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1.  Prenatal Air Pollution Exposures, DNA Methyl Transferase Genotypes, and Associations with Newborn LINE1 and Alu Methylation and Childhood Blood Pressure and Carotid Intima-Media Thickness in the Children’s Health Study 
Environmental Health Perspectives  2016;124(12):1905-1912.
Background:
Although exposure to ambient air pollutants increases cardiovascular disease risk in adults little is known about the effects of prenatal exposure. Genetic variation and epigenetic alterations are two mechanisms that may influence the effects of early-life exposures on cardiovascular phenotypes.
Objectives:
We investigated whether genetic and epigenetic variation modify associations between prenatal air pollution on markers of cardiovascular risk in childhood.
Methods:
We used linear regression analysis to investigate the associations between prenatal pollutants (PM2.5, PM10, NO2, O3), long interspersed nuclear elements (LINE1) and AluYb8 DNA methylation levels measured in newborn blood spot tests, and carotid intima-media thickness (CIMT) and blood pressure (BP) in 459 participants as part of the Children’s Health Study. Interaction terms were also included to test for effect modification of these associations by genetic variation in methylation reprogramming genes.
Results:
Prenatal exposure to NO2 in the third trimester of pregnancy was associated with higher systolic BP in 11-year-old children. Prenatal exposure to multiple air pollutants in the first trimester was associated with lower DNA methylation in LINE1, whereas later exposure to O3 was associated with higher LINE1 methylation levels in newborn blood spots. The magnitude of associations with prenatal air pollution varied according to genotype for 11 SNPs within DNA methyltransferase 1 (DNMT1), DNA methyltransferase 3 Beta (DNMT3B), Tet methylcytosine dioxygenase 2 (TET2), and Thymine DNA glycosylase (TDG) genes. Although first-trimester O3 exposure was not associated with CIMT and systolic BP overall, associations within strata of DNMT1 or DNMT3B were observed, and the magnitude and the direction of these associations depended on DNMT1 genotypes.
Conclusions:
Genetic and epigenetic variation in DNA methylation reprogramming genes and in LINE1 retrotransposons may play important roles in downstream cardiovascular consequences of prenatal air pollution exposure.
Citation:
Breton CV, Yao J, Millstein J, Gao L, Siegmund KD, Mack W, Whitfield-Maxwell L, Lurmann F, Hodis H, Avol E, Gilliland FD. 2016. Prenatal air pollution exposures, DNA methyl transferase genotypes, and associations with newborn LINE1 and Alu methylation and childhood blood pressure and carotid intima-media thickness in the Children’s Health Study. Environ Health Perspect 124:1905–1912; http://dx.doi.org/10.1289/EHP181
doi:10.1289/EHP181
PMCID: PMC5132634  PMID: 27219456
2.  Influence of Pre- and Postdiagnosis Physical Activity on Mortality in Breast Cancer Survivors: The Health, Eating, Activity, and Lifestyle Study 
Journal of Clinical Oncology  2008;26(24):3958-3964.
Purpose
To investigate the association between pre- and postdiagnosis physical activity (as well as change in prediagnosis to postdiagnosis physical activity) and mortality among women with breast cancer.
Patients and Methods
This was a prospective observational study of 933 women enrolled onto the Health, Eating, Activity, and Lifestyle Study who were diagnosed with local or regional breast cancer between 1995 and 1998 and observed until death or September 2004, whichever came first. The primary outcomes measured were total deaths and breast cancer deaths. The primary exposures were physical activity in the year before and 2 years after diagnosis and the pre- to postdiagnosis change in physical activity.
Results
Compared with inactive women, the multivariable hazard ratios (HRs) for total deaths for women expending at least 9 metabolic equivalent hours per week (approximately 2 to 3 h/wk of brisk walking) were 0.69 (95% CI, 0.45 to 1.06; P = .045) for those active in the year before diagnosis and 0.33 (95% CI, 0.15 to 0.73; P = .046) for those active 2 years after diagnosis. Compared with women who were inactive both before and after diagnosis, women who increased physical activity after diagnosis had a 45% lower risk of death (HR = 0.55; 95% CI, 0.22 to 1.38), and women who decreased physical activity after diagnosis had a four-fold greater risk of death (HR = 3.95; 95% CI, 1.45 to 10.50).
Conclusion
Moderate-intensity physical activity after a diagnosis of breast cancer may improve prognosis.
doi:10.1200/JCO.2007.15.9822
PMCID: PMC2654316  PMID: 18711185
3.  Exhaled NO: Determinants and Clinical Application in Children With Allergic Airway Disease 
Nitric oxide (NO) is endogenously released in the airways, and the fractional concentration of NO in exhaled breath (FeNO) is now recognized as a surrogate marker of eosinophilic airway inflammation that can be measured using a noninvasive technique suitable for young children. Although FeNO levels are affected by several factors, the most important clinical determinants of increased FeNO levels are atopy, asthma, and allergic rhinitis. In addition, air pollution is an environmental determinant of FeNO that may contribute to the high prevalence of allergic disease. In this review, we discuss the mechanism for airway NO production, methods for measuring FeNO, and determinants of FeNO in children, including host and environmental factors such as air pollution. We also discuss the clinical utility of FeNO in children with asthma and allergic rhinitis and further useful directions using FeNO measurement.
doi:10.4168/aair.2016.8.1.12
PMCID: PMC4695403  PMID: 26540497
Nitric oxide; children; asthma; allergic rhinitis; air pollution
4.  Implication of a chromosome 15q15.2 locus in regulating UBR1 and predisposing smokers to MGMT methylation in lung 
Cancer research  2015;75(15):3108-3117.
O6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme that protects cells from carcinogenic effects of alkylating agents; however, MGMT is silenced by promoter hypermethylation during carcinogenesis. A single nucleotide polymorphism (SNP) in an enhancer in the MGMT promoter was previously identified to be highly significantly associated with risk for MGMT methylation in lung cancer and sputum from smokers. To further genetic investigations, a genome-wide association and replication study was conducted in two smoker cohorts to identify novel loci for MGMT methylation in sputum that were independent of the MGMT enhancer polymorphism. Two novel trans-acting loci (15q15.2 and 17q24.3) that were identified acted together with the enhancer SNP to empower risk prediction for MGMT methylation. We found that the predisposition to MGMT methylation arising from the 15q15.2 locus involved regulation of the ubiquitin protein ligase E3 component UBR1. UBR1 attenuation reduced turnover of MGMT protein and increased repair of O6-methylguanine in nitrosomethylurea-treated human bronchial epithelial cells (HBEC), while also reducing MGMT promoter activity and abolishing MGMT induction. Overall, our results substantiate reduced gene transcription as a major mechanism for predisposition to MGMT methylation in the lungs of smokers, and support the importance of UBR1 in regulating MGMT homeostasis and DNA repair of alkylated DNA adducts in cells.
doi:10.1158/0008-5472.CAN-15-0243
PMCID: PMC4526392  PMID: 26183928
Genome wide association study; promoter hypermethylation; MGMT; smoker; UBR1
5.  Ambient Air Pollution Is Associated With the Severity of Coronary Atherosclerosis and Incident Myocardial Infarction in Patients Undergoing Elective Cardiac Evaluation 
Background
The effect of air pollution exposure on atherosclerosis severity or incident clinical events in patients with coronary artery disease is not known.
Methods and Results
We conducted a prospective longitudinal cohort study of 6575 Ohio residents undergoing elective diagnostic coronary angiography. Multinomial regression and Cox proportional hazards models were used to assess the relationship between exposure to fine particulate matter <2.5 μm in diameter (PM 2.5) and nitrogen dioxide on coronary artery disease severity at baseline and risk of myocardial infarction, stroke, or all‐cause mortality over 3 years of follow‐up. Among participants with coronary artery disease, exposure to PM 2.5 levels was associated with increased likelihood of having coronary atherosclerosis that was mild (odds ratio 1.43, 95% CI 1.11–1.83, P=0.005) and severe (odds ratio 1.63, 95% CI 1.26–2.11, P<0.0001), with the effect on severe coronary artery disease being significantly increased compared with mild disease (P trend=0.03). Exposure to higher PM 2.5 levels was also significantly associated with increased risk of incident myocardial infarction (hazard ratio 1.33, 95% CI 1.02–1.73, P=0.03) but not stroke or all‐cause mortality. The association of PM 2.5 with incident myocardial infarction was not affected after adjustment for Framingham Adult Treatment Panel III (ATP III) risk score or statin therapy. In comparison, there were no significant associations between nitrogen dioxide levels and all‐cause mortality or risk of stroke after adjustment for Framingham ATP III risk score.
Conclusions
Exposure to PM 2.5 increased the likelihood of having severe coronary artery disease and the risk of incident myocardial infarction among patients undergoing elective cardiac evaluation. These results suggest that ambient air pollution exposure may be a modifiable risk factor for risk of myocardial infarction in a highly susceptible patient population.
doi:10.1161/JAHA.116.003947
PMCID: PMC5015312  PMID: 27468926
air pollution; coronary atherosclerosis; myocardial infarction; Epidemiology; Coronary Artery Disease; Secondary Prevention; Quality and Outcomes
6.  Lifetime prevalence of childhood eczema and the effect of indoor environmental factors: Analysis in Hispanic and non-Hispanic white children 
Allergy and Asthma Proceedings  2016;37(1):64-71.
Background:
The prevalence of eczema varies markedly across the globe. It is unclear whether the geographic variation is due to race and/or ethnic differences, environmental exposures, or genetic factors.
Objective:
We investigated the effects of ethnicity and environmental exposures on eczema in Hispanic white and non-Hispanic white children who participated in the Southern California Children's Health Study.
Methods:
We performed a cross-sectional study with sociodemographic predictors and environmental exposures among Hispanic white and non-Hispanic white children ages 4–8 years enrolled in the Children's Health Study, 2002–2003.
Results:
Eczema prevalence differed by ethnicity: Hispanic whites showed lower prevalence (13.8%) compared with non-Hispanic whites (20.2%), and adjustment for sociodemographic factors did not account for the ethnic difference (odds ratio [OR] 0.79 [95% confidence interval {CI}, 0.65–0.95]). Parental history of allergic disease had a larger effect in Hispanic whites than in non-Hispanic whites (p for interaction = 0.005). High maternal education level (OR 1.46 [95% CI, 1.14–1.87]), parental history of allergic disease (OR 2.21 [95% CI, 1.78–2.76]), and maternal smoking during pregnancy (OR 1.44 [95% CI, 1.06–1.95]) increased the risk of eczema. Indoor environmental factors (e.g., mold, water damage, humidifier use) increased the risk of eczema in non-Hispanic whites independent of a parental history of allergic disease, but, in Hispanic whites, increased risks were observed, primarily in children without a parental history of allergic disease.
Conclusion:
Hispanic white children in southern California had a lower prevalence of eczema than non-Hispanic whites, and this ethnic difference was not accounted for by sociodemographic differences. The effects of a parental history of allergic disease and indoor environmental exposures on eczema varied by ethnicity, which indicated that the etiology of eczema may differ in Hispanic whites and in non-Hispanic whites.
doi:10.2500/aap.2016.37.3913
PMCID: PMC4704378  PMID: 26831849
Eczema; ethnicity; children; parental history of allergic disease; water damage; mold; prevalence
7.  A prospective and retrospective analysis of smoking behavior changes in ever smokers with high risk for lung cancer from New Mexico and Pennsylvania 
Cigarette smoking is the leading preventable cause of death worldwide. The aim of this study is to conduct a prospective and retrospective analysis of smoking behavior changes in the Lovelace Smokers Cohort (LSC) and the Pittsburgh Lung Screening Study cohort (PLuSS). Area under the curve (AUC) for risk models predicting relapse based on demographic, smoking, and relevant clinical variables was 0.93 and 0.79 in LSC and PLuSS, respectively. The models for making a quit attempt had limited prediction ability in both cohorts (AUC≤0.62). We identified an ethnic disparity in adverse smoking behavior change that Hispanic smokers were less likely to make a quit attempt and were more likely to relapse after a quit attempt compared to non-Hispanic Whites. SNPs at 15q25 and 11p14 loci were associated with risk for smoking relapse in the LSC. Rs6495308 at 15q25 has a large difference in minor allele frequency between non-Hispanic Whites and Hispanics (0.46 versus 0.23, P<0.0001) and was associated with risk for ever relapse at same magnitude between the two ethnic groups (OR=1.36, 95% CI=1.10 to 1.67 versus 1.59, 95% CI=1.00 to 2.53, P=0.81). In summary, the risk prediction model established in LSC and PLuSS provided an excellent to outstanding distinguishing for abstainers who will or will not relapse. The ethnic disparity in adverse smoking behavior between Hispanics and non-Hispanic Whites may be at least partially explained by the sequence variants at 15q25 locus that contains multiple nicotine acetylcholine receptors.
PMCID: PMC4913225  PMID: 27335628
Smoking behavior; risk prediction model; ethnicity; single nucleotide polymorphism
9.  15q12 Variants, Sputum Gene Promoter Hypermethylation, and Lung Cancer Risk: A GWAS in Smokers 
Background:
Lung cancer is the leading cause of cancer-related mortality worldwide. Detection of promoter hypermethylation of tumor suppressor genes in exfoliated cells from the lung provides an assessment of field cancerization that in turn predicts lung cancer. The identification of genetic determinants for this validated cancer biomarker should provide novel insights into mechanisms underlying epigenetic reprogramming during lung carcinogenesis.
Methods:
A genome-wide association study using generalized estimating equations and logistic regression models was conducted in two geographically independent smoker cohorts to identify loci affecting the propensity for cancer-related gene methylation that was assessed by a 12-gene panel interrogated in sputum. All statistical tests were two-sided.
Results:
Two single nucleotide polymorphisms (SNPs) at 15q12 (rs73371737 and rs7179575) that drove gene methylation were discovered and replicated with rs73371737 reaching genome-wide significance (P = 3.3×10–8). A haplotype carrying risk alleles from the two 15q12 SNPs conferred 57% increased risk for gene methylation (P = 2.5×10–9). Rs73371737 reduced GABRB3 expression in lung cells and increased risk for smoking-induced chronic mucous hypersecretion. Furthermore, subjects with variant homozygote of rs73371737 had a two-fold increase in risk for lung cancer (P = .0043). Pathway analysis identified DNA double-strand break repair by homologous recombination (DSBR-HR) as a major pathway affecting susceptibility for gene methylation that was validated by measuring chromatid breaks in lymphocytes challenged by bleomycin.
Conclusions:
A functional 15q12 variant was identified as a risk factor for gene methylation and lung cancer. The associations could be mediated by GABAergic signaling that drives the smoking-induced mucous cell metaplasia. Our findings also substantiate DSBR-HR as a critical pathway driving epigenetic gene silencing.
doi:10.1093/jnci/djv035
PMCID: PMC4555640  PMID: 25713168
10.  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
11.  Genetic Ancestry Influences Asthma Susceptibility and Lung Function Among Latinos 
Background
Childhood asthma prevalence and morbidity varies among Latinos in the United States, with Puerto Ricans having the highest and Mexicans the lowest.
Objective
To determine whether genetic ancestry is associated with the odds of asthma among Latinos, and secondarily whether genetic ancestry is associated with lung function among Latino children.
Methods
We analyzed 5,493 Latinos with and without asthma from three independent studies. For each participant we estimated the proportion of African, European, and Native American ancestry using genome-wide data. We tested whether genetic ancestry was associated with the presence of asthma and lung function among subjects with and without asthma. Odds ratios (OR) and effect sizes were assessed for every 20% increase in each ancestry.
Results
Native American ancestry was associated with lower odds of asthma (OR=0.72, 95% confidence interval [CI]: 0.66–0.78, p=8.0×10−15), while African ancestry was associated with higher odds of asthma (OR=1.40, 95%CI: 1.14–1.72, p=0.001). These associations were robust to adjustment for covariates related to early life exposures, air pollution and socioeconomic status. Among children with asthma, African ancestry was associated with lower lung function, including both pre- and post-bronchodilator measures of forced expiratory volume in the first second (−77±19 ml, p=5.8×10−5 and −83±19 ml, p=1.1×10−5, respectively) and forced vital capacity (−100±21 ml, p=2.7×10−6 and −107±22 ml, p=1.0×10−6, respectively).
Conclusion
Differences in the proportions of genetic ancestry can partially explain disparities in asthma susceptibility and lung function among Latinos.
doi:10.1016/j.jaci.2014.07.053
PMCID: PMC4289103  PMID: 25301036
genetic admixture; childhood asthma; Hispanics; minority; pulmonary function
12.  Inducible Nitric Oxide Synthase Promoter Haplotypes and Residential Traffic-Related Air Pollution Jointly Influence Exhaled Nitric Oxide Level in Children 
PLoS ONE  2015;10(12):e0145363.
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.
doi:10.1371/journal.pone.0145363
PMCID: PMC4695093  PMID: 26714306
13.  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
14.  Genome-wide interaction studies reveal sex-specific asthma risk alleles 
Human Molecular Genetics  2014;23(19):5251-5259.
Asthma is a complex disease with sex-specific differences in prevalence. Candidate gene studies have suggested that genotype-by-sex interaction effects on asthma risk exist, but this has not yet been explored at a genome-wide level. We aimed to identify sex-specific asthma risk alleles by performing a genome-wide scan for genotype-by-sex interactions in the ethnically diverse participants in the EVE Asthma Genetics Consortium. We performed male- and female-specific genome-wide association studies in 2653 male asthma cases, 2566 female asthma cases and 3830 non-asthma controls from European American, African American, African Caribbean and Latino populations. Association tests were conducted in each study sample, and the results were combined in ancestry-specific and cross-ancestry meta-analyses. Six sex-specific asthma risk loci had P-values < 1 × 10−6, of which two were male specific and four were female specific; all were ancestry specific. The most significant sex-specific association in European Americans was at the interferon regulatory factor 1 (IRF1) locus on 5q31.1. We also identify a Latino female-specific association in RAP1GAP2. Both of these loci included single-nucleotide polymorphisms that are known expression quantitative trait loci and have been associated with asthma in independent studies. The IRF1 locus is a strong candidate region for male-specific asthma susceptibility due to the association and validation we demonstrate here, the known role of IRF1 in asthma-relevant immune pathways and prior reports of sex-specific differences in interferon responses.
doi:10.1093/hmg/ddu222
PMCID: PMC4159149  PMID: 24824216
16.  Genetic Ancestry and Asthma and Rhinitis Occurrence in Hispanic Children: Findings from the Southern California Children’s Health Study 
PLoS ONE  2015;10(8):e0135384.
Background
Asthma and rhinitis are common childhood health conditions. Being an understudied and rapidly growing population in the US, Hispanic children have a varying risk for these conditions that may result from sociocultural (including acculturative factors), exposure and genetic diversities. Hispanic populations have varying contributions from European, Amerindian and African ancestries. While previous literature separately reported associations between genetic ancestry and acculturation factors with asthma, whether Amerindian ancestry and acculturative factors have independent associations with development of early-life asthma and rhinitis in Hispanic children remains unknown. We hypothesized that genetic ancestry is an important determinant of early-life asthma and rhinitis occurrence in Hispanic children independent of sociodemographic, acculturation and environmental factors.
Methods
Subjects were Hispanic children (5–7 years) who participated in the southern California Children’s Health Study. Data from birth certificates and questionnaire provided information on acculturation, sociodemographic and environmental factors. Genetic ancestries (Amerindian, European, African and Asian) were estimated based on 233 ancestry informative markers. Asthma was defined by parental report of doctor-diagnosed asthma. Rhinitis was defined by parental report of a history of chronic sneezing or runny or blocked nose without a cold or flu. Sample sizes were 1,719 and 1,788 for investigating the role of genetic ancestry on asthma and rhinitis, respectively.
Results
Children had major contributions from Amerindian and European ancestries. After accounting for potential confounders, per 25% increase in Amerindian ancestry was associated with 17.6% (95% confidence interval [CI]: 0.74–0.99) and 13.6% (95% CI: 0.79–0.98) lower odds of asthma and rhinitis, respectively. Acculturation was not associated with either outcome.
Conclusions
Earlier work documented that Hispanic children with significant contribution from African ancestry are at increased asthma risk; however, in Hispanic children who have little contribution from African ancestry, Amerindian ancestry was independently associated with lower odds for development of early-childhood asthma and rhinitis.
doi:10.1371/journal.pone.0135384
PMCID: PMC4532441  PMID: 26263549
17.  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
18.  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
19.  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
20.  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
21.  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
22.  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
23.  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
24.  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
25.  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

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