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1.  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
2.  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
3.  Prenatal Tobacco Smoke Exposure Affects Global and Gene-specific DNA Methylation 
Rationale: Prenatal exposure to tobacco smoke increases the risk for diseases later in the child's life that may be mediated through alterations in DNA methylation.
Objectives: To demonstrate that differences in DNA methylation patterns occur in children exposed to tobacco smoke and that variation in detoxification genes may alter these associations.
Methods: Methylation of DNA repetitive elements, LINE1 and AluYb8, was measured using bisulfite conversion and pyrosequencing in buccal cells of 348 children participating in the Children's Health Study. Gene-specific CpG methylation differences associated with smoke exposure were screened in 272 participants in the Children's Health Study children using an Illumina GoldenGate panel. CpG loci that demonstrated a statistically significant difference in methylation were validated by pyrosequencing. Estimates were standardized across loci using a Z score to enable cross-comparison of results.
Measurements and Main Results: DNA methylation patterns were associated with in utero exposure to maternal smoking. Exposed children had significantly lower methylation of AluYb8 (β, −0.31; P = 0.03). Differences in smoking-related effects on LINE1 methylation were observed in children with the common GSTM1 null genotype. Differential methylation of CpG loci in eight genes was identified through the screen. Two genes, AXL and PTPRO, were validated by pyrosequencing and showed significant increases in methylation of 0.37 (P = 0.005) and 0.34 (P = 0.02) in exposed children. The associations with maternal smoking varied by a common GSTP1 haplotype.
Conclusions: Life-long effects of in utero exposures may be mediated through alterations in DNA methylation. Variants in detoxification genes may modulate the effects of in utero exposure through epigenetic mechanisms.
doi:10.1164/rccm.200901-0135OC
PMCID: PMC2742762  PMID: 19498054
DNA methylation; epigenetics; prenatal; smoke
4.  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
5.  Ozone, Oxidant Defense Genes, and Risk of Asthma during Adolescence 
Rationale: Although oxidative stress is a cardinal feature of asthma, the roles of oxidant air pollutants and antioxidant genes heme oxygenase 1 (HMOX-1), catalase (CAT), and manganese superoxide dismutase (MNSOD) in asthma pathogenesis have yet to be determined.
Objectives: We hypothesized that the functional polymorphisms of HMOX-1 ([GT]n repeat), CAT (−262C>T −844C>T), and MNSOD (Ala-9Val) are associated with new-onset asthma, and the effects of these variants vary by exposure to ozone, a potent oxidant air pollutant.
Methods: We assessed this hypothesis in a population-based cohort of non-Hispanic (n = 1,125) and Hispanic white (n = 586) children who resided in 12 California communities and who were followed annually for 8 years to ascertain new-onset asthma.
Measurements and Main Results: Air pollutants were continuously measured in each of the study communities during the 8 years of study follow-up. HMOX-1 “short” alleles (<23 repeats) were associated with a reduced risk for new-onset asthma among non-Hispanic whites (hazard ratio [HR], 0.64; 95% confidence interval [CI], 0.41–0.99). This protective effect was largest in children residing in low-ozone communities (HR, 0.48; 95% CI, 0.25–0.91) (interaction P value = 0.003). Little evidence for an association with HMOX-1 was observed among Hispanic children. In contrast, Hispanic children with a variant of the CAT-262 “T” allele (CT or TT) had an increased risk for asthma (HR, 1.78; P value = 0.01). The effects of these polymorphisms were not modified by personal smoking or secondhand-smoke exposure.
Conclusions: Functional promoter variants in CAT and HMOX-1 showed ethnicity-specific associations with new-onset asthma. Oxidant gene protection was restricted to children living in low-ozone communities.
doi:10.1164/rccm.200706-863OC
PMCID: PMC2258440  PMID: 18048809
asthma; catalase; heme oxygenase-1; MnSOD; oxidative stress; ozone
6.  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
7.  Glutathione S-Transferases M1 and P1 Prevent Aggravation of Allergic Responses by Secondhand Smoke 
Rationale: Secondhand tobacco smoke (SHS) and traffic-related air pollutants are associated with asthma and allergy. Diesel exhaust particles (DEPs) and SHS can interact with allergens in exacerbating allergic airway diseases through generation of reactive oxygen species. Glutathione S-transferases (GSTs) metabolize reactive oxygen species and detoxify electrophilic xenobiotics present in SHS and DEPs.
Objectives: We tested the hypotheses that functional GSTM1-null genotype and GSTP1 codon 105 variants (Ile105 and Val105) are determinants of allergic responses to SHS, and that responses to SHS and DEPs are correlated.
Methods and Measurements: In a randomized, placebo-controlled crossover trial, 19 ragweed allergen–sensitive subjects who had previously participated in a DEP trial were challenged intranasally with allergen after having been exposed to either clean air or SHS at separate visits. Nasal allergen–specific IgE, histamine, IL-4, and IFN-γ levels were measured before and after allergen challenge.
Main Results: Individuals with GSTM1-null or GSTP1 Ile105 genotypes showed larger nasal responses to allergens with SHS compared with clean air. GSTM1-null subjects had a larger increase in IgE than GSTM1-present subjects (median, 173.3 vs. 46.7 U/ml; p = 0.03), and the Ile105 GSTP1 genotype subjects had increased histamine (median, 10.2 vs. 4.6 nM; p = 0.01) after SHS plus allergen challenge. Responses to SHS and DEPs were correlated. Enhancement of IgE and histamine was greatest in the subjects with both the GSTM1-null and GSTP1 Ile/Ile genotypes.
Conclusions: GSTM1 and GSTP1 are important cytoprotective factors that reduce SHS and DEP exacerbation of allergic responses.
doi:10.1164/rccm.200509-1424OC
PMCID: PMC2648296  PMID: 17023730
GSTM1; GSTP1; histamine, IgE; tobacco smoke
8.  Health Effects of the 2003 Southern California Wildfires on Children 
Rationale: In late October 2003, Southern California wildfires burned more than 3,000 km2. The wildfires produced heavy smoke that affected several communities participating in the University of Southern California Children's Health Study (CHS).
Objectives: To study the acute effects of fire smoke on the health of CHS participants.
Methods: A questionnaire was used to assess smoke exposure and occurrence of symptoms among CHS high-school students (n = 873; age, 17–18 yr) and elementary-school children (n = 5,551; age, 6–7 yr), in a total of 16 communities. Estimates of particulate matter (PM10) concentrations during the 5 d with the highest fire activity were used to characterize community smoke level.
Main Results: All symptoms (nose, eyes, and throat irritations; cough; bronchitis; cold; wheezing; asthma attacks), medication usage, and physician visits were associated with individually reported exposure differences within communities. Risks increased monotonically with the number of reported smoky days. For most outcomes, reporting rates between communities were also associated with the fire-related PM10 levels. Associations tended to be strongest among those without asthma. Individuals with asthma were more likely to take preventive action, such as wearing masks or staying indoors during the fire.
Conclusions: Exposure to wildfire smoke was associated with increased eye and respiratory symptoms, medication use, and physician visits.
doi:10.1164/rccm.200604-519OC
PMCID: PMC2648104  PMID: 16946126
air pollution; asthma; sore throat; wheezing
9.  Regular Smoking and Asthma Incidence in Adolescents 
Rationale: Although involuntary exposure to maternal smoking during the in utero period and to secondhand smoke are associated with occurrence of childhood asthma, few studies have investigated the role of active cigarette smoking on asthma onset during adolescence.
Objectives: To determine whether regular smoking is associated with the new onset of asthma during adolescence.
Methods: We conducted a prospective cohort study among 2,609 children with no lifetime history of asthma or wheezing who were recruited from fourth- and seventh-grade classrooms and followed annually in schools in 12 southern California communities. Regular smoking was defined as smoking at least seven cigarettes per day on average over the week before and 300 cigarettes in the year before each annual interview. Incident asthma was defined using new cases of physician-diagnosed asthma.
Measurements and Main Results: Regular smoking was associated with increased risk of new-onset asthma. Children who reported smoking 300 or more cigarettes per year had a relative risk (RR) of 3.9 (95% confidence interval [95% CI], 1.7–8.5) for new-onset asthma compared with nonsmokers. The increased risk from regular smoking was greater in nonallergic than in allergic children. Regular smokers who were exposed to maternal smoking during gestation had the largest risk from active smoking (RR, 8.8; 95% CI, 3.2–24.0).
Conclusions: Regular smoking increased risk for asthma among adolescents, especially for nonallergic adolescents and those exposed to maternal smoking during the in utero period.
doi:10.1164/rccm.200605-722OC
PMCID: PMC2648110  PMID: 16973983
asthma; epidemiology; smoking
10.  Associations of Tumor Necrosis Factor G-308A with Childhood Asthma and Wheezing 
Rationale: Tumor necrosis factor (TNF) mediates a spectrum of airway inflammatory responses, including those to air pollutants, and is an asthma candidate gene. One TNF promoter variant (G–308A) affects expression of TNF and has been associated with inflammatory diseases; however, studies of asthma have been inconsistent. Because ozone produces oxidative stress, increased airway TNF, and inflammation, the associations of the −308 TNF polymorphism with asthma may vary by ozone exposure and variants of oxidant defense genes glutathione-S-transferase (GST) M1 and GSTP1.
Objectives: To investigate the association of TNF G–308A with asthma and wheezing and to determine whether these associations vary with ozone exposure and GSTM1 and GSTP1 genotype.
Methods: We studied associations of TNF–308 genotype with lifetime and current wheezing and asthma among 3,699 children in the Children's Health Study. We examined differences in associations with community ozone and by GSTM1 null and GSTP1 105 Ile/Val (A105G) genotype.
Results: Children with TNF–308 GG had decreased risk of asthma (odds ratio, 0.8; 95% confidence interval, 0.7–0.9) and lifetime wheezing (odds ratio, 0.8; 95% confidence interval, 0.7–0.9). The protective effects of GG genotype on wheezing outcomes were of greater magnitude in lower compared with higher ozone communities. These findings were replicated in the two cohorts of fourth-grade children recruited in 1993 and 1996. The reduction of the protective effect from the −308 GG genotype with higher ozone exposure was most marked in the GSTM1 null and GSTP1 Ile/Ile groups.
Conclusions: The TNF–308 GG genotype may have a protective role in asthma pathogenesis, depending on airway oxidative stress levels.
doi:10.1164/rccm.200508-1256OC
PMCID: PMC2662916  PMID: 16456144
child; genetic epidemiology; lung
11.  TNF-308 Modifies the Effect of Second-Hand Smoke on Respiratory Illness–related School Absences 
Rationale: Exposure to second-hand smoke (SHS) has been associated with increased risk of respiratory illness in children including respiratory illness–related school absences. The role of genetic susceptibility in risk for adverse effects from SHS has not been extensively investigated in children.
Objective: To determine whether the tumor necrosis factor (TNF) G-308A genotype influences the risk for respiratory illness–related school absences associated with SHS exposure.
Methods: Incident school absences were collected, using an active surveillance system, between January and June 1996, as part of the Air Pollution and Absence Study, a prospective cohort study nested in the Children's Health Study. Buccal cells and absence reports were collected on 1,351 students from 27 elementary schools in California.
Measurements and Main Results: Illness-related school absences were classified as nonrespiratory and respiratory illness–related, which were further categorized into upper or lower respiratory illness–related absences based on symptoms. The effect of SHS exposure on respiratory illness–related absences differed by TNF genotype (p interaction, 0.02). In children possessing at least one copy of the TNF-308 A variant, exposure to two or more household smokers was associated with a twofold risk of a school absence due to respiratory illness (relative risk, 2.13; 95% confidence interval, 1.34, 3.40) and a fourfold risk of lower respiratory illness–related school absence (relative risk, 4.15; 95% confidence interval, 2.57, 6.71) compared with unexposed children homozygous for the common TNF-308 G allele.
Conclusions: These results indicate that a subgroup of genetically susceptible children are at substantially greater risk of respiratory illness if exposed to SHS.
doi:10.1164/rccm.200503-490OC
PMCID: PMC2718456  PMID: 16166621
epidemiology; school absence; second-hand smoke; TNF

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