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

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Transcriptome analysis of controlled and therapy-resistant childhood asthma reveals distinct gene expression profiles. / Persson, Helena; Kwon, Andrew T; Ramilowski, Jordan A; Silberberg, Gilad; Söderhäll, Cilla; Orsmark-Pietras, Christina; Nordlund, Björn; Konradsen, Jon R; de Hoon, Michiel J L; Melén, Erik; Hayashizaki, Yoshihide; Hedlin, Gunilla; Kere, Juha; Daub, Carsten O.

I: Journal of Allergy and Clinical Immunology, Vol. 136, Nr. 3, 09.2015, s. 638-48.

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

Harvard

Persson, H, Kwon, AT, Ramilowski, JA, Silberberg, G, Söderhäll, C, Orsmark-Pietras, C, Nordlund, B, Konradsen, JR, de Hoon, MJL, Melén, E, Hayashizaki, Y, Hedlin, G, Kere, J & Daub, CO 2015, 'Transcriptome analysis of controlled and therapy-resistant childhood asthma reveals distinct gene expression profiles', Journal of Allergy and Clinical Immunology, vol. 136, nr. 3, s. 638-48. https://doi.org/10.1016/j.jaci.2015.02.026

APA

CBE

Persson H, Kwon AT, Ramilowski JA, Silberberg G, Söderhäll C, Orsmark-Pietras C, Nordlund B, Konradsen JR, de Hoon MJL, Melén E, Hayashizaki Y, Hedlin G, Kere J, Daub CO. 2015. Transcriptome analysis of controlled and therapy-resistant childhood asthma reveals distinct gene expression profiles. Journal of Allergy and Clinical Immunology. 136(3):638-48. https://doi.org/10.1016/j.jaci.2015.02.026

MLA

Vancouver

Author

Persson, Helena ; Kwon, Andrew T ; Ramilowski, Jordan A ; Silberberg, Gilad ; Söderhäll, Cilla ; Orsmark-Pietras, Christina ; Nordlund, Björn ; Konradsen, Jon R ; de Hoon, Michiel J L ; Melén, Erik ; Hayashizaki, Yoshihide ; Hedlin, Gunilla ; Kere, Juha ; Daub, Carsten O. / Transcriptome analysis of controlled and therapy-resistant childhood asthma reveals distinct gene expression profiles. I: Journal of Allergy and Clinical Immunology. 2015 ; Vol. 136, Nr. 3. s. 638-48.

RIS

TY - JOUR

T1 - Transcriptome analysis of controlled and therapy-resistant childhood asthma reveals distinct gene expression profiles

AU - Persson, Helena

AU - Kwon, Andrew T

AU - Ramilowski, Jordan A

AU - Silberberg, Gilad

AU - Söderhäll, Cilla

AU - Orsmark-Pietras, Christina

AU - Nordlund, Björn

AU - Konradsen, Jon R

AU - de Hoon, Michiel J L

AU - Melén, Erik

AU - Hayashizaki, Yoshihide

AU - Hedlin, Gunilla

AU - Kere, Juha

AU - Daub, Carsten O

N1 - Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

PY - 2015/9

Y1 - 2015/9

N2 - 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.

AB - 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.

KW - Adolescent

KW - Asthma

KW - Case-Control Studies

KW - Child

KW - Child, Preschool

KW - Drug Resistance

KW - Female

KW - Gene Expression Profiling

KW - Genome-Wide Association Study

KW - Glucocorticoids

KW - Humans

KW - JNK Mitogen-Activated Protein Kinases

KW - Male

KW - Nuclear Receptor Subfamily 1, Group F, Member 1

KW - RNA, Messenger

KW - Receptors, Glucocorticoid

KW - Severity of Illness Index

KW - Transcriptome

U2 - 10.1016/j.jaci.2015.02.026

DO - 10.1016/j.jaci.2015.02.026

M3 - Article

VL - 136

SP - 638

EP - 648

JO - Journal of Allergy and Clinical Immunology

T2 - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

SN - 1097-6825

IS - 3

ER -