rs114947103 — CDHR3 CDHR3 intronic variant

CDHR3 — The Rhinovirus C Doorway and Your Genetic Susceptibility

Every autumn, rhinovirus C (RV-C) tears through daycares and schools, triggering wheezing episodes that send hundreds of thousands of children to emergency departments. Unlike rhinovirus A and B — which use ICAM-1 and LDLR as cell-entry receptors — RV-C cannot infect a cell unless that cell displays CDHR3 (cadherin-related family member 3)¹¹ CDHR3 (cadherin-related family member 3)
A transmembrane protein expressed on airway epithelial cells, belonging to the cadherin superfamily of calcium-dependent adhesion proteins; CDHR3 was identified as the rhinovirus C receptor in 2015 on its surface. Variants in the CDHR3 gene that alter receptor activity or expression therefore directly shape how efficiently RV-C can enter and replicate in the airway epithelium.

The rs114947103 variant (T>C, chromosome 7, position 106018481) is an intronic SNP located 476 base pairs downstream of the well-characterized C529Y coding variant (rs6967330). The two variants share almost identical population allele frequencies — approximately 21% for the C allele of rs114947103 and approximately 18–20% for the A allele of rs6967330 across European populations — consistent with high linkage disequilibrium. Carrying the rs114947103 C allele therefore tags the rs6967330 Y529 haplotype, which confers substantially increased RV-C receptor activity.

The Mechanism

The biological driver at this locus is the Y529 protein variant encoded by rs6967330: a cysteine-to-tyrosine change at position 529 of CDHR3. The Y529 form of the receptor binds rhinovirus C virions at roughly 10-fold higher efficiency than the common C529 form²² 10-fold higher efficiency than the common C529 form
Measured in HeLa cells stably transfected with CDHR3-Y529 vs. CDHR3-C529; both binding assays and progeny yield assays showed approximately 10-fold differences. The receptor appears to be expressed in greater amounts on the surface of airway epithelial cells in carriers of the Y529 haplotype, compounding the higher intrinsic binding affinity.

Because rs114947103 is intronic (within an intron of CDHR3 transcript variants 1 and 2, with a low CADD score of 0.894 and low evolutionary conservation), the variant itself is unlikely to be the functional change. It serves as a genomic tag for the Y529 haplotype: when population studies report associations with RV-C illness at the rs114947103 locus, they are capturing the effect of the nearby C529Y variant, which travels on the same chromosome segment.

The Evidence

The landmark 2015 study by Bochkov et al.³³ 2015 study by Bochkov et al.
Bochkov YA et al. Cadherin-related family member 3, a childhood asthma susceptibility gene product, mediates rhinovirus C binding and replication. PNAS 2015;112(17):5485-5490 identified CDHR3 as the rhinovirus C receptor and established that the Y529 variant dramatically amplifies receptor function. This resolved a decade-long mystery: why GWAS studies consistently found association between rs6967330 and childhood asthma hospitalizations, even though the gene was not obviously immune-related.

Bønnelykke et al. 2018⁴⁴ Bønnelykke et al. 2018
Bønnelykke K et al. Cadherin-related Family Member 3 Genetics and Rhinovirus C Respiratory Illnesses. Am J Respir Crit Care Med 2018;197(5):589-594 prospectively tracked respiratory illness episodes in two independent birth cohorts (COPSAC2010 and COAST). The CDHR3 risk allele was specifically associated with rhinovirus C illnesses (combined IRR=1.51, 95% CI 1.13–2.02, p=0.006) but showed no association with non-RV-C viral infections (IRR=1.07, p=0.37). This pathogen specificity — the genotype predicts RV-C illness but not influenza or RSV — is direct evidence that the association operates through the receptor mechanism rather than through a general immune susceptibility pathway.

In Chinese preschool and school-age children, Leung et al. 2020⁵⁵ Leung et al. 2020
Leung TF et al. Cadherin-related family member 3 gene impacts childhood asthma in Chinese children. Pediatr Allergy Immunol 2020;31(2):133-142 replicated the association: rs6967330 linked to current wheeze in preschoolers (OR=1.63) and to school-age asthma (OR=1.32). A haplotype spanning rs4730125, rs6967330, and rs408223 (a panel of CDHR3 tagging SNPs that likely includes rs114947103-correlated variants) was associated with both wheezing and asthma, confirming that the broader CDHR3 haplotype block captures the susceptibility signal across populations.

Shigemasa et al. 2020⁶⁶ Shigemasa et al. 2020
Shigemasa R et al. Genetic impact of CDHR3 on the adult onset of asthma and COPD. Clin Exp Allergy 2020;50(11):1223-1229 extended the observation to adults: in a decade-long longitudinal study of 1,523 healthy adults, the CDHR3 risk allele elevated asthma and COPD development specifically in atopic individuals, suggesting the virus-driven wheezing mechanism established in childhood persists as a risk factor into adult life.

Practical Actions

For adults, the CDHR3 haplotype matters most in the context of respiratory virus exposures. RV-C infection is essentially unavoidable across a lifetime, but the severity of individual episodes — and the likelihood that those episodes drive airway remodeling toward asthma — is influenced by viral load, exposure timing, and the immune context at the time of infection. High-efficiency CDHR3 receptors mean more virus enters more cells per exposure event.

In children and in adults who are atopic (with allergic sensitization), the risk is most actionable: RV-C wheezing episodes are the primary driver of asthma exacerbations, and preventing severe episodes during early childhood windows when airways are still developing reduces the cumulative injury that contributes to persistent asthma.

Interactions

This variant's effect operates through the rs6967330-Y529 haplotype. The functional biology is thus tightly linked to that coding variant; the two cannot be independently analyzed in most real-world genetic datasets and should be considered as co-tracking markers for elevated CDHR3 receptor activity.

The susceptibility this variant captures is specifically rhinovirus C — distinct from broader innate antiviral pathways governed by TLR3 (rs3775291) or IFITM3 (rs12252). Carriers of both a CDHR3 risk haplotype and a TLR3 hypomorphic allele would face compounded risk: higher viral entry efficiency at the epithelial surface combined with blunted interferon signaling once infection is established.