Association Between Polymorphisms on Chromosome 17Q12-Q21 and Rhinovirus-Induced Interferon Responses

Background: Single nucleotide polymorphisms (SNPs) in genes on chromosome 17q12-q21 are associated with childhood-onset asthma and rhinovirus-induced wheeze. There are few mechanistic data linking chromosome 17q12-q21 to wheezing illness. Objective: We investigated whether 17q12-q21 risk alleles were associated with impaired interferon responses to rhinovirus. Methods: In a population-based birth cohort of European ancestry, we stimulated peripheral blood mononuclear cells with rhinovirus A1 (RV-A1) and rhinovirus A16 (RV-A16) and measured IFN and IFN-induced C-X-C motif chemokine ligand 10 (aka IP10) responses in supernatants. We investigated associations between virus-induced cytokines and 6 SNPs in 17q12-q21. Bayesian profile regression was applied to identify clusters of individuals with different immune response profiles and genetic variants. Results: Five SNPs (in high linkage disequilibrium, r(2) >= 0.8) were significantly associated with RV-A1-induced IFN-beta (rs9303277, P = . 010; rs11557467, P = . 012; rs2290400, P = . 006; rs7216389, P = . 008; rs8079416, P = . 005). A reduction in RV-A1-induced IFN-beta was observed among individuals with asthma risk alleles. There were no significant associations for RV-A1-induced IFN-alpha or CXCL10, or for any RV-A16-induced IFN/CXCL10. Bayesian profile regression analysis identified 3 clusters that differed in IFN-beta induction to RV-A1 (low, medium, high). The typical genetic profile of the cluster associated with low RV-A1-induced IFN-beta responses was characterized 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-beta responses than in the high immune response cluster. Conclusions: Polymorphisms on chromosome 17q12-q21 are associated with rhinovirus-induced IFN-beta, suggesting a novel mechanism-impaired IFN-beta induction-links 17q12-q21 risk alleles with asthma/wheeze.