Particulate Matter, DNA Methylation in Nitric Oxide Synthase, and Childhood Respiratory Disease

Background: Air pollutants have been associated with childhood asthma and wheeze. Epigenetic regulation of nitric oxide synthase—the gene responsible for nitric oxide production—may be affected by air pollutants and contribute to the pathogenesis of asthma and wheeze. Objective: Our goal was to investigate the association between air pollutants, DNA methylation, and respiratory outcomes in children. Methods: Given residential address and buccal sample collection date, we estimated 7-day, 1-month, 6-month, and 1-year cumulative average $PM_{2.5}$ and $PM_{10}$ (particulate matter ≤ 2.5 and ≤ 10 µm aerodynamic diameter, respectively) exposures for 940 participants in the Children’s Health Study. Methylation of 12 CpG sites in three NOS (nitric oxide synthase) genes was measured using a bisulfite-polymerase chain reaction Pyrosequencing assay. Beta regression models were used to estimate associations between air pollutants, percent DNA methylation, and respiratory outcomes. Results: A 5-µg/$m^3$ increase in $PM_{2.5}$ was associated with a 0.20% [95% confidence interval (CI): –0.32, –0.07] to 1.0% (95% CI: –1.61, –0.56) lower DNA methylation at NOS2A position 1, 0.06% (95% CI: –0.18, 0.06) to 0.58% (95% CI: –1.13, –0.02) lower methylation at position 2, and 0.34% (95% CI: –0.57, –0.11) to 0.89% (95% CI: –1.57, –0.21) lower methylation at position 3, depending on the length of exposure and CpG locus. One-year $PM_{2.5}$ exposure was associated with 0.33% (95% CI: 0.01, 0.65) higher in average DNA methylation of 4 loci in the NOS2A CpG island. A 5-µg/$m^3$ increase in 7-day and 1-year $PM_{2.5}$ was associated with 0.6% (95% CI: 0.13, 0.99) and 2.8% (95% CI: 1.77, 3.75) higher NOS3 DNA methylation. No associations were observed for NOS1. $PM_{10}$ showed similar but weaker associations with DNA methylation in these genes. Conclusions: $PM_{2.5}$ exposure was associated with percent DNA methylation of several CpG loci in NOS genes, suggesting an epigenetic mechanism through which these pollutants may alter production of nitric oxide

Childhood Incident Asthma and Traffic-Related Air Pollution at Home and School

Background: Traffic-related air pollution has been associated with adverse cardiorespiratory effects, including increased asthma prevalence. However, there has been little study of effects of traffic exposure at school on new-onset asthma. Objectives: We evaluated the relationship of new-onset asthma with traffic-related pollution near homes and schools. Methods: Parent-reported physician diagnosis of new-onset asthma (n = 120) was identified during 3 years of follow-up of a cohort of 2,497 kindergarten and first-grade children who were asthma- and wheezing-free at study entry into the Southern California Children's Health Study. We assessed traffic-related pollution exposure based on a line source dispersion model of traffic volume, distance from home and school, and local meteorology. Regional ambient ozone, nitrogen dioxide (NO2), and particulate matter were measured continuously at one central site monitor in each of 13 study communities. Hazard ratios (HRs) for new-onset asthma were scaled to the range of ambient central site pollutants and to the residential interquartile range for each traffic exposure metric. Results: Asthma risk increased with modeled traffic-related pollution exposure from roadways near homes [HR 1.51; 95% confidence interval (CI), 1.25-1.82] and near schools (HR 1.45; 95% CI, 1.06-1.98). Ambient NO2 measured at a central site in each community was also associated with increased risk (HR 2.18; 95% CI, 1.18-4.01). In models with both NO2 and modeled traffic exposures, there were independent associations of asthma with traffic-related pollution at school and home, whereas the estimate for NO2 was attenuated (HR 1.37; 95% CI, 0.69-2.71). Conclusions: Traffic-related pollution exposure at school and homes may both contribute to the development of asthma. Editor's SummaryTraffic-related air pollution has been associated with adverse cardiorespiratory effects, including increased asthma prevalence. McConnell et al. (p. 1021) evaluated the relationship of new-onset asthma with traffic-related pollution near homes and schools. Parent-reported physician diagnosis of new-onset asthma was identified during 3 years of follow-up of a cohort of kindergarten and first-grade children who were asthma- and wheezing-free at study entry into the Southern California Children's Health Study. Traffic-related pollution exposure was assessed based on a line source dispersion model of traffic volume, distance from home and school, and local meteorology. Regional ambient ozone, nitrogen dioxide (NO2), and particulate matter were measured continuously at one central site monitor in each of 13 study communities. The authors report an increase in asthma risk with modeled traffic-related pollution exposure from roadways near homes and schools. Ambient NO2 was also associated with increased risk. Models that included both NO2 and modeled traffic exposures suggested independent associations of asthma with traffic-related pollution at school and at home, whereas the estimate for NO2 was attenuated. The authors conclude that traffic-related pollution exposure at school and home may both contribute to the development of asthma

Dog Ownership Enhances Symptomatic Responses to Air Pollution in Children with Asthma

BACKGROUND: Experimental data suggest that asthma exacerbation by ambient air pollutants is enhanced by exposure to endotoxin and allergens; however, there is little supporting epidemiologic evidence. METHODS: We evaluated whether the association of exposure to air pollution with annual prevalence of chronic cough, phlegm production, or bronchitis was modified by dog and cat ownership (indicators of allergen and endotoxin exposure). The study population consisted of 475 Southern California children with asthma from a longitudinal cohort of participants in the Children’s Health Study. We estimated average annual ambient exposure to nitrogen dioxide, ozone, particulate matter < 10, 2.5, and 10–2.5 μm in aerodynamic diameter (PM(10), PM(2.5), and PM(10–2.5), respectively), elemental and organic carbon, and acid vapor from monitoring stations in each of the 12 study communities. Multivariate models were used to examine the effect of yearly variation of each pollutant. Effects were scaled to the variability that is common for each pollutant in representative communities in Southern California. RESULTS: Among children owning a dog, there were strong associations between bronchitic symptoms and all pollutants examined. Odds ratios ranged from 1.30 per 4.2 μg/m(3) for PM(10–2.5) [95% confidence interval (CI), 0.91–1.87) to 1.91 per 1.2 μg/m(3) for organic carbon (95% CI, 1.34–2.71). Effects were somewhat larger among children who owned both a cat and dog. There were no effects or small effects with wide CIs among children without a dog and among children who owned only a cat. CONCLUSION: Our results suggest that dog ownership, a source of residential exposure to endotoxin, may worsen the relationship between air pollution and respiratory symptoms in asthmatic children

Prenatal Tobacco Smoke Exposure Is Associated with Childhood DNA CpG Methylation

Background: Smoking while pregnant is associated with a myriad of negative health outcomes in the child. Some of the detrimental effects may be due to epigenetic modifications, although few studies have investigated this hypothesis in detail.Objectives: To characterize site-specific epigenetic modifications conferred by prenatal smoking exposure within asthmatic children.Methods: Using Illumina HumanMethylation27 microarrays, we estimated the degree of methylation at 27,578 distinct DNA sequences located primarily in gene promoters using whole blood DNA samples from the Childhood Asthma Management Program (CAMP) subset of Asthma BRIDGE childhood asthmatics (n = 527) ages 5–12 with prenatal smoking exposure data available. Using beta-regression, we screened loci for differential methylation related to prenatal smoke exposure, adjusting for gender, age and clinical site, and accounting for multiple comparisons by FDR.Results: Of 27,578 loci evaluated, 22,131 (80%) passed quality control assessment and were analyzed. Sixty-five children (12%) had a history of prenatal smoke exposure. At an FDR of 0.05, we identified 19 CpG loci significantly associated with prenatal smoke, of which two replicated in two independent populations. Exposure was associated with a 2% increase in mean CpG methylation in FRMD4A (p = 0.01) and Cllorf52 (p = 0.001) compared to no exposure. Four additional genes, XPNPEP1, PPEF2, SMPD3 and CRYGN, were nominally associated in at least one replication group.Conclusions: These data suggest that prenatal exposure to tobacco smoke is associated with reproducible epigenetic changes that persist well into childhood. However, the biological significance of these altered loci remains unknown.</p

Prenatal Tobacco Smoke Exposure Is Associated with Childhood DNA CpG Methylation

Background: Smoking while pregnant is associated with a myriad of negative health outcomes in the child. Some of the detrimental effects may be due to epigenetic modifications, although few studies have investigated this hypothesis in detail. Objectives: To characterize site-specific epigenetic modifications conferred by prenatal smoking exposure within asthmatic children. Methods: Using Illumina HumanMethylation27 microarrays, we estimated the degree of methylation at 27,578 distinct DNA sequences located primarily in gene promoters using whole blood DNA samples from the Childhood Asthma Management Program (CAMP) subset of Asthma BRIDGE childhood asthmatics (n = 527) ages 5–12 with prenatal smoking exposure data available. Using beta-regression, we screened loci for differential methylation related to prenatal smoke exposure, adjusting for gender, age and clinical site, and accounting for multiple comparisons by FDR. Results: Of 27,578 loci evaluated, 22,131 (80%) passed quality control assessment and were analyzed. Sixty-five children (12%) had a history of prenatal smoke exposure. At an FDR of 0.05, we identified 19 CpG loci significantly associated with prenatal smoke, of which two replicated in two independent populations. Exposure was associated with a 2% increase in mean CpG methylation in FRMD4A (p = 0.01) and Cllorf52 (p = 0.001) compared to no exposure. Four additional genes, XPNPEP1, PPEF2, SMPD3 and CRYGN, were nominally associated in at least one replication group. Conclusions: These data suggest that prenatal exposure to tobacco smoke is associated with reproducible epigenetic changes that persist well into childhood. However, the biological significance of these altered loci remains unknown

Meta-analysis of genome-wide association studies of asthma in ethnically diverse North American populations.

Asthma is a common disease with a complex risk architecture including both genetic and environmental factors. We performed a meta-analysis of North American genome-wide association studies of asthma in 5,416 individuals with asthma (cases) including individuals of European American, African American or African Caribbean, and Latino ancestry, with replication in an additional 12,649 individuals from the same ethnic groups. We identified five susceptibility loci. Four were at previously reported loci on 17q21, near IL1RL1, TSLP and IL33, but we report for the first time, to our knowledge, that these loci are associated with asthma risk in three ethnic groups. In addition, we identified a new asthma susceptibility locus at PYHIN1, with the association being specific to individuals of African descent (P = 3.9 × 10(-9)). These results suggest that some asthma susceptibility loci are robust to differences in ancestry when sufficiently large samples sizes are investigated, and that ancestry-specific associations also contribute to the complex genetic architecture of asthma

Genome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis

Allergic rhinitis is the most common clinical presentation of allergy, affecting 400 million people worldwide, with increasing incidence in westernized countries1,2. To elucidate the genetic architecture and understand the underlying disease mechanisms, we carried out a meta-analysis of allergic rhinitis in 59,762 cases and 152,358 controls of European ancestry and identified a total of 41 risk loci for allergic rhinitis, including 20 loci not previously associated with allergic rhinitis, which were confirmed in a replication phase of 60,720 cases and 618,527 controls. Functional annotation implicated genes involved in various immune pathways, and fine mapping of the HLA region suggested amino acid variants important for antigen binding. We further performed genome-wide association study (GWAS) analyses of allergic sensitization against inhalant allergens and nonallergic rhinitis, which suggested shared genetic mechanisms across rhinitis-related traits. Future studies of the identified loci and genes might identify novel targets for treatment and prevention of allergic rhinitis

Exposure to Perfluoroalkyl Substances and Glucose Homeostasis in Youth

Background: Exposure to per- and polyfluoroalkyl substances (PFAS), a prevalent class of persistent pollutants, may increase the risk of type 2 diabetes. &nbsp; Objective: We examined associations between PFAS exposure and glucose metabolism in youth. &nbsp; Methods: Overweight/obese adolescents from the Study of Latino Adolescents at Risk of Type 2 Diabetes (SOLAR; n=310) participated in annual visits for an average of 3.3&plusmn;2.9y. Generalizability of findings were tested in young adults from the Southern California Children&rsquo;s Health Study (CHS; n=135) who participated in a clinical visit with a similar protocol. At each visit, oral glucose tolerance tests were performed to estimate glucose metabolism and &beta;-cell function via the insulinogenic index. Four PFAS were measured at baseline using liquid chromatography&ndash;high-resolution mass spectrometry; high levels were defined as concentrations &gt;66th percentile. &nbsp; Results: In females from the SOLAR, high perfluorohexane sulfonate (PFHxS) levels (&ge;2.0&thinsp;ng/mL) were associated with the development of dysregulated glucose metabolism beginning in late puberty. The magnitude of these associations increased postpuberty and persisted through 18 years of age. For example, postpuberty, females with high PFHxS levels had 25-mg/dL higher 60-min glucose (95% CI: 12,&thinsp;39mg/dL; p&lt;0.0001), 15-mg/dL higher 2-h glucose (95% CI: 1,&thinsp;28mg/dL; p=0.04), and 25% lower &beta;-cell function (p=0.02) compared with females with low levels. Results were largely consistent in the CHS, where females with elevated PFHxS levels had 26-mg/dL higher 60-min glucose (95% CI: 6.0,&thinsp;46mg/dL; p=0.01) and 19-mg/dL higher 2-h glucose, which did not meet statistical significance (95% CI: &ndash;1,&thinsp;39mg/dL; p=0.08). In males, no consistent associations between PFHxS and glucose metabolism were observed. No consistent associations were observed for other PFAS and glucose metabolism. &nbsp; Discussion: Youth exposure to PFHxS was associated with dysregulated glucose metabolism in females, which may be due to changes in &beta;-cell function. These associations appeared during puberty and were most pronounced postpuberty. <a href="https://doi.org/10.1289/EHP9200" target="_blank" rel="noopener" data-ga-action="click_feat_