Rs6967330

rs6967330, a SNP found to be associated with early childhood asthma characterized by severe exacerbations, is situated at chr7:105658451 in the CDHR3 gene coding region. The CDHR3 gene encodes a transmembrane protein that belongs to the cadherin family. Proteins in the cadherin family are involved in homologous cell adhesion and important for several cellular processes, including epithelial polarity, cell-cell interaction and differentiation, but the specific role of CDHR3 is unclear. The identification of rs6967330 in a genome-wide association study (GWAS) of asthma indicates that CDHR3 might be an asthma susceptibility locus.

Asthma and Genetics
Asthma is a common inflammatory disease of the airways characterized by symptoms of wheezing, chest tightness, and shortness of breath. Asthma is caused by a complex interaction between genetic and environmental factors. Asthma heritability is estimated to be 70-90%. Several asthma-associated loci have been identified using family-based linkage study or GWAS. Given that asthma has large heterogeneity, increasing phenotype specificity in GWAS study would be helpful for identifying new susceptibility loci.

GWAS study of rs6967330
The association of rs6967330 with asthma was found by Bønnelykke et al. in 2013. A GWAS study in a phenotype-specific population of asthma patients was performed with 1173 Danish children at 2-6 years old with recurrent acute hospitalizations for asthma. 2511 individuals of Danish descent without asthma were used as controls. In this study, five SNPs were identified with excess of association signals beyond those expected by chance, including rs2305480 in GSDMB, rs928413 near IL33, rs6871536 in RAD50, rs1558641 in IL1RL1 and rs6967330 in CDHR3. Among the five, rs6967330 was the only SNP that had not been previously reported to be associated with asthma. This study showed that rs6871536 had a p-value of 1.4×10−8 and an odds ratio (OR) of 1.45 (95% CI 1.28-1.66). The result was further validated in two other birth cohorts of European ancestry and 1 cohort with a population of mixed ancestry. So far, no other studies have validated this result in a non-European population.

It is worth noting that rs6967330 was shown to be associated with greater risk in younger children (6 vs. 16 years old) and with recurrent hospitalizations and exacerbations (i.e. OR increases with number of hospitalizations). This indicates that the CDHR3 locus is associated with an early onset asthma phenotype characterized by recurrent exacerbations. Moreover, rs6967330 also showed weak association with neonatal bronchial responsiveness (P=0.10).

The results of this paper demonstrate the strength of using well-defined specific phenotyping for GWAS. This study found a statistically significant association for an asthma susceptibility locus using a smaller sample size, in part because a strict case definition decreased heterogeneity in the case population. However, the general applicability of this finding to other sub-types of asthma has yet to be determined.

Mechanism
For rs6967330 the major allele is G and the minor allele is A. The risk allele A causes a nonsynonymous cysteine to tyrosine (Cys529Tyr) mutation in the CDHR3 protein. The mutant protein is expressed at higher levels at the cell surface when compared to the wild type protein.

Changes in protein expression levels could be caused by perturbations of the interdomain or overall stability of the CDHR3 protein. Structural analysis indicates that the amino acid alteration is located at the interface between two proximal cadherin membrane domains, D5 and D6. Cys592 and Cys566 in D6 are expected to form a disulfide bridge within D6 and are close to Cys529 in D5. The short distance could allow for disulfide rearrangement, leading to a change in protein conformation and stability.

Elevated expression level of CDHR3, caused by rs6967330 risk allele, was speculated as the possible mechanism of its association with asthma. CDHR3 is highly expressed in lung tissue and specifically in the bronchial epithelium. Abnormalities in airway epithelium are known to play an important role in asthma pathogenesis. Epithelial integrity is largely dependent on the interaction of proteins in cell-cell junction complexes, including adhesion molecules. Cadherin-family proteins are typically involved in homologous cell adhesion. Therefore, the alteration of expression in CDHR3, which belongs to the cadherin family, could lead to abnormalities in airway epithelium. Future research to fully understand the role of CDHR3 variants in the development of asthma could lead to new therapeutics of asthma.