Transcriptome analysis of controlled and therapy-resistant childhood asthma reveals distinct gene expression profiles

Background Children with problematic severe asthma have poor disease control despite high doses of inhaled corticosteroids and additional therapy, leading to personal suffering, early deterioration of lung function, and significant consumption of health care resources. If no exacerbating factors, su...

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Veröffentlicht in:Journal of allergy and clinical immunology 2015-09, Vol.136 (3), p.638-648
Hauptverfasser: Persson, Helena, PhD, Kwon, Andrew T., PhD, Ramilowski, Jordan A., PhD, Silberberg, Gilad, PhD, Söderhäll, Cilla, PhD, Orsmark-Pietras, Christina, PhD, Nordlund, Björn, RN, PhD, Konradsen, Jon R., MD, PhD, de Hoon, Michiel J.L., PhD, Melén, Erik, MD, PhD, Hayashizaki, Yoshihide, MD, PhD, Hedlin, Gunilla, MD, PhD, Kere, Juha, MD, PhD, Daub, Carsten O., PhD
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container_issue 3
container_start_page 638
container_title Journal of allergy and clinical immunology
container_volume 136
creator Persson, Helena, PhD
Kwon, Andrew T., PhD
Ramilowski, Jordan A., PhD
Silberberg, Gilad, PhD
Söderhäll, Cilla, PhD
Orsmark-Pietras, Christina, PhD
Nordlund, Björn, RN, PhD
Konradsen, Jon R., MD, PhD
de Hoon, Michiel J.L., PhD
Melén, Erik, MD, PhD
Hayashizaki, Yoshihide, MD, PhD
Hedlin, Gunilla, MD, PhD
Kere, Juha, MD, PhD
Daub, Carsten O., PhD
description Background Children with problematic severe asthma have poor disease control despite high doses of inhaled corticosteroids and additional therapy, leading to personal suffering, early deterioration of lung function, and significant consumption of health care resources. If no exacerbating factors, such as smoking or allergies, are found after extensive investigation, these children are given a diagnosis of therapy-resistant (or therapy-refractory) asthma (SA). Objective We sought to deepen our understanding of childhood SA by analyzing gene expression and modeling the underlying regulatory transcription factor networks in peripheral blood leukocytes. Methods Gene expression was analyzed by using Cap Analysis of Gene Expression in children with SA (n = 13), children with controlled persistent asthma (n = 15), and age-matched healthy control subjects (n = 9). Cap Analysis of Gene Expression sequencing detects the transcription start sites of known and novel mRNAs and noncoding RNAs. Results Sample groups could be separated by hierarchical clustering on 1305 differentially expressed transcription start sites, including 816 known genes and several novel transcripts. Ten of 13 tested novel transcripts were validated by means of RT-PCR and Sanger sequencing. Expression of RAR-related orphan receptor A  (RORA) , which has been linked to asthma in genome-wide association studies, was significantly upregulated in patients with SA. Gene network modeling revealed decreased glucocorticoid receptor signaling and increased activity of the mitogen-activated protein kinase and Jun kinase cascades in patients with SA. Conclusion Circulating leukocytes from children with controlled asthma and those with SA have distinct gene expression profiles, demonstrating the possible development of specific molecular biomarkers and supporting the need for novel therapeutic approaches.
doi_str_mv 10.1016/j.jaci.2015.02.026
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If no exacerbating factors, such as smoking or allergies, are found after extensive investigation, these children are given a diagnosis of therapy-resistant (or therapy-refractory) asthma (SA). Objective We sought to deepen our understanding of childhood SA by analyzing gene expression and modeling the underlying regulatory transcription factor networks in peripheral blood leukocytes. Methods Gene expression was analyzed by using Cap Analysis of Gene Expression in children with SA (n = 13), children with controlled persistent asthma (n = 15), and age-matched healthy control subjects (n = 9). Cap Analysis of Gene Expression sequencing detects the transcription start sites of known and novel mRNAs and noncoding RNAs. Results Sample groups could be separated by hierarchical clustering on 1305 differentially expressed transcription start sites, including 816 known genes and several novel transcripts. Ten of 13 tested novel transcripts were validated by means of RT-PCR and Sanger sequencing. Expression of RAR-related orphan receptor A  (RORA) , which has been linked to asthma in genome-wide association studies, was significantly upregulated in patients with SA. Gene network modeling revealed decreased glucocorticoid receptor signaling and increased activity of the mitogen-activated protein kinase and Jun kinase cascades in patients with SA. Conclusion Circulating leukocytes from children with controlled asthma and those with SA have distinct gene expression profiles, demonstrating the possible development of specific molecular biomarkers and supporting the need for novel therapeutic approaches.</description><identifier>ISSN: 0091-6749</identifier><identifier>ISSN: 1097-6825</identifier><identifier>EISSN: 1097-6825</identifier><identifier>DOI: 10.1016/j.jaci.2015.02.026</identifier><identifier>PMID: 25863981</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Adolescent ; Allergy and Immunology ; Asthma ; Asthma - drug therapy ; Asthma - genetics ; Asthma - pathology ; Case-Control Studies ; Child ; Child, Preschool ; childhood asthma ; Drug Resistance - genetics ; Female ; Gene expression ; Gene Expression Profiling ; Genome-Wide Association Study ; Glucocorticoids - therapeutic use ; Humans ; JNK Mitogen-Activated Protein Kinases - genetics ; long noncoding RNA ; Male ; Medicin och hälsovetenskap ; Nuclear Receptor Subfamily 1, Group F, Member 1 - genetics ; peripheral blood leukocytes ; Receptors, Glucocorticoid - genetics ; RNA polymerase ; RNA, Messenger - genetics ; Severity of Illness Index ; Therapy-resistant asthma ; Transcriptome</subject><ispartof>Journal of allergy and clinical immunology, 2015-09, Vol.136 (3), p.638-648</ispartof><rights>The Authors</rights><rights>2015 The Authors</rights><rights>Copyright © 2015 The Authors. Published by Elsevier Inc. 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If no exacerbating factors, such as smoking or allergies, are found after extensive investigation, these children are given a diagnosis of therapy-resistant (or therapy-refractory) asthma (SA). Objective We sought to deepen our understanding of childhood SA by analyzing gene expression and modeling the underlying regulatory transcription factor networks in peripheral blood leukocytes. Methods Gene expression was analyzed by using Cap Analysis of Gene Expression in children with SA (n = 13), children with controlled persistent asthma (n = 15), and age-matched healthy control subjects (n = 9). Cap Analysis of Gene Expression sequencing detects the transcription start sites of known and novel mRNAs and noncoding RNAs. Results Sample groups could be separated by hierarchical clustering on 1305 differentially expressed transcription start sites, including 816 known genes and several novel transcripts. Ten of 13 tested novel transcripts were validated by means of RT-PCR and Sanger sequencing. Expression of RAR-related orphan receptor A  (RORA) , which has been linked to asthma in genome-wide association studies, was significantly upregulated in patients with SA. Gene network modeling revealed decreased glucocorticoid receptor signaling and increased activity of the mitogen-activated protein kinase and Jun kinase cascades in patients with SA. Conclusion Circulating leukocytes from children with controlled asthma and those with SA have distinct gene expression profiles, demonstrating the possible development of specific molecular biomarkers and supporting the need for novel therapeutic approaches.</description><subject>Adolescent</subject><subject>Allergy and Immunology</subject><subject>Asthma</subject><subject>Asthma - drug therapy</subject><subject>Asthma - genetics</subject><subject>Asthma - pathology</subject><subject>Case-Control Studies</subject><subject>Child</subject><subject>Child, Preschool</subject><subject>childhood asthma</subject><subject>Drug Resistance - genetics</subject><subject>Female</subject><subject>Gene expression</subject><subject>Gene Expression Profiling</subject><subject>Genome-Wide Association Study</subject><subject>Glucocorticoids - therapeutic use</subject><subject>Humans</subject><subject>JNK Mitogen-Activated Protein Kinases - genetics</subject><subject>long noncoding RNA</subject><subject>Male</subject><subject>Medicin och hälsovetenskap</subject><subject>Nuclear Receptor Subfamily 1, Group F, Member 1 - genetics</subject><subject>peripheral blood leukocytes</subject><subject>Receptors, Glucocorticoid - genetics</subject><subject>RNA polymerase</subject><subject>RNA, Messenger - genetics</subject><subject>Severity of Illness Index</subject><subject>Therapy-resistant asthma</subject><subject>Transcriptome</subject><issn>0091-6749</issn><issn>1097-6825</issn><issn>1097-6825</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>D8T</sourceid><recordid>eNqNkl2L1DAUhoso7rj6B7yQgjfedMxHk2lAhGVxVVjwwvU6pMmpk26mqUm7Ov9-T5nZXVhQhEDS5HkOp5y3KF5TsqaEyvf9ujfWrxmhYk0YLvmkWFGiNpVsmHharAhRtJKbWp0UL3LuCX7zRj0vTphoJFcNXRXzVTJDtsmPU9xBaQYT9tnnMnaljcOUYgjg8NqV0xaSGfdVAnyfzDCVduuD28aI73na7kyZ4AZMyKVDwA92Kn_CACX8GdHJPg7lmGLnA-SXxbMOQXh13E-LHxefrs6_VJffPn89P7usLHY9VU66prOUuZYx4YhshKRcNF0tG0NIDVwQ21oAVTsmW0dbZZmowXWLp4zhp0V1qJt_wzi3ekx-Z9JeR-P18eoaT6AFrTknyKu_8ti7e5DuRMqpklJtGnTfHVwEf82QJ73z2UIIZoA4Z003FCchOOP_gxIpaqZqRN8-Qvs4J5zSQhHFaioVRYodKJtizgm6-84p0UtWdK-XrOglK5owXBKlN8fSc7sDd6_chQOBDwcAcEQ3HpLO1sNgwfkEdtIu-n_X__hIt8EP3ppwDXvID_-hMwr6-5LWJaxUEMJZQ_gt9svoOQ</recordid><startdate>20150901</startdate><enddate>20150901</enddate><creator>Persson, Helena, PhD</creator><creator>Kwon, Andrew T., PhD</creator><creator>Ramilowski, Jordan A., PhD</creator><creator>Silberberg, Gilad, PhD</creator><creator>Söderhäll, Cilla, PhD</creator><creator>Orsmark-Pietras, Christina, PhD</creator><creator>Nordlund, Björn, RN, PhD</creator><creator>Konradsen, Jon R., MD, PhD</creator><creator>de Hoon, Michiel J.L., PhD</creator><creator>Melén, Erik, MD, PhD</creator><creator>Hayashizaki, Yoshihide, MD, PhD</creator><creator>Hedlin, Gunilla, MD, PhD</creator><creator>Kere, Juha, MD, PhD</creator><creator>Daub, Carsten O., PhD</creator><general>Elsevier Inc</general><general>Elsevier Limited</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7SS</scope><scope>7T5</scope><scope>H94</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>7X8</scope><scope>ADTPV</scope><scope>AOWAS</scope><scope>D8T</scope><scope>ZZAVC</scope><orcidid>https://orcid.org/0000-0002-3295-8729</orcidid><orcidid>https://orcid.org/0000-0002-5187-6446</orcidid></search><sort><creationdate>20150901</creationdate><title>Transcriptome analysis of controlled and therapy-resistant childhood asthma reveals distinct gene expression profiles</title><author>Persson, Helena, PhD ; Kwon, Andrew T., PhD ; Ramilowski, Jordan A., PhD ; Silberberg, Gilad, PhD ; Söderhäll, Cilla, PhD ; Orsmark-Pietras, Christina, PhD ; Nordlund, Björn, RN, PhD ; Konradsen, Jon R., MD, PhD ; de Hoon, Michiel J.L., PhD ; Melén, Erik, MD, PhD ; Hayashizaki, Yoshihide, MD, PhD ; Hedlin, Gunilla, MD, PhD ; Kere, Juha, MD, PhD ; Daub, Carsten O., PhD</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c674t-d6d8fc12db225d068561358f468a004e350cbcee94d26bd1b9c254edf6d8f9aa3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Adolescent</topic><topic>Allergy and Immunology</topic><topic>Asthma</topic><topic>Asthma - drug therapy</topic><topic>Asthma - genetics</topic><topic>Asthma - pathology</topic><topic>Case-Control Studies</topic><topic>Child</topic><topic>Child, Preschool</topic><topic>childhood asthma</topic><topic>Drug Resistance - genetics</topic><topic>Female</topic><topic>Gene expression</topic><topic>Gene Expression Profiling</topic><topic>Genome-Wide Association Study</topic><topic>Glucocorticoids - therapeutic use</topic><topic>Humans</topic><topic>JNK Mitogen-Activated Protein Kinases - genetics</topic><topic>long noncoding RNA</topic><topic>Male</topic><topic>Medicin och hälsovetenskap</topic><topic>Nuclear Receptor Subfamily 1, Group F, Member 1 - genetics</topic><topic>peripheral blood leukocytes</topic><topic>Receptors, Glucocorticoid - genetics</topic><topic>RNA polymerase</topic><topic>RNA, Messenger - genetics</topic><topic>Severity of Illness Index</topic><topic>Therapy-resistant asthma</topic><topic>Transcriptome</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Persson, Helena, PhD</creatorcontrib><creatorcontrib>Kwon, Andrew T., PhD</creatorcontrib><creatorcontrib>Ramilowski, Jordan A., PhD</creatorcontrib><creatorcontrib>Silberberg, Gilad, PhD</creatorcontrib><creatorcontrib>Söderhäll, Cilla, PhD</creatorcontrib><creatorcontrib>Orsmark-Pietras, Christina, PhD</creatorcontrib><creatorcontrib>Nordlund, Björn, RN, PhD</creatorcontrib><creatorcontrib>Konradsen, Jon R., MD, PhD</creatorcontrib><creatorcontrib>de Hoon, Michiel J.L., PhD</creatorcontrib><creatorcontrib>Melén, Erik, MD, PhD</creatorcontrib><creatorcontrib>Hayashizaki, Yoshihide, MD, PhD</creatorcontrib><creatorcontrib>Hedlin, Gunilla, MD, PhD</creatorcontrib><creatorcontrib>Kere, Juha, MD, PhD</creatorcontrib><creatorcontrib>Daub, Carsten O., PhD</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health &amp; 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If no exacerbating factors, such as smoking or allergies, are found after extensive investigation, these children are given a diagnosis of therapy-resistant (or therapy-refractory) asthma (SA). Objective We sought to deepen our understanding of childhood SA by analyzing gene expression and modeling the underlying regulatory transcription factor networks in peripheral blood leukocytes. Methods Gene expression was analyzed by using Cap Analysis of Gene Expression in children with SA (n = 13), children with controlled persistent asthma (n = 15), and age-matched healthy control subjects (n = 9). Cap Analysis of Gene Expression sequencing detects the transcription start sites of known and novel mRNAs and noncoding RNAs. Results Sample groups could be separated by hierarchical clustering on 1305 differentially expressed transcription start sites, including 816 known genes and several novel transcripts. Ten of 13 tested novel transcripts were validated by means of RT-PCR and Sanger sequencing. Expression of RAR-related orphan receptor A  (RORA) , which has been linked to asthma in genome-wide association studies, was significantly upregulated in patients with SA. Gene network modeling revealed decreased glucocorticoid receptor signaling and increased activity of the mitogen-activated protein kinase and Jun kinase cascades in patients with SA. Conclusion Circulating leukocytes from children with controlled asthma and those with SA have distinct gene expression profiles, demonstrating the possible development of specific molecular biomarkers and supporting the need for novel therapeutic approaches.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>25863981</pmid><doi>10.1016/j.jaci.2015.02.026</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0002-3295-8729</orcidid><orcidid>https://orcid.org/0000-0002-5187-6446</orcidid><oa>free_for_read</oa></addata></record>
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subjects Adolescent
Allergy and Immunology
Asthma
Asthma - drug therapy
Asthma - genetics
Asthma - pathology
Case-Control Studies
Child
Child, Preschool
childhood asthma
Drug Resistance - genetics
Female
Gene expression
Gene Expression Profiling
Genome-Wide Association Study
Glucocorticoids - therapeutic use
Humans
JNK Mitogen-Activated Protein Kinases - genetics
long noncoding RNA
Male
Medicin och hälsovetenskap
Nuclear Receptor Subfamily 1, Group F, Member 1 - genetics
peripheral blood leukocytes
Receptors, Glucocorticoid - genetics
RNA polymerase
RNA, Messenger - genetics
Severity of Illness Index
Therapy-resistant asthma
Transcriptome
title Transcriptome analysis of controlled and therapy-resistant childhood asthma reveals distinct gene expression profiles
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