Inducible Nitric Oxide Synthase Promoter Haplotypes and Residential Traffic-Related Air Pollution Jointly Influence Exhaled Nitric Oxide Level in Children

Abstract

Background: Exhaled nitric oxide (FeNO), a biomarker of airway inflammation, predicts asthma risk in children. We previously found that the promoter haplotypes in inducible nitric oxide synthase (NOS2) and exposure to residential traffic independently influence FeNO level. Because NOS2 is inducible by environmental exposures such as traffic-related exposure, we tested the hypothesis that common NOS2 promoter haplotypes modulate the relationship between residential traffic-related exposure and FeNO level in children.

Methods: In a cross-sectional population-based study, subjects (N = 2,457; 7-11 year-old) were Hispanic and non-Hispanic white children who participated in the Southern California Children's Health Study and had FeNO measurements. For residential traffic, lengths of local roads within circular buffers (50m, 100m and 200m radii around homes) around the subjects' homes were estimated using geographic information system (GIS) methods. We interrogated the two most common NOS2 promoter haplotypes that were found to affect FeNO level.

Results: The relationship between local road lengths within 100m and 200m circular buffers and FeNO level varied significantly by one of the NOS2 promoter haplotypes (P-values for interaction between road length and NOS2 promoter haplotype = 0.02 and 0.03, respectively). In children who had ≤250m of local road lengths within 100m buffer around their homes, those with two copies of the haplotype had significantly lower FeNO (adjusted geometric mean = 11.74ppb; 95% confidence intervals (CI): 9.99 to 13.80) than those with no copies (adjusted geometric mean = 15.28ppb; 95% CI: 14.04 to 16.63) with statistically significant trend of lower FeNO level with increasing number of haplotype copy (P-value for trend = 0.002). In contrast, among children who had >250m of local road lengths within 100m buffer, FeNO level did not significantly differ by the haplotype copy-number (P-value for trend = 0.34). Similar interactive effects of this haplotype and local road lengths within 200m buffer on FeNO were also observed.

Conclusions: Higher exposure from residential traffic nullifies the protective effect of one common NOS2 promoter haplotype on FeNO level. Regulation of traffic-related pollution may protect children's respiratory health.

Fig 1. Influence of NOS2 H1 haplotype copies on the association between length of local roads around home and FeNO.

The x-axis shows H1 haplotype copies (0, 1, and 2) within categories of local road-lengths within (A) 100m and (B) 200m circular buffers of home. The circles represent adjusted geometric mean FeNO and the vertical bars represent 95% confidence intervals. The 95%CIs for the adjusted geometric means that cross the dashed horizontal line in each figure are not statistically significantly different from the adjusted geometric mean FeNO in children who had 2 copies of the H1 haplotype and had less than 250m and 1000m total local road lengths within 100m and 200m buffers, respectively.