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1.  Living near a Freeway is Associated with Lower Bone Mineral Density among Mexican Americans 
Purpose
Adults residing in rural areas have been linked with higher bone mineral density (BMD). We aimed to determine if this difference is due in part to air pollution by examining the relationships between traffic metrics and ambient air pollution with total body and pelvic BMD.
Methods
Mexican-American adults (n=1,175; mean 34 years; 72% female) who had participated in the BetaGene study of air pollution, obesity and insulin resistance were included in this analysis. Total body and pelvic BMD were estimated using dual-energy X-ray absorptiometry. Traffic and ambient air pollutant exposures were estimated at residences using location and ambient monitoring data. Variance component models were used to analyze the associations between residential distance to the nearest freeway and ambient air pollutants with BMD.
Results
Residential proximity to a freeway was associated with lower total body BMD (p-trend=0.01) and pelvic BMD (p-trend=0.03) after adjustment for age, sex, weight and height. The adjusted mean total body and pelvic BMD in participants living within 500m of a freeway were 0.02 g/cm2 and 0.03 g/cm2 lower than participants living greater than 1,500m from a freeway. These associations did not differ significantly by age, sex or obesity status. Results were similar after further adjustment for body fat and weekly physical activity minutes. Ambient air pollutants (NO2, O3 and PM2.5) were not significantly associated with BMD.
Conclusions
Traffic-related exposures in overweight and obese Mexican-Americans may adversely affect BMD. Our findings indicate that long-term exposures to traffic may contribute to the occurrence of osteoporosis and its consequences.
doi:10.1007/s00198-015-3051-z
PMCID: PMC4470808  PMID: 25677718
osteopenia; osteoporosis; bone mineral density; BMD; traffic-related pollution; air pollution
2.  Chronic effects of air pollution on respiratory health in Southern California children: findings from the Southern California Children’s Health Study 
Journal of Thoracic Disease  2015;7(1):46-58.
Outdoor air pollution is one of the leading contributors to adverse respiratory health outcomes in urban areas around the world. Children are highly sensitive to the adverse effects of air pollution due to their rapidly growing lungs, incomplete immune and metabolic functions, patterns of ventilation and high levels of outdoor activity. The Children’s Health Study (CHS) is a continuing series of longitudinal studies that first began in 1993 and has focused on demonstrating the chronic impacts of air pollution on respiratory illnesses from early childhood through adolescence. A large body of evidence from the CHS has documented that exposures to both regional ambient air and traffic-related pollutants are associated with increased asthma prevalence, new-onset asthma, risk of bronchitis and wheezing, deficits of lung function growth, and airway inflammation. These associations may be modulated by key genes involved in oxidative-nitrosative stress pathways via gene-environment interactions. Despite successful efforts to reduce pollution over the past 40 years, air pollution at the current levels still brings many challenges to public health. To further ameliorate adverse health effects attributable to air pollution, many more toxic pollutants may require regulation and control of motor vehicle emissions and other combustion sources may need to be strengthened. Individual interventions based on personal susceptibility may be needed to protect children’s health while control measures are being implemented.
doi:10.3978/j.issn.2072-1439.2014.12.20
PMCID: PMC4311073  PMID: 25694817
Air pollution; traffic pollution; asthma; genetic susceptibility; respiratory disease
3.  Microsomal epoxide hydrolase, glutathione S‐transferase P1, traffic and childhood asthma 
Thorax  2007;62(12):1050-1057.
Background
Microsomal epoxide hydrolase (EPHX1) metabolises xenobiotics including polyaromatic hydrocarbons (PAHs). Functional variants at this locus have been associated with respiratory diseases. The effects of EPHX1 variants may depend upon exposures from tobacco smoke and traffic emissions that contain PAHs as well as variants in other enzymes in the PAH metabolic pathway such as glutathione S‐transferase (GST) genes. A study was undertaken to investigate associations of variants in EPHX1, GSTM1, GSTP1 and GSTT1 with asthma and the relationships between asthma, EPHX1 metabolic phenotypes and exposure to sources of PAHs.
Methods
Odds ratios (ORs) and 95% confidence intervals (CIs) were computed to estimate the associations of genetic variants and exposures with asthma phenotypes using data from 3124 children from the Children's Health Study.
Results
High EPHX1 activity was associated with an increased risk for lifetime asthma (OR 1.51, 95% CI 1.14 to 1.98) which varied by GSTP1 Ile105Val genotype and by residential proximity to major roads (p for interaction = 0.006 and 0.03, respectively). Among children with GSTP1 105Val/Val genotype, those who had high EPHX1 phenotype had a fourfold (95% CI 1.97 to 8.16) increased risk of lifetime asthma than children with low/intermediate EPHX1 phenotype. Among children living within 75 metres of a major road, those with high EPHX1 activity had a 3.2‐fold (95% CI 1.75 to 6.00) higher lifetime asthma risk than those with low/intermediate activity. The results were similar for current, early persistent and late onset asthma. Children with high EPHX1 phenotype, GSTP1 Val/Val genotype who lived <75 metres from a major road were at the highest asthma risk.
Conclusion
EPHX1 and GSTP1 variants contribute to the occurrence of childhood asthma and increase asthma susceptibility to exposures from major roads.
doi:10.1136/thx.2007.080127
PMCID: PMC2094290  PMID: 17711870
4.  Respiratory Symptoms Following Wildfire Smoke Exposure 
Epidemiology (Cambridge, Mass.)  2009;20(3):451-459.
Background
Associations between exposure to smoke during wild-fire events and respiratory symptoms are well documented, but the role of airway size remains unclear. We conducted this analysis to assess whether small airway size modifies these relationships.
Methods
We analyzed data from 465 nonasthmatic 16- to 19-year-old participants in the Children’s Health Study. Following an outbreak of wildfires in 2003, each student completed a questionnaire about smoke exposure, dry and wet cough, wheezing, and eye symptoms. We used log-binomial regression to evaluate associations between smoke exposure and fire-related health symptoms, and to assess modification of the associations by airway size. As a marker of airway size, we used the ratio of maximum midexpiratory flow to forced vital capacity.
Results
Forty percent (186 of 465) of this population (including students from 11 of 12 surveyed communities) reported the odor of wildfire smoke at home. We observed increased respiratory and eye symptoms with increasing frequency of wildfire smoke exposure. Associations between smoke exposure and having any of 4 respiratory symptoms were stronger in the lowest quartile of the lung function ratio (eg, fire smoke 6+ days: prevalence ratio: 3.8; 95% confidence interval (CI = 2.0 –7.2), compared with the remaining quartiles (fire smoke 6+ days: prevalence ratio = 2.0; 1.2–3.2). Analysis of individual symptoms suggests that this interaction may be strongest for effects on wheezing.
Conclusions
Small airways may serve as a marker of susceptibility to effects of wildfire smoke. Future studies should investigate the role of airway size for more common exposures and should include persons with asthma.
doi:10.1097/EDE.0b013e31819d128d
PMCID: PMC4517186  PMID: 19276978
5.  Determinants of Children's Exhaled Nitric Oxide: New Insights from Quantile Regression 
PLoS ONE  2015;10(7):e0130505.
While the fractional concentration of exhaled nitric oxide (FeNO) has proven useful in asthma research, its exact role in clinical care remains unclear, in part due to unexplained inter-subject heterogeneity. In this study, we assessed the hypothesis that the effects of determinants of the fractional concentration of exhaled nitric oxide (FeNO) vary with differing levels of FeNO. In a population-based cohort of 1542 school children aged 12–15 from the Southern California Children's Health Study, we used quantile regression to investigate if the relationships of asthma, socio-demographic and clinical covariates with FeNO vary across its distribution. Differences in FeNO between children with and without asthma increased steeply as FeNO increased (Estimated asthma effects (in ppb) at selected 20th, 50th and 80th percentiles of FeNO are 2.4, 6.3 and 22.2, respectively) but the difference was steeper with increasing FeNO in boys and in children with active rhinitis (p-values<0.01). Active rhinitis also showed significantly larger effects on FeNO at higher concentrations of FeNO (Estimated active rhinitis effects (in ppb) at selected 20th, 50th and 80th percentiles of FeNO are 2.1, 5.7 and 14.3, respectively). Boys and children of Asian descent had higher FeNO than girls and non-Hispanic whites; these differences were significantly larger in those with higher FeNO (p-values<0.01). In summary, application of quantile regression techniques provides new insights into the determinants of FeNO showing substantially varying effects in those with high versus low concentrations.
doi:10.1371/journal.pone.0130505
PMCID: PMC4516246  PMID: 26214692
6.  Ethnic-Specific Associations of Rare and Low Frequency DNA Sequence Variants with Asthma 
Nature communications  2015;6:5965.
Common variants at many loci have been robustly associated with asthma but explain little of the overall genetic risk. Here we investigate the role of rare (<1%) and low frequency (1–5%) variants using the Illumina HumanExome BeadChip array in 4,794 asthma cases, 4,707 non-asthmatic controls, and 590 case-parent trios representing European Americans, African Americans/African Caribbeans, and Latinos. Our study reveals one low frequency missense mutation in the GRASP gene that is associated with asthma in the Latino sample (P=4.31×10−6; OR=1.25; MAF=1.21%) and two genes harboring functional variants that are associated with asthma in a gene-based analysis: GSDMB at the 17q12-21 asthma locus in the Latino and combined samples (P=7.81×10−8 and 4.09×10−8, respectively) and MTHFR in the African ancestry sample (P=1.72×10−6). Our results suggest that associations with rare and low frequency variants are ethnic specific and not likely to explain a significant proportion of the “missing heritability” of asthma.
doi:10.1038/ncomms6965
PMCID: PMC4309441  PMID: 25591454
7.  Fractional exhaled nitric oxide in childhood is associated with 17q11.2-q12 and 17q12-q21 variants 
Background
The fractional concentration of nitric oxide in exhaled air (FeNO) is a biomarker of eosinophilic airway inflammation and associated with childhood asthma. Identification of common genetic variants associated with childhood FeNO may help to define biological mechanisms related to specific asthma phenotypes.
Objective
To identify genetic variants associated with childhood FeNO, and their relation with asthma.
Methods
FeNO was measured in children aged 5 to 15 years. In 14 genome-wide association (GWA) studies (N = 8,858), we examined the associations of ~2.5 million single nucleotide polymorphisms (SNPs) with FeNO. Subsequently, we assessed whether significant SNPs were expression quantitative trait loci (eQTLs) in genome-wide expression datasets of lymphoblastoid cell lines (N = 1,830), and were related with asthma in a previously published GWA dataset (cases: n=10,365; controls: n=16,110).
Results
We identified 3 SNPs associated with FeNO: rs3751972 in LYR motif containing 9 (LYRM9) (P = 1.97×10−10) and rs944722 in inducible nitric oxide synthase 2 (NOS2) (P = 1.28×10−9) both located at 17q11.2-q12, and rs8069176 near gasdermin B (GSDMB) (P = 1.88×10−8) at 17q12-q21. We found a cis eQTL for the transcript soluble galactoside-binding lectin 9 (LGALS9) that is in linkage disequilibrium with rs944722. Rs8069176 was associated with GSDMB and ORM1-like 3 (ORMDL3) expression. Rs8069176 at 17q12-q21, and not rs3751972 and rs944722 at 17q11.2-q12, were associated with physician-diagnosed asthma.
Conclusion
This study identified 3 variants associated with FeNO, explaining 0.95% of the variance. Identification of functional SNPs and haplotypes in these regions might provide novel insight in the regulation of FeNO. This study highlights that both shared and distinct genetic factors affect FeNO and childhood asthma.
doi:10.1016/j.jaci.2013.08.053
PMCID: PMC4334587  PMID: 24315451
airway inflammation; asthma phenotypes; biomarker; genetics; genome-wide association study
8.  Associations of Children’s Lung Function with Ambient Air Pollution: Joint Effects of Regional and Near-roadway Pollutants 
Thorax  2013;69(6):540-547.
Background
Prior studies have reported adverse effects of either regional or near-roadway air pollution (NRAP) on lung function. However, there has been little study of the joint effects of these exposures.
Objectives
To assess the joint effects of NRAP and regional pollutants on childhood lung function in the Children’s Health Study.
Methods
Lung function was measured on 1,811 children from eight Southern Californian communities. NRAP exposure was assessed based on (1) residential distance to the nearest freeway or major road and (2) estimated near-roadway contributions to residential nitrogen dioxide (NO2), nitric oxide (NO), and total nitrogen oxides (NOx). Exposure to regional ozone (O3), NO2, particulate matter with aerodynamic diameter less than 10 μm (PM10) and 2.5 μm (PM2.5) was measured continuously at community monitors.
Results
A 17.9 ppb (two standard deviation) increase in near-roadway NOx was associated with deficits of 1.6% in FVC (p=0.005) and 1.1% in FEV1 (p=0.048). Effects were observed in all communities and were similar for NO2 and NO. Residential proximity to a freeway was associated with a reduction in FVC. Lung function deficits of 2–3% were associated with regional PM10 and PM2.5 (FVC and FEV1) and with O3 (FEV1), but not NO2, across the range of exposure between communities. Associations with regional pollution and NRAP were independent in models adjusted for each. Effects of NRAP were not modified by regional pollutant concentrations.
Conclusions
Results indicate that NRAP and regional air pollution have independent adverse effects on childhood lung function.
doi:10.1136/thoraxjnl-2012-203159
PMCID: PMC4191894  PMID: 24253832
traffic; lung function; air pollution; children; land-use regression
9.  NOS1 Methylation and Carotid Artery Intima Media Thickness in Children 
Background
Nitric oxide (NO) plays an important role in cardiovascular health by maintaining and regulating vascular tone and blood flow. Epigenetic regulation of nitric oxide synthase (NOS), the genes responsible for NO production, may affect cardiovascular disease including development of atherosclerosis in children.
Methods and Results
We measured percentage DNA methylation using bisulfite conversion and Pyrosequencing assays on DNA from buccal cells provided by 377 participants of the Children’s Health Study on whom carotid artery intima-media thickness (CIMT) measurements were also collected. We examined a total of 16 CpG loci located within NOS1, NOS2A, NOS3, ARG1 and ARG, genes responsible for NO production. CIMT was measured using high-resolution B-mode carotid ultrasound. The association between percentage DNA methylation in ARG and NOS genes with CIMT was evaluated using linear regression adjusted for sex, Cethnicity, body mass index, age at CIMT, town of residence and experimental plate for pyrosequencing reactions. Differences in the association by ethnicity and ancestral group were also evaluated. For a 1% increase in average DNA methylation of NOS1, CIMT increased by 1.2 μm (p=0.02). This association was greater in Hispanic children of Native American descent (β = 2.3, p=0.004) than in Non-Hispanic Whites (β = 0.3, p=0.71) or Hispanic Whites (β = 1.0, p=0.35).
Conclusions
DNA methylation of NOS1 has a plausible role in atherogenesis through regulation of NO production, though ancestry may alter the magnitude of this association.
doi:10.1161/CIRCGENETICS.113.000320
PMCID: PMC4008829  PMID: 24622112
epigenetics; intima-media thickness; cardiovascular disease; nitric oxide synthase
10.  A Longitudinal Cohort Study of Body Mass Index and Childhood Exposure to Secondhand Tobacco Smoke and Air Pollution: The Southern California Children’s Health Study 
Environmental Health Perspectives  2014;123(4):360-366.
Background:
Childhood body mass index (BMI) and obesity prevalence have been associated with exposure to secondhand smoke (SHS), maternal smoking during pregnancy, and vehicular air pollution. There has been little previous study of joint BMI effects of air pollution and tobacco smoke exposure.
Methods:
Information on exposure to SHS and maternal smoking during pregnancy was collected on 3,318 participants at enrollment into the Southern California Children’s Health Study. At study entry at average age of 10 years, residential near-roadway pollution exposure (NRP) was estimated based on a line source dispersion model accounting for traffic volume, proximity, and meteorology. Lifetime exposure to tobacco smoke was assessed by parent questionnaire. Associations with subsequent BMI growth trajectory based on annual measurements and attained BMI at 18 years of age were assessed using a multilevel modeling strategy.
Results:
Maternal smoking during pregnancy was associated with estimated BMI growth over 8-year follow-up (0.72 kg/m2 higher; 95% CI: 0.14, 1.31) and attained BMI (1.14 kg/m2 higher; 95% CI: 0.66, 1.62). SHS exposure before enrollment was positively associated with BMI growth (0.81 kg/m2 higher; 95% CI: 0.36, 1.27) and attained BMI (1.23 kg/m2 higher; 95% CI: 0.86, 1.61). Growth and attained BMI increased with more smokers in the home. Compared with children without a history of SHS and NRP below the median, attained BMI was 0.80 kg/m2 higher (95% CI: 0.27, 1.32) with exposure to high NRP without SHS; 0.85 kg/m2 higher (95% CI: 0.43, 1.28) with low NRP and a history of SHS; and 2.15 kg/m2 higher (95% CI: 1.52, 2.77) with high NRP and a history of SHS (interaction p-value 0.007). These results suggest a synergistic effect.
Conclusions:
Our findings strengthen emerging evidence that exposure to tobacco smoke and NRP contribute to development of childhood obesity and suggest that combined exposures may have synergistic effects.
Citation:
McConnell R, Shen E, Gilliland FD, Jerrett M, Wolch J, Chang CC, Lurmann F, Berhane K. 2015. A longitudinal cohort study of body mass index and childhood exposure to secondhand tobacco smoke and air pollution: the Southern California Children’s Health Study. Environ Health Perspect 123:360–366; http://dx.doi.org/10.1289/ehp.1307031
doi:10.1289/ehp.1307031
PMCID: PMC4384197  PMID: 25389275
11.  The Effect of Ambient Air Pollution on Exhaled Nitric Oxide in the Children’s Health Study 
The European respiratory journal  2010;37(5):1029-1036.
We assessed the effect of daily variations in ambient air pollutants on exhaled nitric oxide (FeNO) using data from a cohort of schoolchildren with large differences in air pollutant exposures from the Children’s Health Study.
Based on a cohort of 2240 schoolchildren from 13 Southern California communities, cumulative lagged average regression models were fitted to determine the association between FeNO and ambient air pollution levels from central site monitors with lags of up to 30 days prior to FeNO testing.
Daily 24-hr cumulative lagged averages of PM2.5 (over 1–8 days) and PM10 (over 1–7 days), as well as 10AM–6PM cumulative lagged average of O3 (over 1–23 days) were significantly associated with 17.42% (p<0.01), 9.25% (P<0.05) and 14.25% (p<0.01) higher FeNO levels over the inter-quartile range of 7.5 μg/m3, 12.97 μg/m3, and 15.42 ppb, respectively. The effects of PM2.5, PM10 and O3 were higher in the warm season. The PM effects were robust to adjustments for effects of O3 and temperature and did not vary by asthma or allergy status.
In Summary, short-term increases in PM2.5, PM10, and O3 were associated with airway inflammation independent of asthma and allergy status, with PM10 effects significantly higher in the warm season.
doi:10.1183/09031936.00081410
PMCID: PMC4340653  PMID: 20947676
Air pollution; Airway inflammation; Children’s respiratory health; Environmental epidemiology; Exhaled nitric oxide
12.  Longitudinal Effects of Air Pollution on Exhaled Nitric Oxide: The Children’s Health Study 
OBJECTIVES
To assess the effects of long-term variations in ambient air pollutants on longitudinal changes in exhaled nitric oxide (FeNO), a potentially useful biomarker of eosinophilic airway inflammation, based on data from the southern California Children’s Health Study.
METHODS
Based on a cohort of 1,211 schoolchildren from 8 Southern California communities with FeNO measurements in 2006/07 and 2007/08, regression models adjusted for short-term effects of air pollution were fitted to assess the association between changes in annual long-term exposures and changes in FeNO.
RESULTS
Increases in annual average concentrations of 24-hr average NO2 and PM2.5 (scaled to the interquartile range (IQR) of 1.8 ppb and 2.4 μg/m3, respectively) were associated with a 2.29 ppb (CI=[0.36,4.21]; p =0.02) and a 4.94 ppb (CI=[1.44,8.47]; p = 0.005) increase in FeNO, respectively, after adjustments for short term effects of the respective pollutants. In contrast, changes in annual averages of PM10 and O3 were not significantly associated with changes in FeNO. These findings did not differ significantly by asthma status.
CONCLUSIONS
Changes in annual average exposure to current levels of ambient air pollutants are significantly associated with changes in FeNO levels in children, independent of short-term exposures and asthma status. Use of this biomarker in population-based epidemiologic research has great potential for assessing the impact of changing real world mixtures of ambient air pollutants on children’s respiratory health.
doi:10.1136/oemed-2013-101874
PMCID: PMC4310696  PMID: 24696513
Air pollution; chronic exposures; Children’s respiratory health; Environmental epidemiology; Exhaled nitric oxide; Airway inflammation
13.  Ethnic-specific associations of rare and low-frequency DNA sequence variants with asthma 
Nature Communications  2015;6:5965.
Common variants at many loci have been robustly associated with asthma but explain little of the overall genetic risk. Here we investigate the role of rare (<1%) and low-frequency (1–5%) variants using the Illumina HumanExome BeadChip array in 4,794 asthma cases, 4,707 non-asthmatic controls and 590 case–parent trios representing European Americans, African Americans/African Caribbeans and Latinos. Our study reveals one low-frequency missense mutation in the GRASP gene that is associated with asthma in the Latino sample (P=4.31 × 10−6; OR=1.25; MAF=1.21%) and two genes harbouring functional variants that are associated with asthma in a gene-based analysis: GSDMB at the 17q12–21 asthma locus in the Latino and combined samples (P=7.81 × 10−8 and 4.09 × 10−8, respectively) and MTHFR in the African ancestry sample (P=1.72 × 10−6). Our results suggest that associations with rare and low-frequency variants are ethnic specific and not likely to explain a significant proportion of the ‘missing heritability’ of asthma.
Common variants account for only a small amount of the heritable risk for developing asthma. Using a meta-analysis approach, Igartua et al. identify one low-frequency missense mutation and two genes with functional variants that are associated with asthma, but only in specific ethnic groups.
doi:10.1038/ncomms6965
PMCID: PMC4309441  PMID: 25591454
14.  HDL anti-oxidant function associates with LDL level in young adults 
Atherosclerosis  2013;232(1):165-170.
Objectives
The primary objective was to evaluate predictors of HDL anti-oxidant function in young adults.
Background
High-density lipoprotein (HDL) cholesterol is considered a protective factor for cardiovascular disease (CVD). However, increased levels are not always associated with decreased cardiovascular risk. A better understanding of the importance of HDL functionality and how it affects CVD risk is needed.
Methods
Fifty non-Hispanic white subjects from the Testing Responses on Youth (TROY) study were randomly selected to investigate whether differences in HDL anti-oxidant function are associated with traditional cardiovascular risk factors, including carotid intima media thickness (CIMT), arterial stiffness and other inflammatory/metabolic parameters. HDL anti-oxidant capacity was evaluated by assessing its ability to inhibit low-density lipoprotein (LDL) cholesterol oxidation by air using a DCF-based fluorescent assay and expressed as a HDL oxidant index (HOI). The associations between HOI and other variables were assessed using both linear and logistic regression.
Results
Eleven subjects (25%) had an HOI ≥ 1, indicating a pro-oxidant HDL. Age, LDL, high sensitivity C-reactive protein (hsCRP), and paraoxonase activity (PON1), but not HDL, were all associated with HOI level in univariate linear regression models. In multivariate models that mutually adjusted for these variables, LDL remained the strongest predictor of HOI (0.13 increase in HOI per 1 SD increase in LDL, 95% CI 0.04, 0.22).
Atherogenic index of plasma, pulse pressure, homocysteine, glucose, insulin, CIMT and measurements of arterial stiffness were not associated with HOI in this population.
Conclusions
These results suggest LDL, hsCRP and DBP might predict HDL anti-oxidant function at an early age.
doi:10.1016/j.atherosclerosis.2013.10.034
PMCID: PMC4039385  PMID: 24401232
high density lipoprotein; antioxidant; paraoxonase; atherosclerosis
15.  Genetic Variations in Nitric Oxide Synthase and Arginase Influence Exhaled Nitric Oxide Levels in Children 
Allergy  2010;66(3):412-419.
Background
Exhaled nitric oxide (FeNO) is a biomarker of airway inflammation. In the nitric oxide (NO) synthesis pathway, nitric oxide synthases (encoded by NOS1, NOS2A and NOS3) and arginases (encoded by ARG1 and ARG2) compete for L-arginine. Although FeNO levels are higher in children with asthma/allergy, influence of these conditions on the relationships between variations in these genes and FeNO remains unknown. The aims of the study were to evaluate the role of genetic variations in nitric oxide synthases and arginases on FeNO in children and to assess the influence of asthma and respiratory allergy on these genetic associations.
Methods
Among children (6–11 years) who participated in the southern California Children’s Health Study, variations in these five genetic loci were characterized by tagSNPs. FeNO was measured in two consecutive years (N = 2298 and 2515 in Years 1 and 2, respectively). Repeated measures analysis of variance was used to evaluate the associations between these genetic variants and FeNO.
Results
Sequence variations in the NOS2A and ARG2 loci were globally associated with FeNO (P = 0.0002 and 0.01, respectively). The ARG2 association was tagged by intronic variant rs3742879 with stronger association with FeNO in asthmatic children (P-interaction = 0.01). The association of a NOS2A promoter haplotype with FeNO varied significantly by rs3742879 genotypes and by asthma.
Conclusion
Variants in the NO synthesis pathway genes jointly contribute to differences in FeNO concentrations. Some of these genetic influences were stronger in children with asthma. Further studies are required to confirm our findings.
doi:10.1111/j.1398-9995.2010.02492.x
PMCID: PMC3058253  PMID: 21039601
airway inflammation; asthma; biomarker; exhaled nitric oxide; nitrosative stress
16.  Native American Ancestry Affects the Risk for Gene Methylation in the Lungs of Hispanic Smokers from New Mexico 
Rationale: Gene promoter methylation detected in sputum predicts lung cancer risk in smokers. Compared with non-Hispanic whites (NHW), Hispanics have a lower age-standardized incidence for lung cancer.
Objectives: This study compared the methylation prevalence in sputum of NHWs with Hispanics using the Lovelace Smokers cohort (n = 1998) and evaluated the effect of Native American ancestry (NAA) and diet on biomarkers for lung cancer risk.
Methods: Genetic ancestry was estimated using 48 ancestry markers. Diet was assessed by the Harvard University Dietary Assessment questionnaire. Methylation of 12 genes was measured in sputum using methylation-specific polymerase chain reaction. The association between NAA and risk for methylation was assessed using generalized estimating equations. The ethnic difference in the association between pack-years and risk for lung cancer was assessed in the New Mexico lung cancer study.
Measurements and Main Results: Overall Hispanics had a significantly increased risk for methylation across the 12 genes analyzed (odds ratio, 1.18; P = 0.007). However, the risk was reduced by 32% (P = 0.032) in Hispanics with high versus low NAA. In the New Mexico lung cancer study, Hispanic non–small cell lung cancer cases have significantly lower pack-years than NHW counterparts (P = 0.007). Furthermore, compared with NHW smokers, Hispanic smokers had a more rapidly increasing risk for lung cancer as a function of pack-years (P = 0.058).
Conclusions: NAA may be an important risk modifier for methylation in Hispanic smokers. Smoking intensity may have a greater impact on risk for lung cancer in Hispanics compared with NHWs.
doi:10.1164/rccm.201305-0925OC
PMCID: PMC3863742  PMID: 24032348
ethnicity; sputum; diet; risk; lung cancer
17.  Functional Variants in the Catalase and Myeloperoxidase Genes, Ambient Air Pollution, and Respiratory-related School Absences: An Example of Epistasis in Gene-Environment Interactions 
American Journal of Epidemiology  2009;170(12):1494-1501.
The individual effect of functional single nucleotide polymorphisms within the catalase and myeloperoxidase genes (CAT and MPO) has been studied in relation to asthma; however, their interrelationship with ambient air pollution exposures has yet to be determined. The authors investigated the interrelationships between variants in CAT and MPO, ambient air pollutants, and acute respiratory illness. Health information, air pollution, and incident respiratory-related school absences were ascertained in January–June 1996 for 1,136 Hispanic and non-Hispanic white US elementary schoolchildren as part of the prospective Children's Health Study. Functional and tagging single nucleotide polymorphisms for the CAT and MPO loci were genotyped. The authors found epistasis between functional polymorphisms in the CAT/MPO loci, which differed by levels of oxidant-stress-producing air pollutants. Risk of respiratory-related school absences was elevated for children with the CAT (G/G) and MPO (G/A or A/A) genes (relative risk = 1.35, 95% confidence interval: 1.03, 1.77; P-interaction = 0.005). The epistatic effect of CAT and MPO variants was most evident in communities exhibiting high ambient ozone levels (P-interaction = 0.03). The association of respiratory-illness absences with functional variants in CAT and MPO that differ by air pollution levels illustrates the need to consider genetic epistasis in assessing gene-environment interactions.
doi:10.1093/aje/kwp310
PMCID: PMC2800273  PMID: 19897513
air pollution; catalase; epistasis, genetic; peroxidase; respiratory tract infections
18.  MULTIPLE-FLOW EXHALED NITRIC OXIDE, ALLERGY, AND ASTHMA IN A POPULATION OF OLDER CHILDREN 
Pediatric pulmonology  2013;48(9):885-896.
SUMMARY
"Extended" (multiple-flow) measurements of exhaled nitric oxide (FeNO) potentially can distinguish proximal and distal airway inflammation, but have not been evaluated previously in large populations. We performed extended NO testing within a longitudinal study of a school-based population, to relate bronchial flux (J'awNO) and peripheral NO concentration (CalvNO) estimates with respiratory health status determined from questionnaires. We measured FeNO at 30, 50, 100, and 300 ml/sec in 1640 subjects aged 12–15 from 8 communities, then estimated J'awNO and CalvNO from linear and nonlinear regressions of NO output vs. flow. J'awNO, as well as FeNO at all flows, showed influences of asthma, allergy, Asian or African ancestry, age, and height (positive), and of weight (negative), generally corroborating past findings. By contrast, CalvNO results were inconsistent across different extended NO regression models, and appeared more sensitive to small measurement artifacts. Conclusions: Extended NO testing is feasible in field surveys of young populations. In interpreting results, size, age, and ethnicity require attention, as well as instrumental and environmental artifacts. J'awNO and conventional FeNO provide similar information, probably reflecting proximal-airway inflammation. CalvNO may give additional information relevant to peripheral-airway, alveolar, or systemic pathology. However, it needs additional research, including testing of populations with independently verifiable peripheral or systemic pathology, to optimize measurement technique and interpretation.
doi:10.1002/ppul.22708
PMCID: PMC3748140  PMID: 23687084
exhaled nitric oxide; airway inflammation; airways; asthma; allergy; epidemiology; public health; population survey
19.  Relationship between air pollution, lung function and asthma in adolescents 
Thorax  2007;62(11):957-963.
Background
The interrelationships between air pollution, lung function and the incidence of childhood asthma have yet to be established. A study was undertaken to determine whether lung function is associated with new onset asthma and whether this relationship varies by exposure to ambient air pollutants.
Methods
A cohort of children aged 9–10 years without asthma or wheeze at study entry were identified from the Children's Health Study and followed for 8 years. The participants resided in 12 communities with a wide range of ambient air pollutants that were measured continuously. Spirometric testing was performed and a medical diagnosis of asthma was ascertained annually. Proportional hazard regression models were fitted to investigate the relationship between lung function at study entry and the subsequent development of asthma and to determine whether air pollutants modify these associations.
Results
The level of airway flow was associated with new onset asthma. Over the 10th–90th percentile range of forced expiratory flow over the mid‐range of expiration (FEF25–75, 57.1%), the hazard ratio (HR) of new onset asthma was 0.50 (95% CI 0.35 to 0.71). This protective effect of better lung function was reduced in children exposed to higher levels of particulate matter with an aerodynamic diameter <2.5 μm (PM2.5). Over the 10th–90th percentile range of FEF25–75, the HR of new onset asthma was 0.34 (95% CI 0.21 to 0.56) in communities with low PM2.5 (<13.7 μg/m3) and 0.76 (95% CI 0.45 to 1.26) in communities with high PM2.5 (⩾13.7 μg/m3). A similar pattern was observed for forced expiratory volume in 1 s. Little variation in HR was observed for ozone.
Conclusion
Exposure to high levels of PM2.5 attenuates the protective effect of better lung function against new onset asthma.
doi:10.1136/thx.2007.078964
PMCID: PMC2117135  PMID: 17517830
20.  Roles of Arginase variants, Atopy and Ozone in Childhood Asthma 
Background
Arginases (encoded by ARG1 and ARG2 genes) may play an important role in asthma pathogenesis through effects on nitrosative stress. Arginase expression is upregulated in asthma and varies with T helper type-2 cytokine levels and oxidative stress.
Objective
We aimed to examine whether variants in these genes are associated with asthma, and whether atopy, and exposures to smoking and air pollution influence the associations.
Methods
Among non-Hispanic and Hispanic white participants of the Children’s Health Study (N=2,946), we characterized variation in each locus (including promoter region) with 6 tagSNPs for ARG1 and 10 for ARG2. Asthma was defined by parental report of physician-diagnosed asthma at study entry.
Results
Both ARG1 and ARG2 genetic loci were significantly associated with asthma (global locus level p-values=0.02 and 0.04, respectively). Compared to the most common haplotype within each locus, one ARG1 haplotype was associated with reduced risk (odds ratio (OR) per haplotype copy=0.55; 95% confidence interval (CI): 0.36–0.84) and one ARG2 haplotype was associated with increased risk (OR per haplotype copy=1.35; 95% CI: 1.04–1.76) of asthma. The effect of the ARG1 haplotype that was significantly associated with asthma varied by child’s history of atopy and ambient ozone (Pinteraction=0.04 and 0.02, respectively). Among atopic children living in high ozone communities, those carrying the ARG1 haplotype had reduced asthma risk (OR per haplotype copy=0.12; 95% CI: 0.04–0.43; Pheterogeneity across atopy/ozone categories=0.008).
Conclusions
ARG1 and ARG2 loci are associated with childhood asthma. The association between ARG1 variation and asthma may depend on atopy and ambient ozone.
doi:10.1016/j.jaci.2008.12.020
PMCID: PMC2913574  PMID: 19281908
air pollution; asthma genetics; atopy; gene-environment interaction; nitrosative stress
21.  Effects of In Utero and Childhood Tobacco Smoke Exposure and β2-Adrenergic Receptor Genotype on Childhood Asthma and Wheezing 
Pediatrics  2008;122(1):e107-e114.
Objective
Associations between single-nucleotide polymorphisms in the β2-adrenergic receptor gene and asthma and wheeze have been inconsistent. Recent studies indicated that tobacco smoke affects β2-adrenergic receptor gene expression and associations of β2-adrenergic receptor gene variants with asthma in adults. We aimed to investigate the joint effects of in utero and childhood secondhand tobacco smoke exposure and 2 well-characterized functional single-nucleotide polymorphisms (Arg16Gly and Glu27Gln) of β2-adrenergic receptor gene on asthma and wheezing in 3128 non-Hispanic and Hispanic white children of the Children's Health Study.
Methods
We fitted logistic regression models to estimate odds ratios and 95% confidence intervals for the independent and joint effects of these single-nucleotide polymorphisms and in utero and secondhand tobacco smoke exposure on asthma and wheeze outcomes.
Results
Exposures to in utero maternal smoking and secondhand tobacco smoke were associated with wheezing. Children who were homozygous for the Arg16 allele and were exposed to maternal smoking in utero were at a threefold increased risk for lifetime wheeze compared with children who were unexposed and had at least 1 Gly16 allele. We found similar joint effects of secondhand tobacco smoke and Arg16Gly with wheezing. The risk for lifetime, current, and nocturnal wheeze increased with the number of smokers at home among Arg16 homozygous children. The results were consistent in 2 cohorts of children recruited in 1993 and 1996. Diplotype-based analyses were consistent with the single-nucleotide polymorphism–specific results. No associations were found for Glu27Gln.
Conclusions
Both in utero and childhood exposure to tobacco smoke were associated with an increased risk for wheeze in children, and the risks were greater for children with the Arg16Arg genotype or 2 copies of the Arg16–Gln27 diplotype. Exposures to smoking need to be taken into account when evaluating the effects of β2-adrenergic receptor gene variants on respiratory health outcomes.
doi:10.1542/peds.2007-3370
PMCID: PMC2748980  PMID: 18558635
β-2 adrenergic receptor; prenatal exposure; secondhand-smoke exposure; asthma; wheeze
22.  Development of a regional-scale pollen emission and transport modeling framework for investigating the impact of climate change on allergic airway disease 
Biogeosciences (Online)  2013;10(3):3977-4023.
Exposure to bioaerosol allergens such as pollen can cause exacerbations of allergenic airway disease (AAD) in sensitive populations, and thus cause serious public health problems. Assessing these health impacts by linking the airborne pollen levels, concentrations of respirable allergenic material, and human allergenic response under current and future climate conditions is a key step toward developing preventive and adaptive actions. To that end, a regional-scale pollen emission and transport modeling framework was developed that treats allergenic pollens as non-reactive tracers within the WRF/CMAQ air-quality modeling system. The Simulator of the Timing and Magnitude of Pollen Season (STaMPS) model was used to generate a daily pollen pool that can then be emitted into the atmosphere by wind. The STaMPS is driven by species-specific meteorological (temperature and/or precipitation) threshold conditions and is designed to be flexible with respect to its representation of vegetation species and plant functional types (PFTs). The hourly pollen emission flux was parameterized by considering the pollen pool, friction velocity, and wind threshold values. The dry deposition velocity of each species of pollen was estimated based on pollen grain size and density. An evaluation of the pollen modeling framework was conducted for southern California for the period from March to June 2010. This period coincided with observations by the University of Southern California's Children's Health Study (CHS), which included O3, PM2.5, and pollen count, as well as measurements of exhaled nitric oxide in study participants. Two nesting domains with horizontal resolutions of 12 km and 4 km were constructed, and six representative allergenic pollen genera were included: birch tree, walnut tree, mulberry tree, olive tree, oak tree, and brome grasses. Under the current parameterization scheme, the modeling framework tends to underestimate walnut and peak oak pollen concentrations, and tends to overestimate grass pollen concentrations. The model shows reasonable agreement with observed birch, olive, and mulberry tree pollen concentrations. Sensitivity studies suggest that the estimation of the pollen pool is a major source of uncertainty for simulated pollen concentrations. Achieving agreement between emission modeling and observed pattern of pollen releases is the key for successful pollen concentration simulations.
doi:10.5194/bgd-10-3977-2013
PMCID: PMC4021721  PMID: 24839448
23.  Exhaled Nitric Oxide, Susceptibility and New-Onset Asthma in the Children’s Health Study 
The European respiratory journal  2010;37(3):523-531.
A substantial body of evidence suggests an etiologic role of inflammation and oxidative/nitrosative stress in asthma pathogenesis. Fractional concentration of nitric oxide in exhaled air (FeNO) may provide a non-invasive marker of oxidative/nitrosative stress and aspects of airway inflammation. We examined whether children with elevated FeNO are at increased risk for new-onset asthma.
We prospectively followed 2206 asthma-free children (age 7–10 years) who participated in the Children’s Health Study. We measured FeNO and followed these children for three years to ascertain incident asthma cases. Cox proportional hazard models were fitted to examine the association between FeNO and new-onset asthma.
We found that FeNO was associated with increased risk of new-onset asthma. Children with the highest quartile of FeNO had more than a two-fold increased risk of new-onset asthma compared to those with the lowest quartile (hazard ratio: 2.1; 95% confidence interval: 1.3–3.5). This effect did not vary by child’s history of respiratory allergic symptoms. However, the effect of elevated FeNO on new-onset asthma was most apparent among those without a parental history of asthma.
Our results indicate that children with elevated FeNO are at increased risk for new-onset asthma, especially if they have no parental history of asthma.
doi:10.1183/09031936.00021210
PMCID: PMC4020940  PMID: 20634264
Incident Asthma; Exhaled Nitric Oxide; Airway Inflammation
24.  Genetic variation in SIRT1 affects susceptibility of lung squamous cell carcinomas in former uranium miners from the Colorado plateau 
Carcinogenesis  2013;34(5):1044-1050.
Epidemiological studies of underground miners suggested that occupational exposure to radon causes lung cancer with squamous cell carcinoma (SCC) as the predominant histological type. However, the genetic determinants for susceptibility of radon-induced SCC in miners are unclear. Double-strand breaks induced by radioactive radon daughters are repaired primarily by non-homologous end joining (NHEJ) that is accompanied by the dynamic changes in surrounding chromatin, including nucleosome repositioning and histone modifications. Thus, a molecular epidemiological study was conducted to assess whether genetic variation in 16 genes involved in NHEJ and related histone modification affected susceptibility for SCC in radon-exposed former miners (267 SCC cases and 383 controls) from the Colorado plateau. A global association between genetic variation in the haplotype block where SIRT1 resides and the risk for SCC in miners (P = 0.003) was identified. Haplotype alleles tagged by the A allele of SIRT1 rs7097008 were associated with increased risk for SCC (odds ratio = 1.69, P = 8.2×10−5) and greater survival in SCC cases (hazard ratio = 0.79, P = 0.03) in miners. Functional validation of rs7097008 demonstrated that the A allele was associated with reduced gene expression in bronchial epithelial cells and compromised DNA repair capacity in peripheral lymphocytes. Together, these findings substantiate genetic variation in SIRT1 as a risk modifier for developing SCC in miners and suggest that SIRT1 may also play a tumor suppressor role in radon-induced cancer in miners.
doi:10.1093/carcin/bgt024
PMCID: PMC3643420  PMID: 23354305
25.  Transforming Growth Factor-β1 C-509T Polymorphism, Oxidant Stress, and Early-Onset Childhood Asthma 
Rationale: Transforming growth factor (TGF)-β1 is involved in airway inflammation and remodeling, two key processes in asthma pathogenesis. Tobacco smoke and traffic emissions induce airway inflammation and modulate TGF-β1 gene expression. We hypothesized that the effects of functional TGF-β1 variants on asthma occurrence vary by these exposures.
Objectives: We tested these hypotheses among 3,023 children who participated in the Children's Health Study.
Methods: Tagging single-nucleotide polymorphisms rs4803457 C>T and C-509T (a functional promoter polymorphism) accounted for 94% of the haplotype diversity of the upstream region. Exposure to maternal smoking in utero was based on smoking by biological mother during pregnancy. Residential distance from nearest freeway was calculated based on residential address at study entry.
Measurements and Main Results: Children with the −509TT genotype had a 1.8-fold increased risk of early persistent asthma (95% confidence interval [CI], 1.11–2.95). This association varied marginally significantly by in utero exposure to maternal smoking. Compared with children with the −509CC/CT genotype with no in utero exposure to maternal smoking, those with the −509TT genotype with such exposure had a 3.4-fold increased risk of early persistent asthma (95% CI, 1.46–7.80; interaction, P = 0.11). The association between TGF-β1 C-509T and lifetime asthma varied by residential proximity to freeways (interaction P = 0.02). Children with the −509TT genotype living within 500 m of a freeway had over three-fold increased lifetime asthma risk (95% CI, 1.29–7.44) compared with children with CC/CT genotype living > 1500 m from a freeway.
Conclusions: Children with the TGF-β1 −509TT genotype are at increased risk of asthma when they are exposed to maternal smoking in utero or to traffic-related emissions.
doi:10.1164/rccm.200704-561OC
PMCID: PMC2176104  PMID: 17673695
maternal smoking; traffic; asthma; genetics; gene–environment interaction; association study

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