Abstract
BackgroundAcute lower respiratory tract infection is the commonest disease affecting children under five worldwide. Respiratory syncytial virus (RSV) is among the most common causative pathogens. Epidemiological data suggest an association between severe viral respiratory infections in infancy and increased incidence of childhood wheeze and asthma. DNA methylation is involved in immune cell differentiation and identity. It provides an avenue for environmental influences on the genome and therefore has potential as a marker for sustained effects of infectious insults. In this study we investigated the association between DNA methylation patterns in the perforin gene (PRF1) in childhood and a history of hospitalisation for severe RSV disease in the first two years of life.MethodsIn this retrospective study, we explored patterns of whole blood DNA methylation at a methylation sensitive region of the proximal PRF1 enhancer in a group of children with a record of hospitalisation for severe RSV disease during infancy (n = 43) compared to healthy controls matched for age and sex with no similar hospitalisation history, no allergy and no persistent wheeze (n = 43). Univariate and bivariate conditional logistic regression analyses were conducted to test the association between PRF1 enhancer methylation and record of hospitalisation for RSV disease.ResultsChildren with a record of hospitalisation for severe RSV bronchiolitis demonstrated markedly lower levels of DNA methylation at two cytosine-phosphate-guanine dinucleotide (CpG) loci of the PRF1 proximal enhancer, corresponding to a signal transducer and activator of transcription 5 (STAT5) responsive element, compared to controls, adjusted odds ratios of 0.82 (95% confidence interval [CI] 0.71, 0.94) and 0.73 (95% CI 0.58, 0.92) for each 1% increase in DNA methylation. Smoking in the household showed a significant influence on DNA methylation at the assayed positions.ConclusionsOur findings support an association between childhood DNA methylation patterns in PRF1 and a record of severe RSV infection in infancy. Longitudinal studies are required to establish the utility of PRF1 methylation as a marker of severe RSV disease.
Highlights
Acute lower respiratory tract infection is the commonest disease affecting children under five worldwide
We previously reported higher methylation of specific cytosine-phosphate-guanine dinucleotide (CpG) positions corresponding to a signal transducer and activator of transcription 5 (STAT5) binding element in an enhancer region of PRF1 in cord blood DNA of infants who subsequently developed frequent lower respiratory tract infection (LRTI) during their first year of life [14]
Respiratory syncytial virus (RSV) cases had a median age of 3.3 years while controls had a median age of 4 years (IQR 4.0, 5.0)
Summary
Acute lower respiratory tract infection is the commonest disease affecting children under five worldwide. In this study we investigated the association between DNA methylation patterns in the perforin gene (PRF1) in childhood and a history of hospitalisation for severe RSV disease in the first two years of life. Evidence is strong that viral respiratory infections in infancy are associated with increased risk of childhood wheezing, atopy and asthma [3], up to adolescence [4] and possibly early adulthood [5]. It is not entirely clear whether viral LRTIs including RSV are a causal factor or indicate heightened susceptibility to asthma considerable evidence supports a causal link [6]. Epigenetic modifications have been characterized in key effector and regulator genes as determinants of cell type and function in the immune system and modulators of immune response [9]
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