Genome-wide study of early and severe childhood asthma identifies interaction between CDHR3 and GSDMB.

Asthma / genetics Cadherin Related Proteins Cadherins / genetics Genetic Predisposition to Disease Genome-Wide Association Study Humans Interleukin-17 / genetics Membrane Proteins / genetics Neoplasm Proteins / genetics Polymorphism, Single Nucleotide Pore Forming Cytotoxic Proteins
Childhood asthma early life genetic interactions immunology

Journal

The Journal of allergy and clinical immunology
ISSN: 1097-6825
Titre abrégé: J Allergy Clin Immunol
Pays: United States
ID NLM: 1275002

Informations de publication

Date de publication:
09 2022
Historique:
received: 23 08 2021
revised: 11 03 2022
accepted: 18 03 2022
pubmed: 6 4 2022
medline: 14 9 2022
entrez: 5 4 2022
Statut: ppublish

Résumé

Asthma with severe exacerbation is one of the most common causes of hospitalization among young children. Exacerbations are typically triggered by respiratory infections, but the host factors causing recurrent infections and exacerbations in some children are poorly understood. As a result, current treatment options and preventive measures are inadequate. We sought to identify genetic interaction associated with the development of childhood asthma. We performed an exhaustive search for pairwise interaction between genetic single nucleotide polymorphisms using 1204 cases of a specific phenotype of early childhood asthma with severe exacerbations in patients aged 2 to 6 years combined with 5328 nonasthmatic controls. Replication was attempted in 3 independent populations, and potential underlying immune mechanisms were investigated in the COPSAC2010 and COPSAC2000 birth cohorts. We found evidence of interaction, including replication in independent populations, between the known childhood asthma loci CDHR3 and GSDMB. The effect of CDHR3 was dependent on the GSDMB genotype, and this interaction was more pronounced for severe and early onset of disease. Blood immune analyses suggested a mechanism related to increased IL-17A production after viral stimulation. We found evidence of interaction between CDHR3 and GSDMB in development of early childhood asthma, possibly related to increased IL-17A response to viral infections. This study demonstrates the importance of focusing on specific disease subtypes for understanding the genetic mechanisms of asthma.

Sections du résumé

BACKGROUND
Asthma with severe exacerbation is one of the most common causes of hospitalization among young children. Exacerbations are typically triggered by respiratory infections, but the host factors causing recurrent infections and exacerbations in some children are poorly understood. As a result, current treatment options and preventive measures are inadequate.
OBJECTIVE
We sought to identify genetic interaction associated with the development of childhood asthma.
METHODS
We performed an exhaustive search for pairwise interaction between genetic single nucleotide polymorphisms using 1204 cases of a specific phenotype of early childhood asthma with severe exacerbations in patients aged 2 to 6 years combined with 5328 nonasthmatic controls. Replication was attempted in 3 independent populations, and potential underlying immune mechanisms were investigated in the COPSAC2010 and COPSAC2000 birth cohorts.
RESULTS
We found evidence of interaction, including replication in independent populations, between the known childhood asthma loci CDHR3 and GSDMB. The effect of CDHR3 was dependent on the GSDMB genotype, and this interaction was more pronounced for severe and early onset of disease. Blood immune analyses suggested a mechanism related to increased IL-17A production after viral stimulation.
CONCLUSIONS
We found evidence of interaction between CDHR3 and GSDMB in development of early childhood asthma, possibly related to increased IL-17A response to viral infections. This study demonstrates the importance of focusing on specific disease subtypes for understanding the genetic mechanisms of asthma.

Identifiants

DOI: 10.1016/j.jaci.2022.03.019 PMID: 35381269
pubmed: 35381269
pii: S0091-6749(22)00439-0
doi: 10.1016/j.jaci.2022.03.019
pii:
doi:

Substances chimiques

CDHR3 protein, human 0
Cadherin Related Proteins 0
Cadherins 0
GSDMB protein, human 0
Interleukin-17 0
Membrane Proteins 0
Neoplasm Proteins 0
Pore Forming Cytotoxic Proteins 0

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

622-630

Subventions

Organisme : Medical Research Council
ID : MC_PC_17228
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_QA137853
Pays : United Kingdom

Informations de copyright

Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Auteurs

Anders U Eliasen (AU)

Copenhagen Prospective Studies on Asthma in Childhood (COPSAC), Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark; Department of Health Technology, Section for Bioinformatics, Technical University of Denmark, Kongens Lyngby, Denmark.

Casper Emil T Pedersen (CET)

Copenhagen Prospective Studies on Asthma in Childhood (COPSAC), Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.

Morten A Rasmussen (MA)

Copenhagen Prospective Studies on Asthma in Childhood (COPSAC), Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark; Department of Food Science, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.

Ni Wang (N)

Copenhagen Prospective Studies on Asthma in Childhood (COPSAC), Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.

Matteo Soverini (M)

Copenhagen Prospective Studies on Asthma in Childhood (COPSAC), Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.

Amelie Fritz (A)

Copenhagen Prospective Studies on Asthma in Childhood (COPSAC), Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark; Department of Health Technology, Section for Bioinformatics, Technical University of Denmark, Kongens Lyngby, Denmark.

Jakob Stokholm (J)

Copenhagen Prospective Studies on Asthma in Childhood (COPSAC), Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.

Bo L Chawes (BL)

Copenhagen Prospective Studies on Asthma in Childhood (COPSAC), Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.

Andréanne Morin (A)

Department of Human Genetics, University of Chicago, Chicago, Ill.

Jette Bork-Jensen (J)

Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Copenhagen, Denmark.

Niels Grarup (N)

Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Copenhagen, Denmark.

Oluf Pedersen (O)

Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Copenhagen, Denmark.

Torben Hansen (T)

Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Copenhagen, Denmark.

Allan Linneberg (A)

Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, The Capital Region, Copenhagen, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.

Preben B Mortensen (PB)

iPSYCH, The Lundbeck Foundation Initiative for Integrated Psychiatric Research, Aarhus, Denmark; National Center for Register-Based Research (NCRR), Business and Social Sciences, Aarhus University, Aarhus, Denmark; Center for Integrated Register-Based Research (CIRRAU), Aarhus University, Aarhus, Denmark.

David M Hougaard (DM)

iPSYCH, The Lundbeck Foundation Initiative for Integrated Psychiatric Research, Aarhus, Denmark; Department for Congenital Disorders, Statens Serum Institut (SSI), Copenhagen, Denmark; Den Neonatale Screenings Biobank, SSI, Copenhagen, Denmark.

Jonas Bybjerg-Grauholm (J)

iPSYCH, The Lundbeck Foundation Initiative for Integrated Psychiatric Research, Aarhus, Denmark; Den Neonatale Screenings Biobank, SSI, Copenhagen, Denmark.

Marie Bækvad-Hansen (M)

iPSYCH, The Lundbeck Foundation Initiative for Integrated Psychiatric Research, Aarhus, Denmark; Department for Congenital Disorders, Statens Serum Institut (SSI), Copenhagen, Denmark.

Ole Mors (O)

iPSYCH, The Lundbeck Foundation Initiative for Integrated Psychiatric Research, Aarhus, Denmark; Psychosis Research Unit, Aarhus University Hospital-Psychiatry, Risskov, Denmark.

Merete Nordentoft (M)

Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark; iPSYCH, The Lundbeck Foundation Initiative for Integrated Psychiatric Research, Aarhus, Denmark; Mental Health Center Copenhagen, Capital Region of Denmark, Copenhagen University Hospital, Copenhagen, Denmark.

Anders D Børglum (AD)

Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark; iPSYCH, The Lundbeck Foundation Initiative for Integrated Psychiatric Research, Aarhus, Denmark; Center for Integrative Sequencing, Department of Biomedicine and iSEQ, Aarhus University, Aarhus, Denmark.

Thomas Werge (T)

iPSYCH, The Lundbeck Foundation Initiative for Integrated Psychiatric Research, Aarhus, Denmark; Institute of Biological Psychiatry, Copenhagen Mental Health Services, Copenhagen, Denmark; Institute of Clinical Medicine and GLOBE Institute, University of Copenhagen, Copenhagen, Denmark.

Esben Agerbo (E)

iPSYCH, The Lundbeck Foundation Initiative for Integrated Psychiatric Research, Aarhus, Denmark; National Center for Register-Based Research (NCRR), Business and Social Sciences, Aarhus University, Aarhus, Denmark; Center for Integrated Register-Based Research (CIRRAU), Aarhus University, Aarhus, Denmark.

Cilla Söderhall (C)

Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Wash.

Matthew C Altman (MC)

Department of Medicine, University of Washington, Seattle, Sweden.

Anna H Thysen (AH)

Copenhagen Prospective Studies on Asthma in Childhood (COPSAC), Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark; Department of Biotechnology and Biomedicine, Technical University of Denmark, Kongens Lyngby, Denmark.

Chris G McKennan (CG)

Department of Statistics, University of Pittsburgh, Pittsburgh, Pa.

Susanne Brix (S)

Department of Biotechnology and Biomedicine, Technical University of Denmark, Kongens Lyngby, Denmark.

James E Gern (JE)

Department of Pediatrics, University of Wisconsin, Madison, Wis.

Carole Ober (C)

Department of Human Genetics, University of Chicago, Chicago, Ill.

Tarunveer S Ahluwalia (TS)

Steno Diabetes Center Copenhagen, Gentofte, Denmark; Bioinformatics Center, University of Copenhagen, Copenhagen, Denmark.

Hans Bisgaard (H)

Copenhagen Prospective Studies on Asthma in Childhood (COPSAC), Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.

Anders G Pedersen (AG)

Department of Health Technology, Section for Bioinformatics, Technical University of Denmark, Kongens Lyngby, Denmark.

Klaus Bønnelykke (K)

Copenhagen Prospective Studies on Asthma in Childhood (COPSAC), Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark. Electronic address: kb@copsac.com.

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Classifications MeSH

questionsmedicales.fr › Maladies du système immunitaire › Hypersensibilité › Hypersensibilité immédiate › Hypersensibilité respiratoire › Asthme › Genome-wide study of early and severe...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Protéines apparentées aux cadhérines › Genome-wide study of early and severe...
questionsmedicales.fr › Facteurs biologiques › Antigènes › Antigènes de surface › Molécules d'adhérence cellulaire › Cadhérines › Genome-wide study of early and severe...
questionsmedicales.fr › Phénomènes génétiques › Génotype › Prédisposition génétique à une maladie › Genome-wide study of early and severe...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Épidémiologie moléculaire › Étude d'association pangénomique › Genome-wide study of early and severe...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Genome-wide study of early and severe...
questionsmedicales.fr › Facteurs biologiques › Protéines et peptides de signalisation intercellulaire › Cytokines › Interleukines › Interleukine-17 › Genome-wide study of early and severe...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Genome-wide study of early and severe...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines tumorales › Genome-wide study of early and severe...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Polymorphisme génétique › Polymorphisme de nucléotide simple › Genome-wide study of early and severe...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Perforines › Genome-wide study of early and severe...