Association between polymorphisms on chromosome 17q12-q21 and rhinovirus-induced interferon responses - 05/08/24
Abstract |
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, r2 ≥ 0.8) were significantly associated with RV-A1–induced IFN-β (rs9303277, P = .010; rs11557467, P = .012; rs2290400, P = .006; rs7216389, P = .008; rs8079416, P = .005). A reduction in RV-A1–induced IFN-β was observed among individuals with 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 3 clusters that differed in IFN-β induction to RV-A1 (low, medium, high). The typical genetic profile of the cluster associated with low RV-A1–induced IFN-β 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-β responses than in the high immune response cluster.
Conclusions |
Polymorphisms on chromosome 17q12-q21 are associated with rhinovirus-induced IFN-β, suggesting a novel mechanism—impaired IFN-β induction—links 17q12-q21 risk alleles with asthma/wheeze.
El texto completo de este artículo está disponible en PDF.Key words : 17q12-q21, rhinovirus, interferons, innate immune response, asthma, childhood, birth cohorts, Bayesian methods
Abbreviations used : BPR, CXCL10, ICAM-1, LD, PBMC, RV-A1/A16, SNP
Esquema
| The first 2 authors contributed equally to this article, and both should be considered first author. The last 3 authors contributed equally to this article, and all should be considered senior author. |
Vol 154 - N° 2
P. 308-315 - août 2024 Regresar al número
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