The rs6967330 minor allele in CDHR3 is a significant risk factor for severe acute exacerbations in chronic rhinosinusitis

Sunny Palumbo; Joseph Irish; Nirushan Narendran; Debra A Stern; Sophia Volpe; Christopher H Le; Rebekah Starks; Anthony Bosco; Fernando D Martinez; Eugene H Chang

doi:10.1016/j.jaci.2024.09.025

The rs6967330 minor allele in CDHR3 is a significant risk factor for severe acute exacerbations in chronic rhinosinusitis

J Allergy Clin Immunol. 2024 Oct 9:S0091-6749(24)01028-5. doi: 10.1016/j.jaci.2024.09.025. Online ahead of print.

Authors

Affiliations

¹ Department of Otolaryngology, University of Arizona, Tucson, Ariz; Asthma and Airway Disease Research Center, University of Arizona, Tucson, Ariz.
² Asthma and Airway Disease Research Center, University of Arizona, Tucson, Ariz.
³ Department of Otolaryngology, University of Arizona, Tucson, Ariz.
⁴ Asthma and Airway Disease Research Center, University of Arizona, Tucson, Ariz; Department of Immunobiology, University of Arizona College of Medicine, Tucson, Ariz.
⁵ Department of Otolaryngology, University of Arizona, Tucson, Ariz; Asthma and Airway Disease Research Center, University of Arizona, Tucson, Ariz. Electronic address: echang@arizona.edu.

PMID: 39389125
DOI: 10.1016/j.jaci.2024.09.025

Abstract

Background: Acute exacerbations of chronic rhinosinusitis (AECRS) are commonly triggered by rhinovirus (RV) infections with secondary bacterial infections. Risk factors for AECRS are not well understood.

Objective: We sought to determine whether carriers of the minor allele rs6967330 (AA/AG) in the cadherin-related family member 3 (CDHR3) gene have an increased risk for RV infections in AECRS in vivo and identify CDHR3 genotype-dependent host responses to RV infection in differentiated nasal airway-liquid interface (ALI) cultures ex vivo.

Methods: We performed a prospective year-long study of adult subjects with chronic rhinosinusitis by the rs6967330 genotype (AA/AG, n = 16; GG, n = 38). We contacted subjects every 2 weeks, and if they reported AECRS, then clinical data were collected. ALI cultures of adults with chronic rhinosinusitis (AG/AA, n = 19; GG, n = 19) were challenged with RV-A and RV-C. We measured viral copy numbers at 4 and 48 hours postinfection and RNA transcriptomes and cytokines at 48 hours postinfection.

Results: Subjects with the minor allele had significantly higher rates of RV and bacterial infections than those with the major allele. ALI minor allele cultures had higher viral copy numbers of RV-A and RV-C after 48 hours compared with the major allele. Differentially expressed genes and pathways identified an upregulation of IL-10 and IL-4/IL-13 pathways and a significant downregulation of Toll-like receptor pathways in the minor allele cultures after RV-A and RV-C infection. Unsupervised hierarchical analysis of all differentially expressed genes suggested that allergic rhinitis had an additive effect on this response.

Conclusions: The rs6967330 minor allele is associated with increased RV-A and RV-C replication, downregulation of Toll-like receptor-mediated responses, and increased type-2 and cytokine and chemokine responses during RV infection.

Keywords: Rhinovirus; Toll-like receptor; allergic; bacterial infection; cadherin-related family member 3 gene; epithelial barriers; exacerbation; interferon; longitudinal; prospective study; sinusitis; translational.