Genetic and epigenetic susceptibility of airway inflammation to PM2.5 in school children: new insights from quantile regression

Abstract

Background: The fractional concentration of exhaled nitric oxide (FeNO) is a biomarker of airway inflammation that has proved to be useful in investigations of genetic and epigenetic airway susceptibility to ambient air pollutants. For example, susceptibility to airway inflammation from exposure to particulate matter with aerodynamic diameter < =2.5 μm (PM_2.5) varies by haplotypes and promoter region methylation in inducible nitric oxide synthase (iNOS encoded by NOS2). We hypothesized that PM2.5 susceptibility associated with these epigenetic and genetic variants may be greater in children with high FeNO from inflamed airways. In this study, we investigated genetic and epigenetic susceptibility to airborne particulate matter by examining whether the joint effects of PM2.5, NOS2 haplotypes and iNOS promoter methylation significantly vary across the distribution of FeNO in school children.

Methods: The study included 940 school children in the southern California Children's Health Study who provided concurrent buccal samples and FeNO measurements. We used quantile regression to examine susceptibility by estimating the quantile-specific joint effects of PM_2.5, NOS2 haplotype and methylation on FeNO.

Results: We discovered striking differences in susceptibility to PM_2.5 in school children. The joint effects of short-term PM_2.5 exposure, NOS2 haplotypes and methylation across the FeNO distribution were significantly larger in the upper tail of the FeNO distribution, with little association in its lower tail, especially among children with asthma and Hispanic white children.

Conclusion: School-aged children with higher FeNO have greater genetic and epigenetic susceptibility to PM_2.5, highlighting the importance of investigating effects across the entire distribution of FeNO.

Keywords: Asthma; Exhaled nitric oxide; Haplotype; Inducible nitric oxide synthase; Methylation; PM2.5.

Fig. 1

Estimated joint effects of NOS2 H1 haplotype, iNOS methylation and 7-day average PM_2.5 exposure across the selected quantiles of FeNO distribution and its mean. In each panel, data are presented by number of H1 haplotype copy. The X-axis shows the combination of levels in methylation (first number in the bracket) and short-term PM_2.5 exposure (second number in the bracket). Selected methylation levels are population average, 5% and 10% lower than averages, which are indexed by 0,-5 and −10, respectively. Selected PM_2.5 exposure levels are population average, 5 μg/m³ and 10 μg/m³ higher PM_2.5 exposure levels than average, which are indexed by 0, 5 and 10, respectively. The estimated joint effects when methylation levels are at population average, 5% and 10% lower than average are represented by black, red and green lines, respectively

Fig. 2

Empirical log-FeNO distribution among children without copy of the haplotype (black line) and its associated predicted distribution among children with two copies of haplotype, 10 μg/m³ increases in short-term PM_2.5 exposure and 10% decreases in methylation level (Red line). Panel a) shows the density curves of both distributions and selected percentiles (10%, 30%, 50%, 70% and 90%), respectively. Panel b) is a QQ plot and plotted the quantiles of predicted distribution against those of empirical distribution

Fig. 3

Estimated joint effects of NOS2 H1 haplotype, iNOS methylation and 7-day average PM_2.5 exposure across the selected quantiles of FeNO distribution and its mean by asthma status. In each panel, data are presented by number of H1 haplotype copy. The X-axis shows the combination of levels in methylation (first number in the bracket) and short-term PM_2.5 exposure (second number in the bracket). Selected methylation levels are population average, 5% and 10% lower than averages, which are indexed by 0,-5 and −10, respectively. Selected PM_2.5 exposure levels are population average, 5 μg/m³ and 10 μg/m³ higher PM_2.5 exposure levels than average, which are indexed by 0, 5 and 10, respectively. The estimated joint effects when methylation levels are at population average, 5% and 10% lower than average are represented by black, red and green lines, respectively. Note: Y-axis limit for asthma group is wider than that for non-asthma group. a Asthma Group b Non-Asthma Group

Fig. 4

Estimated joint effects of NOS2 H1 haplotype, iNOS methylation and 7-day average PM_2.5 exposure across the selected quantiles of FeNO distribution and its mean by race. In each panel, data are presented by number of H1 haplotype copy. The X-axis shows the combination of levels in methylation (first number in the bracket) and short-term PM_2.5 exposure (second number in the bracket). Selected methylation levels are population average, 5% and 10% lower than averages, which are indexed by 0,-5 and −10, respectively. Selected PM_2.5 exposure levels are population average, 5 μg/m³ and 10 μg/m³ higher PM_2.5 exposure levels than average, which are indexed by 0, 5 and 10, respectively. The estimated joint effects when methylation levels are at population average, 5% and 10% lower than average are represented by black, red and green lines, respectively. a Non-Hispanic White Group b Hispanic White Group