Association between polymorphisms on chromosome 17q12-q21 and rhinovirus-induced interferon responses - 05/04/24

Doi : 10.1016/j.jaci.2024.03.005

Eteri Regis, PhD ^a, Sara Fontanella, PhD ^a, John A. Curtin, PhD ^b, Angela Pinot de Moira, PhD ^a, Michael R. Edwards, PhD ^a, Clare S. Murray, MD ^b, Angela Simpson, MD, PhD ^b, Sebastian L. Johnston, MD, PhD ^a, Adnan Custovic, MD, PhD, FAAAAI ^a,^⁎
^a National Heart and Lung Institute, Imperial College London, London, United Kingdom
^b 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

^∗Corresponding author: Adnan Custovic, MD, PhD, FAAAAI, Imperial College London, St Mary’s Campus Medical School, Room 220, Norfolk Place, London W2 1PG, United Kingdom.Imperial College LondonSt Mary’s Campus Medical SchoolRoom 220Norfolk PlaceLondonW2 1PGUnited Kingdom

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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.

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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

Plan

Methods

Study design, setting, participants, and data sources

Definition of clinical outcomes

In vitro cell stimulation and cytokine measurement

SNP selection and genotyping

Statistical analysis

Results

Innate antiviral immune responses

Associations between 17q12-q21 variants and immune responses to rhinoviruses

Associations between 17q12-q21 variant and clinical outcome

Discussion

Disclosure statement

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.