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Concurrently, nasal secretions from the same patients and visits were collected, and high-sensitivity mesoscale technology was employed to measure IFN protein levels.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Measurements and Main Results<\/jats:title>\n                    <jats:p>This study revealed that the 17q21 risk allele induces a genotype- and asthma\/wheeze phenotype\u2013dependent enhancement of mucosal GSDMB expression as the only relevant 17q21-encoded gene in children with preschool wheeze. Increased GSDMB expression correlated with the activation of a type-1 proinflammatory, cell-lytic immune, and natural killer signature, encompassing key genes linked to an IFN type-2-signature (IFNG, CXCL9, CXCL10, KLRC1, CD8A, GZMA). Conversely, there was a reduction in IFN type 1 and type 3 expression signatures at the mRNA and protein levels.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                    <jats:p>The All-Age-Asthma (ALLIANCE) cohort is registered at www.clinicaltrials.gov (pediatric arm, NCT 02496468).<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1164\/rccm.202305-0934oc","type":"journal-article","created":{"date-parts":[[2023,12,8]],"date-time":"2023-12-08T11:27:21Z","timestamp":1702034841000},"page":"947-959","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":32,"title":["17q21 Variants Disturb Mucosal Host Defense in Childhood Asthma"],"prefix":"10.1093","volume":"209","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2902-0393","authenticated-orcid":false,"given":"Constanze A.","family":"Jakwerth","sequence":"first","affiliation":[{"name":"Center of Allergy and Environment (ZAUM), Technical University and Helmholtz Center Munich, Munich, Germany"},{"name":"Member of the German Center for Lung Research (DZL), Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Weckmann","sequence":"additional","affiliation":[{"name":"Member of the German Center for Lung Research (DZL), Germany"},{"name":"Division of Epigenetics in Chronic Lung Disease, Priority Area Chronic Lung Diseases, Research Center Borstel-Leibniz Lung Center, Borstel, Germany"},{"name":"Department of Pediatric Pneumology and Allergology, University Medical Center Schleswig-Holstein, L\u00fcbeck, Germany"},{"name":"Airway Research Center North, Borstel, L\u00fcbeck, Kiel, Grosshansdorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabina","family":"Illi","sequence":"additional","affiliation":[{"name":"Member of the German Center for 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