted two major clusters; a positive correlation with epithelial and vascular functions and an inverse correlation with inflammatory gene cluster.
    [Show full text]
  • Role of Chymotrypsin-Like Elastase 1 in Lung Physiology and in Α1-Antitrypsin Deficiency
    bioRxiv preprint doi: https://doi.org/10.1101/138776; this version posted May 16, 2017. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Role of Chymotrypsin-like Elastase 1 in Lung Physiology and in α1-Antitrypsin Deficiency Authors: Rashika Joshi1a, Andrea Heinz2;3†, Qiang Fan1a, Shuling Guo4, Brett Monia4, Christian E.H. Schmelzer2,5, Anthony S. Weiss6a-c, Matthew Batie1b, Harikrishnan Parameswaran7, Brian M. Varisco*1a,8 Affiliations: 1-Cincinnati Childrens Hospital Medical Center, Cincinnati, Ohio a-Division of Critical Care Medicine b-Division of Clinical Engineering 2-Martin Luther University, Halle-Wittenberg, Germany 3-University of Copenhagen, Copenhagen, Denmark 4-Ionis Pharmaceuticals, Carlsbad, California 5-Fraunhofer Institute for Microstructure of Materials and Systems IMWS, Freiburg, Germany 6-University of Sydney, Sydney, Australia a-Charles Perkins Centre b-Life and Environmental Sciences c-Bosch Institute 7-Northeastern University Department of Biomedical Engineering, Boston, Massachusetts 8-Univeristy of Cincinnati Department of Pediatrics, Cincinnati, Ohio † Co-first Author * Corresponding Author. [email protected]. SUMMARY α1-antitrypsin (AAT) deficiency-related emphysema is the fourth leading indication for lung transplantation. We previously demonstrated that AAT covalently neutralizes chymotrypsin-like elastase 1 (Cela1) in vitro, that Cela1 is expressed during the alveolar stage of lung development in association with regions of lung elastin remodeling, and that lung stretch increases Cela1 expression and binding to lung elastin. Here we show that Cela1 is exclusively responsible for stretch-inducible lung elastase activity, reduces postnatal lung elastance, and is required for emphysema in an antisense oligo model of AAT deficiency.
    [Show full text]
  • Pancreatic Islet Beta Cell-Specific Deletion of G6pc2 Reduces Fasting Blood Glucose
    64 4 Journal of Molecular K J Bosma et al. G6pc2 deletion reduces fasting 64:4 235–248 Endocrinology blood glucose RESEARCH Pancreatic islet beta cell-specific deletion of G6pc2 reduces fasting blood glucose Karin J Bosma1, Mohsin Rahim2, Kritika Singh3, Slavina B Goleva3, Martha L Wall2, Jing Xia4, Kristen E Syring1, James K Oeser1, Greg Poffenberger3, Owen P McGuinness1, Anna L Means5, Alvin C Powers1,3,6, Wen-hong Li4, Lea K Davis1,3, Jamey D Young2 and Richard M O’Brien1 1Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA 2Department of Chemical and Biomolecular Engineering, Vanderbilt University School of Medicine, Nashville, Tennessee, USA 3Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA 4Departments of Cell Biology and of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA 5Department of Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee, USA 6VA Tennessee Valley Healthcare System, Nashville, Tennessee, USA Correspondence should be addressed to R M O’Brien: [email protected] Abstract The G6PC1, G6PC2 and G6PC3 genes encode distinct glucose-6-phosphatase catalytic Key Words subunit (G6PC) isoforms. In mice, germline deletion of G6pc2 lowers fasting blood glucose f diabetes II (FBG) without affecting fasting plasma insulin (FPI) while, in isolated islets, glucose-6- f islet cells phosphatase activity and glucose cycling are abolished and glucose-stimulated insulin f metabolism secretion (GSIS) is enhanced at submaximal but not high glucose. These observations are f pancreatic beta cell all consistent with a model in which G6PC2 regulates the sensitivity of GSIS to glucose by opposing the action of glucokinase.
    [Show full text]