Association between polymorphisms on chromosome 17q12-q21 and rhinovirus-induced interferon responses

Abstract

BackgroundSingle nucleotide polymorphisms (SNPs) in genes on chromosome 17q12-q21 are associated with childhood-onset asthma and rhinovirus-induced wheezing. There is little mechanistic data linking chromosome 17q12-q21 to wheezing illness. ObjectiveTo investigate whether 17q12-q21 risk alleles may be associated with impaired interferon (IFN) responses to rhinovirus. MethodsIn a population-based birth cohort of European ancestry, we stimulated peripheral blood mononuclear cells (PBMCs) with rhinovirus-A1 (RV-A1) and rhinovirus-A16 (RV-A16) and measured IFN and IFN-induced chemokine CXCL10/IP10 responses in supernatants. We investigated associations between virus-induced cytokines and six SNPs in 17q12-q21. Bayesian profile regression was applied to identify clusters of individuals with different immune response profiles and genetic variants. ResultsFive SNPs (in high linkage disequilibrium, r2≥0.8) were significantly associated with RV-A1-induced IFN-β (rs9303277: P=0.010; rs11557467: P=0.012; rs2290400: P=0.006; rs7216389: P=0.008; rs8079416: P=0.005). A reduction in RV-A1-induced IFN-β was observed among individuals carrying asthma risk alleles. There were no significant associations for RV-A1-induced IFN-α or CXCL10, or for any RV-A16-induced IFN/CXCL10. Bayesian profile regression analysis identified three clusters which differed in IFN-β induction to RV-A1 (low, medium and high). The typical genetic profile of the cluster associated with low RV-A1-induced IFN-β responses was characterised by a very high probability of being homozygous for the asthma risk allele for all SNPs. Children with persistent wheeze were almost 3-times more likely to be in clusters with reduced/average RV-A1-induced IFN- β responses than in the high immune response cluster. ConclusionsPolymorphisms on chromosome 17q12-q21 are associated with rhinovirus-induced IFN-β, suggesting a novel mechanism (impaired IFN-β induction) linking 17q12-q21 risk alleles with asthma/wheeze.