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Jakwerth, C.A. ; Weckmann, M.* ; Illi, S. ; Charles, H. ; Zissler, U.M.* ; Oelsner, M.* ; Guerth, F. ; Omony, J. ; Nemani, S.S.P.* ; Grychtol, R.* ; Dittrich, A.M.* ; Skevaki, C.* ; Foth, S.* ; Weber, S.* ; Alejandre Alcazar, M.A.* ; van Koningsbruggen-Rietschel, S.* ; Brock, R.* ; Blau, S.* ; Hansen, G.* ; Bahmer, T.* ; Rabe, K.F.* ; Brinkmann, F.* ; Kopp, M.V.* ; Chaker, A.M.* ; Schaub, B.* ; Von Mutius, E.* ; Schmidt-Weber, C.B.

17q21 variants disturb mucosal host defense in childhood asthma.

Am. J. Respir. Crit. Care Med. 209, 947-959 (2023)
Verlagsversion DOI PMC
Open Access Gold (Paid Option)
RATIONALE: The strongest genetic risk factor for childhood-onset asthma, the 17q21 locus, is associated with increased viral susceptibility and disease-promoting processes. OBJECTIVES: To identify biological targets underlying the escalated viral susceptibility associated with the clinical phenotype mediated by the 17q21 locus. METHODS: Genome-wide transcriptome analysis of nasal brushes from 261 children (78 healthy, 79 preschool wheezers, 104 asthmatics) within the ALLIANCE cohort, with a median age of 10.0 [1.0-20.0], was conducted to explore the impact of their 17q21 genotype (SNP rs72163891). Concurrently, nasal secretions from the same patients and visits were collected, and high-sensitivity mesoscale technology employed to measure IFN-protein levels. MEASUREMENTS AND MAIN RESULTS: This study revealed that the 17q21 risk allele induces a genotype- and asthma/wheeze phenotype-dependent enhancement of mucosal GSDMB expression as the only relevant 17q21-encoded gene in children with preschool wheeze. Elevated GSDMB expression correlated with the activation of a type-1 pro-inflammatory, cell-lytic immune, and NK signature, encompassing key genes linked to an IFN-type-II-signature (IFNG, CXCL9, CXCL10, KLRC1, CD8A, GZMA). Conversely, there was a reduction in IFN-type-I and type-III expression signatures at both mRNA and protein levels. CONCLUSIONS: This study demonstrates a novel disease-driving mechanism induced by the 17q21 risk allele. Increased mucosal GSDMB expression is associated with a cell-lytic immune response coupled with compromised airway immunocompetence. These findings suggest that GSDMB-related airway cell death and perturbations in the mucosal IFN signature account for the increased vulnerability of 17q21 risk allele carriers to respiratory viral infections during early life, opening new options for future biological interventions.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Asthma ; Nasal ; Transcriptome ; Wheezing; Ormdl3/gsdmb Genotype; Risk; Susceptibility; Association; Exposure; Infections; Contribute; Illness; Gene
ISSN (print) / ISBN 1073-449X
e-ISSN 1535-4970
Zeitschrift American Journal of Respiratory and Critical Care Medicine
Quellenangaben Band: 209, Heft: 8, Seiten: 947-959 Artikelnummer: , Supplement: ,
Verlag American Thoracic Society
Verlagsort 25 Broadway, 18 Fl, New York, Ny 10004 Usa
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute for Allergy Research (IAF)
Institute of Asthma and Allergy Prevention (IAP)
Förderungen Stiftung fur Pathobiochemie und Molekulare Diagnostik
Bavarian State Office for Health and Food Safety grant
initiative of the Bavarian State Ministry of Health and Care
Universities Giessen and Marburg Lung Center
Deutsche Forschungsgemeinschaft
KFO 309
German Center of Lung Research (DZL) - Federal Ministry of Education and Research (BMBF)