Jakwerth CA, Weckmann M, Illi S et al. 17q21 Variants Disturb Mucosal Host Defense in Childhood Asthma. Am J Respir Crit Care Med. 2023 Dec 8. doi: 10.1164/rccm.202305-0934OC.
Abstract
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 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.
At a Glance Commentary
Scientific Knowledge on the Subject
This study is focused on genetic predisposition in pediatric asthma. Genome-wide association studies identified one of the most replicated childhood-onset asthma susceptibility loci on chromosome 17q21, which is the best validated genetic risk factor for childhood-onset asthma. However, it is unclear how the genetic defect relates to cellular mechanisms that would explain the association with human rhinovirus (HRV) wheezing illness in early life.
What This Study Adds to the Field
Taking advantage of minimally invasive nasal transcriptome analysis, this study provides a key piece of evidence necessary to understand the 17q21 risk allele–driven pathogenesis. Here, we show for the first time that GSDMB is a key 17q21 risk allele–encoded gene that mediates genotype-dependent and phenotype-relevant mucosal manifestations of the 17q21 risk allele in the airways. Specifically, increased mucosal GSDMB, but not ORMDL3, expression in the airway mucosa was associated with a GSDMB-associated reduction of type 1 and 3 IFN expression in wheezing children. The complex local GSDMB-mediated pathogenic mechanisms may explain the increased susceptibility of 17q21 risk allele–carrying children with preschool wheezing to respiratory viral infections, particularly HRV-infections, as a result of increased mucosal barrier dysfunction by excessive airway cell death compounded by disturbed IFN-mediated antiviral host defense.