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1.  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
2.  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
3.  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
Air pollution; traffic pollution; asthma; genetic susceptibility; respiratory disease
4.  Subdural porous and notched mini-grid electrodes for wireless intracranial electroencephalographic recordings 
Background
Intracranial electroencephalography (EEG) studies are widely used in the presurgical evaluation of drug-refractory patients with partial epilepsy. Because chronic implantation of intracranial electrodes carries a risk of infection, hemorrhage, and edema, it is best to limit the number of electrodes used without compromising the ability to localize the epileptogenic zone (EZ). There is always a risk that an intracranial study may fail to identify the EZ because of suboptimal coverage. We present a new subdural electrode design that will allow better sampling of suspected areas of epileptogenicity with lower risk to patients.
Method
Impedance of the proposed electrodes was characterized in vitro using electrochemical impedance spectroscopy. The appearance of the novel electrodes on magnetic resonance imaging (MRI) was tested by placing the electrodes into a gel solution (0.9% NaCl with 14 g gelatin). In vivo neural recordings were performed in male Sprague Dawley rats. Performance comparisons were made using microelectrode recordings from rat cortex and subdural/depth recordings from epileptic patients. Histological examinations of rat brain after 3-week icEEG intracerebral electroencephalography (icEEG) recordings were performed.
Results
The in vitro results showed minimum impedances for optimum choice of pure gold materials for electrode contacts and wire. Different attributes of the new electrodes were identified on MRI. The results of in vivo recordings demonstrated signal stability, 50% noise reduction, and up to 6 dB signal-to-noise ratio (SNR) improvement as compared to commercial electrodes. The wireless icEEG recording system demonstrated on average a 2% normalized root-mean-square (RMS) deviation. Following the long-term icEEG recording, brain histological results showed no abnormal tissue reaction in the underlying cortex.
Conclusion
The proposed subdural electrode system features attributes that could potentially translate into better icEEG recordings and allow sampling of large of areas of epileptogenicity at lower risk to patients. Further validation for use in humans is required.
doi:10.2147/JMDH.S64269
PMCID: PMC4266360  PMID: 25525368
epilepsy; seizure; monitoring; surgery; electrodes
5.  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
7.  Birth Weight and Carotid Artery Intima-Media Thickness 
The Journal of pediatrics  2012;162(5):906-11.e1-2.
Objectives
To determine the association between birth weight and carotid artery intima-media thickness (CIMT), a measure of atherogenesis, in a population of 11-year-old children.
Study design
CIMT measured by high-resolution ultrasound, and birth registry data were available for 670 children of the Southern California Children’s Health Study. Multivariate regression analyses were performed to investigate the association between birth weight and CIMT, with adjustment for child’s health status and lifestyle, pregnancy information, and parental health.
Results
Mean CIMT was 0.57 mm (SD 0.04). We found a nonlinear association between birth weight and CIMT, with an increase in CIMT of 0.014 mm in the fifth (P value .01) compared with the third birth weight quintile. These associations were robust in subsample analyses in children considered normal-weight by gestational age or in term-born children. No significant association with CIMT was found for the lowest quintile.
Conclusions
Greater birth weight was significantly associated with increased CIMT at age 11 years. No evidence for an impact of lower birth weight was found. The predictive value of childhood CIMT on future cardiovascular outcomes is largely unknown, but strong associations between childhood cardiovascular disease risk factors and adult vascular disease suggest that increased CIMT in childhood may be clinically important.
doi:10.1016/j.jpeds.2012.10.060
PMCID: PMC4030536  PMID: 23260106
8.  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
9.  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
10.  Estimation of Parameters in the Two-Compartment Model for Exhaled Nitric Oxide 
PLoS ONE  2014;9(1):e85471.
The fractional concentration of exhaled nitric oxide (FeNO) is a biomarker of airway inflammation that is being increasingly considered in clinical, occupational, and epidemiological applications ranging from asthma management to the detection of air pollution health effects. FeNO depends strongly on exhalation flow rate. This dependency has allowed for the development of mathematical models whose parameters quantify airway and alveolar compartment contributions to FeNO. Numerous methods have been proposed to estimate these parameters using FeNO measured at multiple flow rates. These methods—which allow for non-invasive assessment of localized airway inflammation—have the potential to provide important insights on inflammatory mechanisms. However, different estimation methods produce different results and a serious barrier to progress in this field is the lack of a single recommended method. With the goal of resolving this methodological problem, we have developed a unifying framework in which to present a comprehensive set of existing and novel statistical methods for estimating parameters in the simple two-compartment model. We compared statistical properties of the estimators in simulation studies and investigated model fit and parameter estimate sensitivity across methods using data from 1507 schoolchildren from the Southern California Children's Health Study, one of the largest multiple flow FeNO studies to date. We recommend a novel nonlinear least squares model with natural log transformation on both sides that produced estimators with good properties, satisfied model assumptions, and fit the Children's Health Study data well.
doi:10.1371/journal.pone.0085471
PMCID: PMC3894971  PMID: 24465571
11.  Epigenetics and childhood asthma: current evidence and future research directions 
Epigenomics  2012;4(4):415-429.
Asthma is the most common chronic disease of childhood, affecting one in eight children in the USA and worldwide. It is a complex disease, influenced by both environmental exposures and genetic factors. Although epigenetic modifications (DNA methylation, histone modification and miRNA) can affect transcriptional activity in multiple genetic pathways relevant for asthma development, very limited work has been carried out so far to examine the role of epigenetic variations on asthma development and management. This review provides a brief overview of epigenetic modifications, summarizes recent findings, and discusses some of the major methodological concerns that are relevant for asthma epigenetics.
doi:10.2217/epi.12.32
PMCID: PMC3458510  PMID: 22920181
asthma; DNA methylation; epidemiology; epigenetics; genetics; histone modifications; miRNA; natural history; risk factors
12.  Genetic and Epigenetic Variations in Inducible Nitric Oxide Synthase Promoter, Particulate Pollution and Exhaled Nitric Oxide in Children 
Background
Inducible nitric oxide synthase (iNOS, encoded by NOS2) is the major enzyme for nitric oxide synthesis in airways. As such, measurement of exhaled nitric oxide (FeNO) provides an in vivo assessment of iNOS activity. Short-term exposure to air pollution, haplotypes and DNA methylation in NOS2 promoter have been associated independently with iNOS expression and/or FeNO.
Objective
We aimed to examine the effects of ambient air pollutants, NOS2 promoter haplotypes and NOS2 promoter methylation on FeNO level in children.
Methods
We selected 940 participants in the Children’s Health Study who provided buccal samples and had undergone FeNO measurement on the same day. DNA methylation was measured using a bisulfite-polymerase chain reaction Pyrosequencing assay. Seven single nucleotide polymorphisms captured the haplotype diversity in the NOS2 promoter. Average particulate matter with aerodynamic diameter ≤2.5μm and ≤10μm (PM2.5 and PM10), ozone and nitrogen dioxide levels 7 days before FeNO measurement were estimated based on air pollution data obtained at central monitoring sites.
Results
We found interrelated effects of PM2.5, NOS2 promoter haplotypes and iNOS methylation on FeNO. Elevated 7-day average PM2.5 exposure was associated with lower iNOS methylation (P=.01). NOS2 promoter haplotypes were globally associated with NOS2 promoter methylation (P=6.2 × 10−8). There was interaction among one common promoter haplotype, iNOS methylation level and PM2.5 exposure on FeNO (Pinteraction=.00007).
Conclusion
Promoter variants in NOS2 and short term PM2.5 exposure affect iNOS methylation. This is one of the first studies showing contributions of genetic and epigenetic variations in air pollution mediated phenotype expression.
doi:10.1016/j.jaci.2011.09.037
PMCID: PMC3487398  PMID: 22055874
air pollution; biomarker; DNA methylation; epigenetics; genetics; gene-environment interaction; nitrosative stress
13.  Meta-analysis of Genome-wide Association Studies of Asthma In Ethnically Diverse North American Populations 
Torgerson, Dara G. | Ampleford, Elizabeth J. | Chiu, Grace Y. | Gauderman, W. James | Gignoux, Christopher R. | Graves, Penelope E. | Himes, Blanca E. | Levin, Albert M. | Mathias, Rasika A. | Hancock, Dana B. | Baurley, James W. | Eng, Celeste | Stern, Debra A. | Celedón, Juan C. | Rafaels, Nicholas | Capurso, Daniel | Conti, David V. | Roth, Lindsey A. | Soto-Quiros, Manuel | Togias, Alkis | Li, Xingnan | Myers, Rachel A. | Romieu, Isabelle | Van Den Berg, David J. | Hu, Donglei | Hansel, Nadia N. | Hernandez, Ryan D. | Israel, Elliott | Salam, Muhammad T. | Galanter, Joshua | Avila, Pedro C. | Avila, Lydiana | Rodriquez-Santana, Jose R. | Chapela, Rocio | Rodriguez-Cintron, William | Diette, Gregory B. | Adkinson, N. Franklin | Abel, Rebekah A. | Ross, Kevin D. | Shi, Min | Faruque, Mezbah U. | Dunston, Georgia M. | Watson, Harold R. | Mantese, Vito J. | Ezurum, Serpil C. | Liang, Liming | Ruczinski, Ingo | Ford, Jean G. | Huntsman, Scott | Chung, Kian Fan | Vora, Hita | Li, Xia | Calhoun, William J. | Castro, Mario | Sienra-Monge, Juan J. | del Rio-Navarro, Blanca | Deichmann, Klaus A. | Heinzmann, Andrea | Wenzel, Sally E. | Busse, William W. | Gern, James E. | Lemanske, Robert F. | Beaty, Terri H. | Bleecker, Eugene R. | Raby, Benjamin A. | Meyers, Deborah A. | London, Stephanie J. | Gilliland, Frank D. | Burchard, Esteban G. | Martinez, Fernando D. | Weiss, Scott T. | Williams, L. Keoki | Barnes, Kathleen C. | Ober, Carole | Nicolae, Dan L.
Nature genetics  2011;43(9):887-892.
Asthma is a common disease with a complex risk architecture including both genetic and environmental factors. We performed a meta-analysis of North American genome-wide association studies (GWAS) of asthma in 5,416 asthma cases representing European Americans, African Americans/African Caribbeans, and Latinos, and replicated five regions among the most significant signals in 12,649 individuals from the same ethnic groups. Four were at previously reported loci on 17q21, and near the IL1RL1, TSLP, and IL33, genes, but we report for the first time that these loci are associated with asthma risk in three ethnic groups. In addition, we identified a novel association with asthma in the PYHIN1, gene that was specific to individuals of African descent (p=3.9×10−9). These results suggest that some asthma susceptibility loci are robust to differences in ancestry when sufficiently large samples sizes are investigated, and that ancestry-specific associations also contribute to the complex genetic architecture of asthma.
doi:10.1038/ng.888
PMCID: PMC3445408  PMID: 21804549
14.  Particulate Matter, DNA Methylation in Nitric Oxide Synthase, and Childhood Respiratory Disease 
Environmental Health Perspectives  2012;120(9):1320-1326.
Background: Air pollutants have been associated with childhood asthma and wheeze. Epigenetic regulation of nitric oxide synthase—the gene responsible for nitric oxide production—may be affected by air pollutants and contribute to the pathogenesis of asthma and wheeze.
Objective: Our goal was to investigate the association between air pollutants, DNA methylation, and respiratory outcomes in children.
Methods: Given residential address and buccal sample collection date, we estimated 7-day, 1-month, 6-month, and 1-year cumulative average PM2.5 and PM10 (particulate matter ≤ 2.5 and ≤ 10 µm aerodynamic diameter, respectively) exposures for 940 participants in the Children’s Health Study. Methylation of 12 CpG sites in three NOS (nitric oxide synthase) genes was measured using a bisulfite-polymerase chain reaction Pyrosequencing assay. Beta regression models were used to estimate associations between air pollutants, percent DNA methylation, and respiratory outcomes.
Results: A 5-µg/m3 increase in PM2.5 was associated with a 0.20% [95% confidence interval (CI): –0.32, –0.07] to 1.0% (95% CI: –1.61, –0.56) lower DNA methylation at NOS2A position 1, 0.06% (95% CI: –0.18, 0.06) to 0.58% (95% CI: –1.13, –0.02) lower methylation at position 2, and 0.34% (95% CI: –0.57, –0.11) to 0.89% (95% CI: –1.57, –0.21) lower methylation at position 3, depending on the length of exposure and CpG locus. One-year PM2.5 exposure was associated with 0.33% (95% CI: 0.01, 0.65) higher in average DNA methylation of 4 loci in the NOS2A CpG island. A 5-µg/m3 increase in 7-day and 1-year PM2.5 was associated with 0.6% (95% CI: 0.13, 0.99) and 2.8% (95% CI: 1.77, 3.75) higher NOS3 DNA methylation. No associations were observed for NOS1. PM10 showed similar but weaker associations with DNA methylation in these genes.
Conclusions: PM2.5 exposure was associated with percent DNA methylation of several CpG loci in NOS genes, suggesting an epigenetic mechanism through which these pollutants may alter production of nitric oxide.
doi:10.1289/ehp.1104439
PMCID: PMC3440108  PMID: 22591701
air pollution; asthma; DNA methylation; epigenetics; PM2.5; wheeze
15.  Comparison of phenotypic versus marker-assisted background selection for the SUB1 QTL during backcrossing in rice 
Breeding Science  2012;62(3):216-222.
Marker assisted backcrossing has been used effectively to transfer the submergence tolerance gene SUB1 into popular rice varieties, but the approach can be costly. The selection strategy comprising foreground marker and phenotypic selection was investigated as an alternative. The non-significant correlation coefficients between ranking of phenotypic selection and ranking of background marker selection in BC2F1, BC3F1 and BC3F2 generations indicated inefficiency of phenotypic selection compared to marker-assisted background selection with respect to recovery of the recipient genome. In addition, the introgression size of the chromosome fragment containing SUB1 was approximately 17 Mb, showing the effects of linkage drag. The significant correlation coefficient between rankings of phenotypic selection with the percentage of recipient alleles in the BC1F1 generation suggested that background selection could be avoided in this generation to minimize the genotyping cost. The phenotypically selected best plant of the BC3F1 generation was selfed and backcross recombinant lines were selected in the resulting BC3F4 generation. The selection strategy could be appropriate for the introgression of SUB1 QTL in countries that lack access to high-throughput genotyping facilities.
doi:10.1270/jsbbs.62.216
PMCID: PMC3501938  PMID: 23226081
Oryza sativa L.; submergence tolerance; marker assisted selection; backcrossing
16.  DNA Methylation in the Arginase–Nitric Oxide Synthase Pathway Is Associated with Exhaled Nitric Oxide in Children with Asthma 
Rationale: Genetic variation in arginase (ARG) and nitric oxide synthase (NOS) has been associated with exhaled nitric oxide (FeNO) levels in children. Little is known about whether epigenetic variation in these genes modulates FeNO.
Objectives: To evaluate whether DNA methylation in ARG and NOS genes is associated with FeNO.
Methods: A subset of 940 participants in the Children's Health Study were selected for this study. Children were eligible if they had FeNO measurements and buccal cells collected on the same day. CpG loci located in the promoter regions of NOS1, NOS2A, NOS3, ARG1, and ARG2 genes were analyzed. Multiple loci in each gene were evaluated individually and averaged together. DNA methylation was measured using a bisulfite–polymerase chain reaction pyrosequencing assay. Linear regression models were used to investigate the association between DNA methylation and FeNO and whether associations differed by asthma status.
Measurements and Main Results: DNA methylation in ARG2 was significantly associated with FeNO. A 1% increase in average DNA methylation of ARG2 was associated with a 2.3% decrease in FeNO (95% confidence interval, −4 to −0.6). This association was significantly larger in children with asthma (%diff = −8.7%) than in children with no asthma (%diff = −1.6%; pint = 0.01). Differences in FeNO by asthma status were also observed for ARG1 (%diffasthma = −4.4%; %diffnon-asthma = 0.3%; pint = 0.02). DNA methylation in NOS genes was not associated with FeNO.
Conclusions: DNA methylation in ARG1 and ARG2 is associated with FeNO in children with asthma and suggests a possible role for epigenetic regulation of nitric oxide production.
doi:10.1164/rccm.201012-2029OC
PMCID: PMC3172885  PMID: 21512169
arginase; nitric oxide synthase; FeNO; asthma
17.  Heritability and role for the environment in DNA methylation in AXL receptor tyrosine kinase 
Epigenetics  2011;6(7):895-898.
DNA methylation in AXL, a receptor tyrosine kinase relevant in cancer and immune function, is reportedly highly heritable. We present evidence to suggest that heritability of DNA methylation in AXL is variable, dependent on population characteristics and cell type studied. Moreover, environmental exposures in utero, particularly exposure to maternal smoking, contributes to variation in DNA methylation of select CpG loci that can affect calculations of heritability. Children exposed to maternal smoking in utero had a 2.3% increase (95% CI 0.3, 4.2) in DNA methylation in AXL, which was magnified in girls as compared to boys. These results present compelling evidence that environmental exposure to tobacco smoke during pregnancy may alter DNA methylation levels in subtle but potentially important ways and that these changes are persistent years after birth.
doi:10.4161/epi.6.7.15768
PMCID: PMC3230541  PMID: 21555911
AXL; DNA methylation; heritability; maternal smoking; receptor tyrosine kinase
18.  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
19.  Genetic Variation in the Glutathione Synthesis Pathway, Air Pollution, and Children's Lung Function Growth 
Rationale: Glutathione plays an important role in antioxidant and inflammatory processes in the lung. Alterations in glutathione metabolism are a central feature of several chronic lung diseases.
Objectives: To determine whether sequence variation in genes in the glutathione synthesis pathway alters susceptibility to air pollution effects on lung function.
Methods: In this prospective study, 14,821 lung function measurements were taken on 2,106 children from 12 Southern California cities. Tagging single-nucleotide polymorphisms in glutathione metabolism pathway genes GSS, GSR, GCLM, and GCLC were genotyped by GoldenGate assay (Illumina, San Diego, CA). Mixed regression models were used to determine whether particular haplotypes were associated with FEV1, maximal mid-expiratory flow rate, and FVC and whether any of the genetic associations varied with levels of exposure to air pollutants.
Measurements and Main Results: We found that variation in the GSS locus was associated with differences in susceptibility of children for lung function growth deficits associated with NO2, PM10, PM2.5, elemental carbon, organic carbon, and O3. The negative effects of air pollutants were largely observed within participants who had a particular GSS haplotype. The effects ranged from −124.2 to −149.1 for FEV1, from –92.9 to −126.7 for FVC, and from −193.9 to −277.9 for maximal mid-expiratory flow rate for all pollutants except O3, which showed a larger decrease in lung function in children without this haplotype.
Conclusions: Variation in GSS was associated with differences in susceptibility to adverse effects of pollutants on lung function growth.
doi:10.1164/rccm.201006-0849OC
PMCID: PMC3040392  PMID: 20802163
GSS; glutathione; lung function; oxidative stress; air pollution
20.  Residential Traffic-Related Pollution Exposures and Exhaled Nitric Oxide in the Children’s Health Study 
Environmental Health Perspectives  2011;119(10):1472-1477.
Background: The fractional concentration of nitric oxide in exhaled air (FeNO) potentially detects airway inflammation related to air pollution exposure. Existing studies have not yet provided conclusive evidence on the association of FeNO with traffic-related pollution (TRP).
Objectives: We evaluated the association of FeNO with residential TRP exposure in a large cohort of children.
Methods: We related FeNO measured on 2,143 children (ages 7–11 years) who participated in the Southern California Children’s Health Study (CHS) to five classes of metrics of residential TRP: distances to freeways and major roads; length of all and local roads within circular buffers around the home; traffic densities within buffers; annual average line source dispersion modeled nitrogen oxides (NOx) from freeways and nonfreeway roads; and predicted annual average nitrogen oxide, nitrogen dioxide, and NOx from a model based on intracommunity sampling in the CHS.
Results: In children with asthma, length of roads was positively associated with FeNO, with stronger associations in smaller buffers [46.7%; 95% confidence interval (CI), 14.3–88.4], 12.4% (95% CI, –8.8 to 38.4), and 4.1% (95% CI, –14.6 to 26.8) higher FeNO for 100-, 300-, and 1,000-m increases in the length of all roads in 50-, 100-, and 200-m buffers, respectively. Other TRP metrics were not significantly associated with FeNO, even though the study design was powered to detect exposures explaining as little as 0.4% of the variation in natural log-transformed FeNO (R2 = 0.004).
Conclusion: Length of road was the only indicator of residential TRP exposure associated with airway inflammation in children with asthma, as measured by FeNO.
doi:10.1289/ehp.1103516
PMCID: PMC3230449  PMID: 21708511
air pollution; airway inflammation; children’s respiratory health; exhaled nitric oxide; traffic
21.  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
22.  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
23.  Residential Proximity to Freeways is Associated with Uncontrolled Asthma in Inner-City Hispanic Children and Adolescents 
Journal of Allergy  2010;2010:157249.
Background. Proximity to heavy traffic has been linked to increased asthma severity. However, it is unknown whether exposure to heavy traffic is associated with the ability to maintain asthma control. Objectives. This study examines whether exposure to heavy traffic is associated with the ability to maintain asthma control in inner-city children. Methods. 756 inner-city asthmatic Hispanic children were followed for one year in a pediatric asthma management program (Breathmobile). At each scheduled visit, asthma specialist tracked patients' asthma severity and managed their asthma based on the NAEPP guidelines. The patients' residential distance from the nearest freeway was calculated based on residential address at study entry. Distance to nearest freeway was used as a surrogate marker for high exposure from traffic-related air pollutants. Results. Patients who lived near a freeway were significantly more likely to have asthma that was not well controlled (P = .03). Patients with intermittent and mild baseline severity have a two-fold increased risk of having asthma that is uncontrolled if they lived <2 miles from a freeway (OR = 2.2, P = .04). Conclusion. In children with asthma, residential proximity to freeways is associated with uncontrolled asthma.
doi:10.1155/2010/157249
PMCID: PMC2948442  PMID: 20948882
24.  Variation in the GST mu Locus and Tobacco Smoke Exposure as Determinants of Childhood Lung Function 
Rationale: The glutathione S-transferases (GSTs) are important detoxification enzymes.
Objectives: To investigate effects of variants in GST mu genes on lung function and assess their interactions with tobacco smoke exposure.
Methods: In this prospective study, 14,836 lung function measurements were collected from 2,108 children who participated in two Southern California cohorts. For each child, tagging single nucleotide polymorphisms in GSTM2, GSTM3, GSTM4, and GSTM5 loci were genotyped. Using principal components and haplotype analyses, the significance of each locus in relation to level and growth of FEV1, maximum midexpiratory flow rate (MMEF), and FVC was evaluated. Interactions between loci and tobacco smoke on lung function were also investigated.
Measurements and Main Results: Variation in the GST mu family locus was associated with lower FEV1 (P = 0.01) and MMEF (0.04). Two haplotypes of GSTM2 were associated with FEV1 and MMEF, with effect estimates in opposite directions. One haplotype in GSTM3 showed a decrease in growth for MMEF (−164.9 ml/s) compared with individuals with other haplotypes. One haplotype in GSTM4 showed significantly decreased growth in FEV1 (−51.3 ml), MMEF (−69.1 ml/s), and FVC (−44.4 ml), compared with all other haplotypes. These results were consistent across two independent cohorts. Variation in GSTM2 was particularly important for FVC and FEV1 among children whose mothers smoked during pregnancy.
Conclusions: Genetic variation across the GST mu locus is associated with 8-year lung function growth. Children of mothers who smoked during pregnancy and had variation in GSTM2 had lower lung function growth.
doi:10.1164/rccm.200809-1384OC
PMCID: PMC2720124  PMID: 19151192
FEV1; in utero; glutathione S-transferase; tobacco smoke
25.  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

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