• Constanze A Jakwerth, Markus Weckmann, Sabina Illi, Helen Charles, Ulrich M Zissler, Madlen Oelsner, Ferdinand Guerth, Jimmy Omony, Sai Sneha Priya Nemani, Ruth Grychtol, Anna-Maria Dittrich, Chrysanthi Skevaki, Svenja Foth, Stefanie Weber, Miguel A Alejandre Alcazar, Silke van Koningsbruggen-Rietschel, Robert Brock, Samira Blau, Gesine Hansen, Thomas Bahmer, Klaus F Rabe, Folke Brinkmann, Matthias Volkmar Kopp, Adam M Chaker, Bianca Schaub, Erika von Mutius, Carsten B Schmidt-Weber, and ALLIANCE Study Group as part of the German Center for Lung Research.
• Center of Allergy and Environment (ZAUM), Technical University and Helmholtz Center Munich, Munich, Germany.
• Am. J. Respir. Crit. Care Med. 2024 Apr 15; 209 (8): 947959947-959.

AbstractRationale: 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 brush samples from 261 children (78 healthy, 79 with wheezing at preschool age, 104 asthmatic) within the ALLIANCE (All-Age-Asthma) cohort, with a median age of 10.0 (range, 1.0-20.0) years, 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 was 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. 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.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.The All-Age-Asthma (ALLIANCE) cohort is registered at www.clinicaltrials.gov (pediatric arm, NCT02496468).

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