17q21 Variants Disturb Mucosal Host Defense in Childhood Asthma.

Jakwerth, Constanze A; Weckmann, Markus; Illi, Sabina; Charles, Helen; Zissler, Ulrich M; Oelsner, Madlen; Guerth, Ferdinand; Omony, Jimmy; Nemani, Sai Sneha Priya; Grychtol, Ruth; Dittrich, Anna-Maria; Skevaki, Chrysanthi; Foth, Svenja; Weber, Stefanie; Alejandre Alcazar, Miguel A; van Koningsbruggen-Rietschel, Silke; Brock, Robert; Blau, Samira; Hansen, Gesine; Bahmer, Thomas; ... (2024). 17q21 Variants Disturb Mucosal Host Defense in Childhood Asthma. American journal of respiratory and critical care medicine, 209(8), pp. 947-959. American Lung Association 10.1164/rccm.202305-0934OC

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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 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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Paediatric Medicine
04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Paediatric Medicine > Paediatric Pneumology

UniBE Contributor:

Kopp, Matthias Volkmar

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1073-449X

Publisher:

American Lung Association

Language:

English

Submitter:

Pubmed Import

Date Deposited:

12 Dec 2023 10:53

Last Modified:

16 Apr 2024 00:13

Publisher DOI:

10.1164/rccm.202305-0934OC

PubMed ID:

38064241

Uncontrolled Keywords:

asthma nasal transcriptome wheezing

BORIS DOI:

10.48350/190088

URI:

https://boris.unibe.ch/id/eprint/190088

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