Prospective Bronchiolitis Cohort Study: Interleukin 17 gene polymorphisms in bronchiolitis, post-bronchiolitis asthma and lung function

Background: Bronchiolitis, a lower respiratory tract infection that occurs during infancy, is mainly caused by respiratory syncytial virus (RSV) and is the leading cause of infant hospitalisation. Susceptibility to severe bronchiolitis and post-bronchiolitis asthma has been established as a multifactorial entity, with genetic and viral factors being particularly prominent. Interleukin (IL)-17A and IL-17F, encoded by the IL17A and IL17F genes, respectively, are mainly proinflammatory cytokines involved in inflammation and asthma.

Aims: The aims of this long-term prospective cohort study were (1) to evaluate the clinical course and the viral aetiology of bronchiolitis in infancy at less than 6 months of age in relation to the IL17A rs2275913, rs4711998 and rs8193036 single nucleotide polymorphisms (SNPs) and the IL17F rs763780, rs11465553 and rs7741835 SNPs, and (2) to evaluate the associations between these IL17A and IL17F SNPs and post-bronchiolitis asthma and lung function in children aged 5–7 years and 11–13 years. Minor allele frequencies (MAFs) of the IL17A rs2275913, rs4711998 and rs8193036 SNPs and the IL17F rs763780, rs11465553 and rs7741835 SNPs in bronchiolitis patients were compared to the MAFs in the Finnish population obtained from two publicly available databases.

Materials and methods: Originally, 166 previously healthy, full-term infants aged less than 6 months who were hospitalised for bronchiolitis were enrolled in the study. The viral aetiology of the bronchiolitis cases was determined by virus antigen and genome detection in nasopharyngeal aspirates, and RSV was the predominant causative agent. During hospitalisation, each patient’s disease severity markers, such as the length of hospital stay and the need for and duration of oxygen administration and/or feeding support, were registered, and blood samples were collected for later genetic studies. Follow-up visits took place when the patients were 5–7 and 11–13 years of age. Asthma and allergy diagnoses, asthma-presumptive symptoms and use of inhaled bronchodilators or inhaled corticosteroids (ICSs) were registered. Lung function was measured with impulse oscillometry (IOS) at 5–7 years of age and with flow-volume spirometry (FVS) at 11–13 years of age.

Results: The MAFs of the IL17A rs2275913 (A), rs4711998 (A) or rs8193036 (C) and the IL17F rs763780 (C), rs11465553 (T) or rs7741835 (T) SNPs did not differ between the cases and the controls, which consisted of 99 Finnish samples from the 1000 Genomes Project and the Finnish data (from 1734 to 12558, depending on the SNP) of the Genome Aggregation Database. There were no significant differences in the severity or RSV aetiology of bronchiolitis during hospitalisation or in the asthma outcomes between children with the wild or variant genotypes of the analysed IL17A or IL17F SNPs until the age of 5–7 years. At 11–13 years of age, children with the variant GA or AA genotype of IL17A rs2275913 had a significantly lower prevalence of asthma, use of ICSs during the last 12 months or prevalence of allergic rhinitis than those with the wild genotype GG. In adjusted analyses, the difference in the use of ICSs during the last 12 months remained statistically significant (aOR 0.25). In the IOS results obtained at 5–7 years of age, the IL17A rs2275913 wild genotype GG was associated with exercise-induced airway resistance; however, in the FVS results obtained at 11–13 years of age, no abnormalities were apparent. Children with the variant genotype TC or CC of IL17F rs763780 had used ICSs more often between the follow-up visits from 5– 7 to 11–13 years (aOR 3.58) than those with the wild genotype TT. The results also showed that the IL17A rs4711998 and rs8193036 SNPs, or the IL17F rs11465553 and rs7741835 SNPs had no obvious impact on post-bronchiolitis asthma.

Conclusions: In this post-bronchiolitis cohort study, some evidence was found that suggests that the variant genotype of IL17A rs2275913 may be protective against post-bronchiolitis asthma at school age; moreover, the same variant genotype was found to already present with less bronchial hyperresponsiveness at preschool age. In addition, the variant genotype of IL17F rs763780 may increase the risk for post-bronchiolitis asthma persisting from 5 to 13 years of age.