F1000Prime Recommendation of [Bønnelykke K et al., Nat Genet 2014, 46(1):51-5]

Abstract

To date, several asthma susceptibility genes have been identified with confidence using approaches such as genome-wide association studies (GWAS). However, a large amount of the heritability of asthma remains to be accounted for, and polymorphisms identified to date individually have very modest effect sizes (odds ratio [OR] 1.1-1.2). One potential explanation for these observations is heterogeneity in the asthma patients selected for these large studies, which suggests a more refined clinical characterisation of asthma may further define the 'missing heritability' of asthma, identify novel genes and clarify effect sizes of existing loci in these patients. To this end, Bønnelykke and colleagues completed a GWAS using a novel sub-set of asthma patients, i.e. subjects with severe exacerbations between the ages of two and six (n=1173). Using a standard GWAS approach with 2522 controls, this study identified a novel susceptibility locus and confirmed four susceptibility loci previously reported to be associated with asthma per se. More specifically, these loci included (i) gasdermin B (GSDMB) (rs2305480), (ii) interleukin 33 (IL33) (rs928413), (iii) RAD50 homolog (Saccharomyces cerevisiae) (RAD50) (rs6871563), (iv) interleukin receptor 1, type 1 (IL1R1) (rs1558641) and (v) the novel cadherin-related family member 3 (CDHR3) (rs6967330) gene. Interestingly, the effect sizes for individual polymorphisms at multiple loci, including for example IL33 key single nucleotide polymorphisms (SNPs), were increased with the number of hospitalisations per genotype (OR 1.32, 1.22, 1.47, 1.91 for 2, 3, 4/5 and 6 or more hospitalisations respectively). These effect sizes are beyond that previously described in asthma per se. Importantly, these previously described associations replicated in a childhood onset stratum of the GABRIEL consortium and in a combined analyses of three independent cohorts (COPSAC2000, MAAS and Generation R), not only presented with elevated effect sizes when compared to earlier asthma-driven genome-wide associations but also presented with elevated odds ratios on increasing hospitalisations. The authors therefore suggest that early-onset asthma with severe exacerbations is at least in part driven by multiple common variants that contribute to severe asthma not defined by severe exacerbations. Importantly, this study has identified a novel asthma susceptibility locus (CDHR3), which exclusively regulates severe childhood asthma, as defined by frequent exacerbations. Focusing on this novel locus, the authors identified an increased risk of asthma hospitalisations, severe exacerbations (combined analysis in COPSAC2000 & MAAS) and bronchial responsiveness (COPSAC2000) on expression of the rs6967330 risk allele, which was considered as the casual gene variant for CDHR3. In a series of well-designed cell-based and bioinformatics experiments, the authors have taken research into this novel locus one step further by investigating the effect of this SNP on protein expression and structure. Utilising a cell-based model, the presence of the risk allele was found to result in a marked increase in cell surface CDHR3 expression, while protein structure modelling suggested that the variant residue interferes with stability, folding or conformation of this protein. Bønnelykke et al. then confirmed, using adult bronchial epithelium and foetal lung tissue, expression of CDHR3 in the developing and adult lung and suggest a role for CDHR3 protein in airway epithelial cell adhesion and interaction in the airways via known roles of other members of the cadherin family. The finding that CDHR3 is involved in airway epithelial functions adds further support to the notion that epithelial alterations are a feature of asthma and contribute to disease susceptibility and expression. Similarly, the finding that the IL33 locus was identified, a protein thought to be elevated in the airway epithelium in asthma, further supports this concept. In summary, using a combination of genetic, bioinformatics and cell biology approaches, the authors have confirmed four previously determined asthma-specific loci and identified in early onset asthma with severe exacerbations a novel region (CDHR3). The authors also identified protein-based effects of region tagging polymorphism and confirmed its expression in the developing and adult lung. Finally this study identifies that specific sub-phenotyping is helpful in determining disease susceptibility genes, as use of a smaller population has not only been able to identify equivalent numbers of asthma associated loci as analyses with significantly larger numbers of participants but also presents higher effect sizes for these same loci. Exacerbations of asthma cause a significant impact on society, both on health-related and pharmacoeconomic outcomes, especially since the regulation of severe asthma exacerbations remains inadequate. CDHR3 and related proteins may prove to be a novel opportunity for therapeutic intervention in these patients.