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

Anders U Eliasen; Casper Emil T Pedersen; Morten A Rasmussen; Ni Wang; Matteo Soverini; Amelie Fritz; Jakob Stokholm; Bo L Chawes; Andreanna Morin; Jette Bork-Jensen; Niels Grarup; Oluf Pedersen; Torben Hansen; Allan Linneberg; Preben B Mortensen; David M Hougaard; Jonas Bybjerg-Grauholm; Marie Bækvad-Hansen; Ole Mors; Merete Nordentoft; Anders D Børglum; Thomas Werge; Esben Agerbo; Cilla Söderhall; Matthew C Altman; Anna H Thysen; Chris G McKennan; Susanne Brix; James E Gern; Carole Ober; Tarunveer S Ahluwalia; Hans Bisgaard; Anders G Pedersen; Klaus Bønnelykke

doi:10.1016/j.jaci.2022.03.019

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

Anders U Eliasen, Casper Emil T Pedersen, Morten A Rasmussen, Ni Wang, Matteo Soverini, Amelie Fritz, Jakob Stokholm, Bo L Chawes, Andreanna Morin, Jette Bork-Jensen, Niels Grarup, Oluf Pedersen, Torben Hansen, Allan Linneberg, Preben B Mortensen, David M Hougaard, Jonas Bybjerg-Grauholm, Marie Bækvad-Hansen, Ole Mors, Merete NordentoftAnders D Børglum, Thomas Werge, Esben Agerbo, Cilla Söderhall, Matthew C Altman, Anna H Thysen, Chris G McKennan, Susanne Brix, James E Gern, Carole Ober, Tarunveer S Ahluwalia, Hans Bisgaard, Anders G Pedersen, Klaus Bønnelykke^*

^*Corresponding author af dette arbejde

14 Citationer (Scopus)

Abstract

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.

Originalsprog	Engelsk
Tidsskrift	The Journal of allergy and clinical immunology
Vol/bind	150
Udgave nummer	3
Sider (fra-til)	622-630
Antal sider	9
ISSN	0091-6749
DOI	https://doi.org/10.1016/j.jaci.2022.03.019
Status	Udgivet - sep. 2022

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Eliasen, A. U., Pedersen, C. E. T., Rasmussen, M. A., Wang, N., Soverini, M., Fritz, A., Stokholm, J., Chawes, B. L., Morin, A., Bork-Jensen, J., Grarup, N., Pedersen, O., Hansen, T., Linneberg, A., Mortensen, P. B., Hougaard, D. M., Bybjerg-Grauholm, J., Bækvad-Hansen, M., Mors, O., ... Bønnelykke, K. (2022). Genome-wide study of early and severe childhood asthma identifies interaction between CDHR3 and GSDMB. The Journal of allergy and clinical immunology, 150(3), 622-630. https://doi.org/10.1016/j.jaci.2022.03.019

Eliasen, AU , Pedersen, CET , Rasmussen, MA, Wang, N, Soverini, M, Fritz, A, Stokholm, J , Chawes, BL, Morin, A, Bork-Jensen, J, Grarup, N, Pedersen, O, Hansen, T, Linneberg, A, Mortensen, PB, Hougaard, DM, Bybjerg-Grauholm, J, Bækvad-Hansen, M, Mors, O, Nordentoft, M, Børglum, AD, Werge, T, Agerbo, E, Söderhall, C, Altman, MC, Thysen, AH, McKennan, CG, Brix, S, Gern, JE, Ober, C, Ahluwalia, TS, Bisgaard, H, Pedersen, AG & Bønnelykke, K 2022, 'Genome-wide study of early and severe childhood asthma identifies interaction between CDHR3 and GSDMB', The Journal of allergy and clinical immunology, bind 150, nr. 3, s. 622-630. https://doi.org/10.1016/j.jaci.2022.03.019

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title = "Genome-wide study of early and severe childhood asthma identifies interaction between CDHR3 and GSDMB",

abstract = "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.",

keywords = "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",

author = "Eliasen, {Anders U} and Pedersen, {Casper Emil T} and Rasmussen, {Morten A} and Ni Wang and Matteo Soverini and Amelie Fritz and Jakob Stokholm and Chawes, {Bo L} and Andreanna Morin and Jette Bork-Jensen and Niels Grarup and Oluf Pedersen and Torben Hansen and Allan Linneberg and Mortensen, {Preben B} and Hougaard, {David M} and Jonas Bybjerg-Grauholm and Marie B{\ae}kvad-Hansen and Ole Mors and Merete Nordentoft and B{\o}rglum, {Anders D} and Thomas Werge and Esben Agerbo and Cilla S{\"o}derhall and Altman, {Matthew C} and Thysen, {Anna H} and McKennan, {Chris G} and Susanne Brix and Gern, {James E} and Carole Ober and Ahluwalia, {Tarunveer S} and Hans Bisgaard and Pedersen, {Anders G} and Klaus B{\o}nnelykke",

note = "Copyright {\textcopyright} 2022. Published by Elsevier Inc.",

year = "2022",

month = sep,

doi = "10.1016/j.jaci.2022.03.019",

language = "English",

volume = "150",

pages = "622--630",

journal = "The Journal of allergy and clinical immunology",

issn = "0091-6749",

publisher = "Elsevier Inc.",

number = "3",

}

TY - JOUR

T1 - Genome-wide study of early and severe childhood asthma identifies interaction between CDHR3 and GSDMB

AU - Eliasen, Anders U

AU - Pedersen, Casper Emil T

AU - Rasmussen, Morten A

AU - Wang, Ni

AU - Soverini, Matteo

AU - Fritz, Amelie

AU - Stokholm, Jakob

AU - Chawes, Bo L

AU - Morin, Andreanna

AU - Bork-Jensen, Jette

AU - Grarup, Niels

AU - Pedersen, Oluf

AU - Hansen, Torben

AU - Linneberg, Allan

AU - Mortensen, Preben B

AU - Hougaard, David M

AU - Bybjerg-Grauholm, Jonas

AU - Bækvad-Hansen, Marie

AU - Mors, Ole

AU - Nordentoft, Merete

AU - Børglum, Anders D

AU - Werge, Thomas

AU - Agerbo, Esben

AU - Söderhall, Cilla

AU - Altman, Matthew C

AU - Thysen, Anna H

AU - McKennan, Chris G

AU - Brix, Susanne

AU - Gern, James E

AU - Ober, Carole

AU - Ahluwalia, Tarunveer S

AU - Bisgaard, Hans

AU - Pedersen, Anders G

AU - Bønnelykke, Klaus

PY - 2022/9

Y1 - 2022/9

N2 - 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.

AB - 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.

KW - Asthma/genetics

KW - Cadherin Related Proteins

KW - Cadherins/genetics

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Humans

KW - Interleukin-17/genetics

KW - Membrane Proteins/genetics

KW - Neoplasm Proteins/genetics

KW - Polymorphism, Single Nucleotide

KW - Pore Forming Cytotoxic Proteins

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U2 - 10.1016/j.jaci.2022.03.019

DO - 10.1016/j.jaci.2022.03.019

M3 - Journal article

C2 - 35381269

SN - 0091-6749

VL - 150

SP - 622

EP - 630

JO - The Journal of allergy and clinical immunology

JF - The Journal of allergy and clinical immunology

IS - 3

ER -

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

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