Regis Eteri, Fontanella Sara, Curtin John A, Pinot de Moira Angela, Edwards Michael R, Murray Clare S, Simpson Angela, Johnston Sebastian L, Custovic Adnan
National Heart and Lung Institute, Imperial College London, London, United Kingdom.
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.
J Allergy Clin Immunol. 2024 Aug;154(2):308-315. doi: 10.1016/j.jaci.2024.03.005. Epub 2024 Mar 15.
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, r ≥ 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.
17号染色体q12-q21区域基因中的单核苷酸多态性（SNP）与儿童期哮喘及鼻病毒诱发的喘息相关。将17号染色体q12-q21区域与喘息性疾病联系起来的机制数据较少。
我们研究了17q12-q21风险等位基因是否与鼻病毒感染后干扰素反应受损有关。
在一个基于人群的欧洲血统出生队列中，我们用鼻病毒A1（RV-A1）和鼻病毒A16（RV-A16）刺激外周血单个核细胞，并测量上清液中干扰素（IFN）和IFN诱导的C-X-C基序趋化因子配体10（即IP10）的反应。我们研究了病毒诱导的细胞因子与17q12-q21区域6个SNP之间的关联。应用贝叶斯轮廓回归来识别具有不同免疫反应特征和基因变异的个体聚类。
5个SNP（处于高度连锁不平衡状态，r≥0.8）与RV-A1诱导的IFN-β显著相关（rs9303277，P = 0.010；rs11557467，P = 0.012；rs2290400，P = 0.006；rs7216389，P = 0.008；rs8079416，P = 0.005）。在携带哮喘风险等位基因的个体中观察到RV-A1诱导的IFN-β降低。对于RV-A1诱导的IFN-α或CXCL10，以及任何RV-A16诱导的IFN/CXCL10，均未发现显著关联。贝叶斯轮廓回归分析确定了3个聚类，它们对RV-A1的IFN-β诱导存在差异（低、中、高）。与低RV-A1诱导的IFN-β反应相关的聚类的典型基因特征是，所有SNP的哮喘风险等位基因纯合的概率非常高。持续性喘息儿童处于RV-A1诱导的IFN-β反应降低/中等聚类中的可能性几乎是高免疫反应聚类中的3倍。
17号染色体q12-q21区域的多态性与鼻病毒诱导的IFN-β相关，提示一种新机制——IFN-β诱导受损——将17q12-q21风险等位基因与哮喘/喘息联系起来。
