Background Respiratory syncytial virus (RSV) is associated with childhood asthma. Nevertheless, not all children exposed to RSV develop asthma symptoms, possibly because genes modulate the effects of RSV on asthma exacerbations.
Objective The purpose of this study was to identify genes that modulate the effect of RSV latent infection on asthma exacerbations.
Methods We performed a meta-analysis to investigate differentially expressed genes (DEGs) of RSV infection from Gene Expression Omnibus datasets. Expression quantitative trait loci (eQTL) methods were applied to select single nucleotide polymorphisms (SNPs) that were associated with DEGs. Gene-based analysis was used to identify SNPs that were significantly associated with asthma exacerbations in the Taiwanese Consortium of Childhood Asthma Study (TCCAS), and validation was attempted in an independent cohort, the Childhood Asthma Management Program (CAMP). Gene–RSV interaction analyses were performed to investigate the association between the interaction of SNPs and RSV latent infection on asthma exacerbations.
Results A total of 352 significant DEGs were found by meta-analysis of RSV-related genes. We used 38 123 SNPs related to DEGs to investigate the genetic main effects on asthma exacerbations. We found that eight RSV-related genes (GADD45A, GYPB, MS4A3, NFE2, RNASE3, EPB41L3, CEACAM6 and CEACAM3) were significantly associated with asthma exacerbations in TCCAS and also validated in CAMP. In TCCAS, rs7251960 (CEACAM3) significantly modulated the effect of RSV latent infection on asthma exacerbations (false-discovery rate <0.05). The rs7251960 variant was associated with CEACAM3 mRNA expression in lung tissue (p for trend=1.2×10−7). CEACAM3 mRNA was reduced in nasal mucosa from subjects with asthma exacerbations in two independent datasets.
Conclusions rs7251960 is an eQTL for CEACAM3, and CEACAM3 mRNA expression is reduced in subjects experiencing asthma exacerbations. CEACAM3 may be a modulator of RSV latent infection on asthma exacerbations.
- asthma genetics
- paediatric asthma
- viral infection
- asthma pharmacology
- clinical epidemiology
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Contributors C-HT designed the study, performed the respiratory syncytial virus (RSV) experiments, analysed the data and wrote the manuscript. ACW provided the Childhood Asthma Management Program (CAMP) data, interpreted the data and revised the manuscript. B-LC, Y-HY and S-PH provided patients’ materials and advice about data collection. M-WS performed the SNP imputation of Taiwanese Consortium of Childhood Asthma Study (TCCAS) and interpreted the data. Y-JC provided advice about the RSV experiments and interpretation of the data. YLL conceived and initiated the project, provided advice about interpretation of the data and revised the manuscript.
Funding This study was supported by grant 106-2314-B-002-131-MY3 (PI: YLL) from the Taiwan Ministry of Science and Technology, grant UN107-002, UN108-007, UN109-012 (PI: YLL and B-LC) and 107-CGN03 (PI: Y-HY and S-PH) from the National Taiwan University Hospital, grant NHRI-EX107-10606PI (PI: YLL) from the National Health Research Institutes, grant AS-TM-108-01-03 (PI: YLL) from Academia Sinica, and R01 HD085993-02 (PI: ACW) from the National Institute of Child Health and Human Development.
Disclaimer The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available in a public, open access repository. Data may be obtained from a third party and are not publicly available. Data availability statement: gene expression profiles are available in the Gene Expression Omnibus resource (https://www.ncbi.nlm.nih.gov/geo/). Expression quantitative trait loci of whole blood and lung tissue are available from the Genotype-Tissue expression dataset (https://gtexportal.org/home/). The datasets supporting the conclusions of this article are included in this published article and its additional files. The raw data from the TCCAS are not publicly available. The genotype and phenotype data of the CAMP are publicly available on dbGAP.