The rs6967330 minor allele in CDHR3 is a significant risk factor for severe acute exacerbations in CRS.

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: To determine if 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 (CRS) by rs6967330 genotype (AA/AG, n=16; GG, n=38). We contacted subjects every 2 weeks, and if they reported AECRS clinical data were collected. ALI cultures of adults with CRS (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 post-infection and RNA transcriptomes and cytokines at 48 hours post infection.

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 to the major allele. Differentially expressed genes (DEG) and pathways identified an upregulation of IL-10 and IL4/13 pathways and a significant downregulation of toll like receptor (TLR) pathways in the minor allele cultures after RV-A and RV-C infection. Unsupervised hierarchical analysis of all DEGs suggest 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 TLR-mediated responses and increased T2-type and cytokine and chemokine responses during RV infection.