Association between polymorphisms on chromosome 17q12-q21 and rhinovirus-induced interferon responses
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
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.
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.
Date Issued
2024-08-01
Date Acceptance
2024-03-01
Citation
Journal of Allergy and Clinical Immunology, 2024, 154 (2), pp.308-315
ISSN
0091-6749
Publisher
Elsevier
Start Page
308
End Page
315
Journal / Book Title
Journal of Allergy and Clinical Immunology
Volume
154
Issue
2
Copyright Statement
© 2024 The Authors. Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
License URL
Sponsor
Medical Research Council (MRC)
Identifier
10.1016/j.jaci.2024.03.005
Grant Number
MR/L012693/1
Subjects
17Q12-21.1 LOCUS
17q12-q21
Allergy
asthma
Bayesian methods
birth cohorts
BRONCHIAL EPITHELIAL-CELLS
childhood
CHILDREN
DEFICIENT
EARLY-ONSET ASTHMA
GENETIC-VARIANTS
ILLNESS
Immunology
INFECTION
innate immune response
interferons
Life Sciences & Biomedicine
PROFILE REGRESSION
rhinovirus
RISK
Science & Technology
Publication Status
Published
Date Publish Online
2024-03-15