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

• Published in: Journal of allergy and clinical immunology 2024-08, Vol.154 (2), p.308-315
• Main Authors: Regis, Eteri, Fontanella, Sara, Curtin, John A., Pinot de Moira, Angela, Edwards, Michael R., Murray, Clare S., Simpson, Angela, Johnston, Sebastian L., Custovic, Adnan
• Format: Article
• Language: English
• Subjects: 17q12-q21; asthma; Asthma - genetics; Asthma - immunology; Bayesian methods; birth cohorts; Chemokine CXCL10 - genetics; Child; Child, Preschool; childhood; Chromosomes, Human, Pair 17 - genetics; Female; Genetic Predisposition to Disease; Humans; innate immune response; Interferons; Leukocytes, Mononuclear - immunology; Male; Picornaviridae Infections - genetics; Picornaviridae Infections - immunology; Polymorphism, Single Nucleotide; Respiratory Sounds - genetics; Respiratory Sounds - immunology; Rhinovirus
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2024.03.005

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. We investigated whether 17q12-q21 risk alleles were associated with impaired interferon responses to rhinovirus. 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. 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. 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.