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. 2025 Feb;155(2):583-593.
doi: 10.1016/j.jaci.2024.09.025. Epub 2024 Oct 9.

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

Sunny Palumbo  1 , Joseph Irish  1 , Nirushan Narendran  1 , Debra A Stern  2 , Sophia Volpe  1 , Christopher H Le  3 , Rebekah Starks  4 , Anthony Bosco  4 , Fernando D Martinez  2 , Eugene H Chang  5
Affiliations

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

Sunny Palumbo et al. J Allergy Clin Immunol. 2025 Feb.

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.

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Conflict of interest statement

Disclosure statement This study was supported by grants from the National Institutes of Health (grant no. R01AI146131 to F.D.M. and E.H.C. and grant nos. R21 AI176305-01A1 and R01AI099108-11A1 to A.B.). Disclosure of potential conflict of interest: E. H. Chang is an advisor for Sanofi/Regeneron. A. Bosco is a cofounder, equity holder, and director of the startup company Respiradigm Pty Ltd and the subsidiary First Breath Health Pty Ltd, which are related to this work; and is the founder of the startup company INSiGENe Pty Ltd, which is related to this work. F. Martinez reports grants from NIH/NHLBI, grants from NIH/NIAID, grants from NIH/Office of the Director, grants from the ALA, and personal fees from OM Pharma. The rest of the authors declare that they have no relevant conflicts of interest.

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