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

Eteri Regis; Sara Fontanella; John A Curtin; Angela Pinot de Moira; Michael R Edwards; Clare S Murray; Angela Simpson; Sebastian L Johnston; Adnan Custovic

doi:10.1016/j.jaci.2024.03.005

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

J Allergy Clin Immunol. 2024 Mar 15:S0091-6749(24)00269-0. doi: 10.1016/j.jaci.2024.03.005. Online ahead of print.

Authors

Eteri Regis¹, Sara Fontanella¹, John A Curtin², Angela Pinot de Moira¹, Michael R Edwards¹, Clare S Murray², Angela Simpson², Sebastian L Johnston¹, Adnan Custovic³

Affiliations

¹ National Heart and Lung Institute, Imperial College London, London, United Kingdom.
² Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, Manchester Academic Health Sciences Centre, University of Manchester and University Hospital of South Manchester NHS Foundation Trust, Manchester, United Kingdom.
³ National Heart and Lung Institute, Imperial College London, London, United Kingdom. Electronic address: a.custovic@imperial.ac.uk.

PMID: 38494094
DOI: 10.1016/j.jaci.2024.03.005

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.

Keywords: 17q12-q21; Bayesian methods; asthma; birth cohorts; childhood; innate immune response; interferons; rhinovirus.