17q21 Variants Disturb Mucosal Host Defense in Childhood Asthma

• DOI: 10.1164/rccm.202305-0934oc
• Publication Date: 2023-12-08T16:27:21Z
• Authors: Constanze A. Jakw...; Markus Weckmann; Sabina Illi; Helen Charles; Ulrich M. Zissler; Madlen Oelsner; Ferdinand Guerth; Jimmy Omony; Sai Sneha Priya N...; Ruth Grychtol; Anna-Maria Dittrich; Chrysanthi Skevaki; Svenja Foth; Stefanie Weber; Miguel A. Alejand...; Silke van Konings...; Robert Brock; Samira Blau; Gesine Hansen; Thomas Bahmer; Klaus F. Rabe; Folke Brinkmann; Matthias Volkmar ...; Adam M. Chaker; Bianca Schaub; Erika von Mutius; Carsten B. Schmid...; ; Oliver Fuchs; Barbara Roesler; Nils Welchering; Naschla Kohistani...; Johanna Kurz; Katja Landgraf-Rauf; Kristina Laubhahn; Nicole Maison; Claudia Liebl; Markus Ege; Alexander Hose; Esther Zeitlmann; Mira Berbig; Carola Marzi; Christina Schaube...; Isabell Ricklefs; Gesa Diekmann; Lena Liboschik; Gesche Voigt; Laila Sultansei; Gyde Nissen; Inke R. König; Dominik Thiele; Anne-Marie Kirsten; Frauke Pedersen; Henrik Watz; Benjamin Waschki; Christian Herzmann; Mustafa Abdo; Heike Biller; Karoline I. Gaede; Xenia Bovermann; Alena Steinmetz; Berrit Liselotte ...; Catharina Nitsche; Vera Veith; Marlen Szewczyk; Christine Happle; Aydin Malik; Nicolaus Schwerk; Christian Dopfer; Mareike Price; Adan Chari Jirmo; Anika Habener; David S. DeLuca; Svenja Gaedcke; Bin Liu; Mifflin-Rae Calveron; Harald Renz; Meike Meyer; Tom Schildberg; Ernst Rietschel
• Keywords: Lytic cycle

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 escalated clinical phenotype mediated by locus.Methods: Genome-wide transcriptome analysis of nasal brush samples from 261 children (78 healthy, 79 wheezing at preschool age, 104 asthmatic) within ALLIANCE (All-Age-Asthma) cohort, a median age 10.0 (range, 1.0–20.0) years, was conducted to explore impact their genotype (SNP rs72163891). Concurrently, secretions same patients visits were collected, high-sensitivity mesoscale technology employed measure IFN protein levels.Measurements Main Results: This study revealed that allele induces genotype- asthma/wheeze phenotype–dependent enhancement mucosal GSDMB expression as only relevant 17q21-encoded gene in wheeze. Increased correlated activation type-1 proinflammatory, cell-lytic immune, natural killer signature, encompassing key genes linked an type-2-signature (IFNG, CXCL9, CXCL10, KLRC1, CD8A, GZMA). Conversely, there reduction type 1 3 signatures mRNA levels.Conclusions: demonstrates novel disease-driving mechanism induced allele. immune response coupled compromised airway immunocompetence. These findings suggest GSDMB-related cell death perturbations signature account vulnerability carriers respiratory infections during early life, opening new options future interventions.The All-Age-Asthma (ALLIANCE) cohort registered www.clinicaltrials.gov (pediatric arm, NCT 02496468).