Jakwerth, Constanze AConstanze AJakwerthWeckmann, MarkusMarkusWeckmannIlli, SabinaSabinaIlliCharles, HelenHelenCharlesZissler, Ulrich MUlrich MZisslerOelsner, MadlenMadlenOelsnerGuerth, FerdinandFerdinandGuerthOmony, JimmyJimmyOmonyNemani, Sai Sneha PriyaSai Sneha PriyaNemaniGrychtol, RuthRuthGrychtolDittrich, Anna-MariaAnna-MariaDittrichSkevaki, ChrysanthiChrysanthiSkevakiFoth, SvenjaSvenjaFothWeber, StefanieStefanieWeberAlejandre Alcazar, Miguel AMiguel AAlejandre Alcazarvan Koningsbruggen-Rietschel, SilkeSilkevan Koningsbruggen-RietschelBrock, RobertRobertBrockBlau, SamiraSamiraBlauHansen, GesineGesineHansenBahmer, ThomasThomasBahmerRabe, Klaus FKlaus FRabeBrinkmann, FolkeFolkeBrinkmannKopp, Matthias VolkmarMatthias VolkmarKoppChaker, Adam MAdam MChakerSchaub, BiancaBiancaSchaubvon Mutius, ErikaErikavon MutiusSchmidt-Weber, Carsten BCarsten BSchmidt-Weber2024-10-262024-10-262024-04-15https://boris-portal.unibe.ch/handle/20.500.12422/172212RATIONALE 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.enasthma nasal transcriptome wheezing600 - Technology::610 - Medicine & healtharticle10.48350/1900883806424110.1164/rccm.202305-0934OC