Cadherin-related Family Member 3 Genetics and Rhinovirus C Respiratory Illnesses

Abstract

Rationale: Experimental evidence suggests that CDHR3 (cadherin-related family member 3) is a receptor for rhinovirus (RV)-C, and a missense variant in this gene (rs6967330) is associated with childhood asthma with severe exacerbations.

Objectives: To determine whether rs6967330 influences RV-C infections and illnesses in early childhood.

Methods: We studied associations between rs6967330 and respiratory infections and illnesses in the COPSAC₂₀₁₀ (Copenhagen Prospective Studies on Asthma in Childhood 2010) and COAST (Childhood Origins of Asthma Birth Cohort Study) birth cohorts, where respiratory infections were monitored prospectively for the first 3 years of life. Nasal samples were collected during acute infections in both cohorts and during asymptomatic periods in COAST and analyzed for RV-A, RV-B, and RV-C, and other common respiratory viruses.

Measurements and main results: The CDHR3 asthma risk allele (rs6967330-A) was associated with increased risk of respiratory tract illnesses (incidence risk ratio [IRR] = 1.14 [95% confidence interval, 1.05-1.23]; P = 0.003). In particular, this variant was associated with risk of respiratory episodes with detection of RV-C in COPSAC₂₀₁₀ (IRR = 1.89 [1.14-3.05]; P = 0.01) and in COAST (IRR = 1.37 [1.02-1.82]; P = 0.03) children, and in a combined meta-analysis (IRR = 1.51 [1.13-2.02]; P = 0.006). In contrast, the variant was not associated with illnesses related to other viruses (IRR = 1.07 [0.92-1.25]; P = 0.37). Consistent with these observations, the CDHR3 variant was associated with increased detection of RV-C, but not of other viruses during scheduled visits at specific ages.

Conclusions: The CDHR3 asthma risk allele is associated specifically with RV-C illnesses in two birth cohorts. This clinical evidence supports earlier molecular evidence indicating that CDHR3 functions as an RV-C receptor, and raises the possibility of preventing RV-C infections by targeting CDHR3.

Keywords: child; genetics; virus diseases; viruses.

Figure 1.

Association between the CDHR3 (cadherin-related family member 3) rs6967330-A (tyrosine) allele and respiratory illnesses with detection of rhinovirus (RV)-C and other viruses in nasal samples (incidence risk ratio [IRR] and 95% confidence intervals). Results are shown for Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC₂₀₁₀) (A), Childhood Origins of Asthma Birth Cohort Study (COAST) (B), and combined (meta-analysis) (META) (C). Solid lines mark no association (IRR = 1). Lower and upper dotted lines mark IRR of 0.5 and 2.0, respectively.