Background Previously identified asthma-susceptibility genes account for a small part of asthma heritability and their role in asthma pathogenesis is unclear. We explored associations between genetic variants in the 17q21 locus, CDHR3 (cadherin-related family member 3) , coding a receptor for Rhinovirus-C, preschool wheeze and asthma at 7 years. Methods Four genetic variants in the 17q21 locus (rs8076131, rs12603332, rs8079416, rs3859192) and rs6967330 in CDHR3 were studied regarding associations with preschool wheeze and asthma at 7 years. We compared 125 cases, enrolled during an acute wheezing episode, with 96 healthy controls at preschool age (6-45 months). At 7 years cases with asthma (N=68) and without asthma (N=31) were compared regarding genetic variants and other clinical parameters. Results Rs8076131 (AA vs GG) was associated with preschool wheeze (OR 3.50, p=0.001), and asthma at 7 years (OR 8.55, p=0.002). Rs12603332 (CC vs TT) was related to asthma at 7 years irrespective of rhinovirus infection at inclusion or current signs of airborne allergy (aOR 7.17, p=0.016). The association of rs6967330 with asthma was restricted to children with specific genotypes in the 17q21 locus; rs8076131-AA (p=0.028) , rs8079416-CC (p=0.006), and rs3859192-TT (p=0.042). Rhinovirus infection at inclusion was significantly related to asthma exclusively in homozygotes rs8079416-CC (p=0.032) and rs3859192-TT (p=0.027). Conclusion Our results highlight the impact of asthma heritability by reporting strong associations between 17q21 locus and asthma in a high-risk cohort. The association of rs6967330 in CDHR3 and early-life rhinovirus infection with asthma at school age might be dependent on specific genotypes in the 17q21 locus.

Background: Exhaled nitric oxide and blood eosinophils are clinical asthma type 2 markers in use. Immunoglobulin E (IgE) is often involved in the inflammation associated with atopic asthma. The effect of both blood eosinophils and allergen-specific IgE on exhaled nitric oxide levels is not completely understood. Twin-design studies can improve understanding of the underlying contribution of genetically and/or environmentally driven inflammation markers in asthma. Our aim was to disentangle the covariance between asthma and exhaled nitric oxide into genetic and environmental contributions that can account for inflammation markers in a paediatric population. Methods: This population-based, cross-sectional twin study enrolled 612 monozygotic (MZ) and same-sex dizygotic (DZ) schoolchildren. Multivariate structural equation modelling was utilized to separate the covariance between asthma and exhaled nitric oxide into genetic and/or environmental effects, taking allergen-specific IgE level and blood eosinophil count into account while controlling for confounding factors. Results: The cross-twin/cross-trait correlations had a higher magnitude in the MZ twins than in the DZ twins indicating that genes affect the association. The likelihood ratio test for model fitting resulted in the AE model as the most parsimonious. A majority, 73%, of the phenotypic correlation between asthma and exhaled nitric oxide, r=0.19 (0.05–0.33), was attributable to genetic effects which mainly was due to the allergen-specific IgE level. Conclusions: This study indicate that the association between asthma - exhaled nitric oxide in children is to a large extent explained by genetics via allergen-specific IgE-level but not blood eosinophils. This might partly explain the clinical heterogeneity in this group. A next step could be to include allergen-specific IgE level in multivariate omic-studies.