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s Objective To explore the causal effect of time-varying z-BMI growth on early menarche using Mendelian randomisation (MR); to identify critical adiposity predictors of early menarche; to compare the effects of birthweight and time-varying z-BMI growth as mediators of the path from genes to early menarche using mediation analysis. Methods We used data from the Taiwan Children Health Study with 21 obesity-related single-nucleotide polymorphisms (SNPs) to yield genetic (instrumental variable)IVs for adiposity. Children with available data on genotyping, birthweight, adiposity, and menarcheal age were included. Results In MR analyses, results based on the time-varying z-BMI growth show more statistical power and capture more information of adiposity growth (p = 0.01) than those based on single point z-BMI (p = 0.02). Among adiposity measures, critical predictors of early menarche are fat free mass (RR = 1.33, 95% CI 1.07–1.65) and waist/height ratio (RR = 1.27, 95% CI 1.03–1.56). Other potential predictors of early menarche are sum of skinfold (RR = 1.24, 95% CI 1.03–1.48) and total body fat (RR = 1.20, 95% CI 1.05–1.38). In both one-mediation and multi-mediation analyses, time-varying z-BMI growth in the prepubertal years plays a crucial mediator in the pathway from the genes to early menarche. Conclusions This study discovered that greater prepubertal adiposity growth is a crucial mediator in the path from genes to early menarche. For girls with genes positively associated with obesity; and/or of lower birthweight, a strategy to prevent childhood adiposity should be implemented in order to avoid early menarche development.

Summary Objective To fully explain the dynamic and comprehensive etiology of the trajectory associated with adiposity indices. Methods This study involved data of 5572 children, aged 6–11 years, as part of the Taiwan Children Health Study (TCHS). The present study introduced four distinct BMI trajectories, identified previously among children: persistently healthy weight; late-onset overweight or obesity; persistent overweight or obesity; and declining BMI class. Logistic regression was used to examine the effect of non-modifiable factors on BMI trajectory classes. Generalized estimating equations were used to examine the effect of dynamically modifiable factors on either BMI trajectory classes or adiposity indices. Results Compared with class 1 (persistently healthy weight), class 2 exhibited a significantly increased risk of weight gain and fat mass, affected by lower family incomes and poor-quality sleep. Class 3 had a higher risk of persistent obesity and abdominal obesity, affected by higher birthweight and sedentary lifestyle. Class 4 approached a healthy weight due to increased physical activity, which was associated with a decrease in body fat and central obesity. Conclusions We found crucially non-modifiable and modifiable factors that could describe each high BMI growth pattern, and calculated their modifiable contributions to adiposity indices. Modifiable factors that focus on those crucially dynamic factors are recommended for preventing obese growth trajectories.

Interleukin-13(IL-13) might play an important role in driving aggregate bronchitic symptoms pathogenesis. However, none of the studies assessed the interaction between air pollutants exposure and IL-13 gene on the risk of aggregate bronchitic symptoms in non-asthma children. To assess the independent and joint effects of the exposure to air pollution and IL-13 haplotypes on the risk of aggregate bronchitic symptoms, we conducted a cross-sectional study and focused on non-asthma children. The study population consisted of 2944 children. The effect of each air pollutant on the risk of aggregate bronchitic symptoms was estimated as odds ratios per interquartile range (IQR) change. In the multiple logistic regressions, adjusted for confounding factors, the risk of chronic phlegm was associated with PM2.5 exposure (aOR, 1.59; 95% CI, 1.07–2.37 per 12.51 μg/m3 change), O3 exposure (aOR, 1.54 95% CI, 1.05–2.27 per 8.28 ppb change) and SO2 exposure (aOR, 1.19; 95% CI, 1.02–1.39 per 0.98 ppb change). Our study further provides the evidence that gene-environment interactions between IL-13 haplotype and O3 exposure on chronic phlegm (95% CI for interaction, 1.01–1.38). Identifying children who are more sensitive to air pollution helps us to provide them an efficient prevention to avoid aggregate bronchitic symptoms., Highlights • Limited studies explored the interactions between IL-13 gene and air pollutants exposure on the risk of bronchitic symptoms. • Genetic susceptibility of IL-13 may interact with O3 exposure causing the pathogenesis of bronchitic symptoms. • Identifying children susceptible to air pollutants helps us to provide them an efficient prevention of bronchitic symptoms. Genetic susceptibility may interact with specific environmental factors causing the pathogenesis of aggregate bronchitic symptoms. Limited studies have explored the interactions between Interleukin-13 (IL-13) gene and air pollutants exposure on the risk of aggregate bronchitic symptoms. Our study further provides the evidence that gene-environment interactions between IL-13 gene and O3 exposure may play an important role in aggregate bronchitic symptoms. Identifying children who are more sensitive to air pollutants helps us to provide them an efficient prevention to avoid aggregate bronchitic symptoms.

The feasibility of genetic screening for deafness-causing mutations in newborns has been reported in several studies. The aim of this study was to investigate the long-term results in those who screened positive for deafness mutations; these results are crucial to determine the cost-effectiveness to justify population-wide genetic screening. We performed simultaneous hearing screening and genetic screening targeting four common deafness mutations (p.V37I and c.235delC of GJB2, c.919-2A>G of SLC26A4, and the mitochondrial m.1555A>G) in 5173 newborns at a tertiary hospital between 2009 and 2015. Serial audiometric results up to 6 years old were then analyzed in children with conclusive genotypes. Newborn genetic screening identified 82 (1.6%) babies with conclusive genotypes, comprising 62 (1.2%) with GJB2 p.V37I/p.V37I, 16 (0.3%) with GJB2 p.V37I/c.235delC, and 4 (0.1%) with m.1555A>G. Of these, 46 (56.1%) passed hearing screening at birth. Long-term follow-up demonstrated progressive hearing loss in children with the GJB2 p.V37I/p.V37I and p.V37I/c.235delC genotypes; this hearing loss deteriorated by approximately 1 decibel hearing level (dBHL) per year. We delineated the longitudinal auditory features of the highly prevalent GJB2 p.V37I mutation on a general population basis and confirmed the utility of newborn genetic screening in identifying infants with late-onset or progressive hearing impairment undetectable by newborn hearing screening. Genet Med 19 1, 6–12.

Teenager smoking is of great importance in public health. Functional roles of microRNAs have been documented in smoke-induced gene expression changes, but comprehensive mechanisms of microRNA-mRNA regulation and benefits remained poorly understood. We conducted the Teenager Smoking Reduction Trial (TSRT) to investigate the causal association between active smoking reduction and whole-genome microRNA and mRNA expression changes in human peripheral blood mononuclear cells (PBMC). A total of 12 teenagers with a substantial reduction in smoke quantity and a decrease in urine cotinine/creatinine ratio were enrolled in genomic analyses. In Gene Set Enrichment Analysis (GSEA) and Ingenuity Pathway Analysis (IPA), differentially expressed genes altered by smoke reduction were mainly associated with glucocorticoid receptor signaling pathway. The integrative analysis of microRNA and mRNA found eleven differentially expressed microRNAs negatively correlated with predicted target genes. CD83 molecule regulated by miR-4498 in human PBMC, was critical for the canonical pathway of communication between innate and adaptive immune cells. Our data demonstrated that microRNAs could regulate immune responses in human PBMC after habitual smokers quit smoking and support the potential translational value of microRNAs in regulating disease-relevant gene expression caused by tobacco smoke.

Perfluoroalkyl acids (PFAAs) are a group of common chemicals that ubiquitously exist in wildlife and humans. Experimental data suggest that they may alter T-lymphocyte functioning in situ by preferentially enhancing the development of T-helper 2 (TH2)- and inhibiting TH1-lymphocyte development and might increase allergic inflammation, but few human studies have been conducted. To evaluate the association between serum PFAAs concentrations and T-lymphocyte-related immunological markers of asthma in children, and further to assess whether gender modified this association, 231 asthmatic children and 225 non-asthmatic control children from Northern Taiwan were recruited into the Genetic and Biomarker study for Childhood Asthma. Serum concentrations of ten PFAAs and levels of TH1 [interferon (IFN)-γ, interleukin (IL)-2] and TH2 (IL-4 and IL-5) cytokines were measured. The results showed that asthmatics had significantly higher serum PFAAs concentrations compared with the healthy controls. When stratified by gender, a greater number of significant associations between PFAAs and asthma outcomes were found in males than in females. Among males, adjusted odds ratios for asthma among those with the highest versus lowest quartile of PFAAs exposure ranged from 2.59 (95% CI: 1.14, 5.87) for the perfluorobutanesulfonate (PFBS) to 4.38 (95% CI: 2.02, 9.50) for perfluorooctanesulfonate (PFOS); and serum PFAAs were associated positively with TH2 cytokines and inversely with TH1 cytokines among male asthmatics. Among females, no significant associations between PFAAs and TH2 cytokines could be detected. In conclusion, increased serum PFAAs levels may promote TH cell dysregulation and alter the availability of key TH1 and TH2 cytokines, ultimately contributing to the development of asthma that may differentially impact males to a greater degree than females. These results have potential relevance in asthma prevention.

Background Atopic dermatitis (AD) is the single most common allergic disease in children. STAT6 has been noted as a hub molecule in IL-4 mediated response and AD pathogenesis. However, the association between STAT6 genetic variants and childhood AD has never been thoroughly examined. Objective We investigate the association between STAT6 genetic variants and childhood AD risk in Taiwanese population. Methods We used data from the Han Chinese in Beijing genome panel of International HapMap Project and the Taiwan Children Health Study cohort to investigate the association of STAT6 genetic variants and childhood AD risks. Four tagged SNPs were selected from HapMap database and rs324011 was most significantly associated with childhood AD. Subsequently, deep sequencing around rs324011 and unconditional/conditional logistic models were applied. Results rs324011 showed statistical significance for the occurrence of childhood AD (OR: 1.23; 95% CI: 1.01–1.51) and rs167769 showed borderline statistical significance (OR: 1.21; 95% CI: 0.99–1.49). Likelihood ratio tests revealed that haplotypes (rs167769/rs324011) were associated with childhood AD (global p = 0.0018). T alleles of two STAT6 intron2 SNPs, rs324011 and rs167769, increased STAT6 promoter activity significantly in luciferase reporter assay. Conclusion T allele of rs324011 in STAT6 would increase the risk of AD occurrence in children. Haplotypes of rs324011/rs167769 were also significantly associated with childhood AD in Taiwanese population.

Age-related hearing impairment (ARHI) is a complex neurodegenerative disorder caused by a combination of environmental and genetic factors. We have reported previously that obesity increases the risk for ARHI, and that plasma levels of adiponectin are associated with ARHI. In the present study, we further explored the role of adiponectin in the pathophysiology of ARHI by investigating the genotypes of ADIPOQ and ADIPOR1, the genes of adiponectin and its type 1 receptor, respectively. A total of 1682 volunteers were enrolled, and their audiological phenotypes were determined according to the z scores converted from their original frequency-specific hearing thresholds. A total of 9 tag-single nucleotide polymorphisms (tagSNPs) in ADIPOQ and 4 tagSNPs in ADIPOR1 were genotyped, and the genotypes were correlated to the audiological phenotypes under the assumption of various inheritance models. Significant associations were identified between certain ADIPOQ tagSNPs and z scores under dominant, codominant, or additive models, whereas no association was identified between ADIPOR1 tagSNPs and z scores. The associations between ADIPOQ tagSNPs and z scores appear to exist only in subjects with specific ADIPOR1 genotypes, indicating an interaction between adiponectin and AdipoR1. Measurement of plasma adiponectin in 736 subjects revealed that ADIPOQ genotypes might exert their effects on hearing levels via modulation of plasma adiponectin levels. Subsequently, we confirmed the expression of AdipoR1 in the inner ear of mice, and demonstrated antiapoptotic effects of adiponectin in cochlear explant cultures. These results provide insights into the physiological function and potential clinical implications of adiponectin against ARHI.

To assess how history and/or anatomical findings differ in diagnosing pediatric obstructive sleep apnea (OSA).Children aged 2-18 years were recruited and assessed for anatomical (ie, tonsil size, adenoid size, and obesity) and historical findings (ie, symptoms) using a standard sheet. History and anatomical findings, as well as those measures significantly correlated with OSA, were identified to establish the historical, anatomical, and the combined model. OSA was diagnosed by polysomnography. The effectiveness of those models in detecting OSA was analyzed by model fit, discrimination (C-index), calibration (Hosmer-Lemeshow test), and reclassification properties.A total of 222 children were enrolled. The anatomical model included tonsil hypertrophy, adenoid hypertrophy, and obesity, whereas the historical model included snoring frequency, snoring duration, awakening, and breathing pause. The C-index was 0.84 for the combined model, which significantly differed from that in the anatomical (0.78, p = 0.003) and historical models (0.72, p 0.001). The Hosmer-Lemeshow test revealed an adequate fit for all of the models. Additionally, the combined model more accurately reclassified 10.3% (p = 0.044) and 21.9% (p = 0.003) of all of the subjects than either the anatomical or historical model. Internal validation of the combined model by the bootstrapping method showed a fair model performance.Overall performance of combined anatomical and historical findings offers incremental utility in detecting OSA. Results of this study suggest integrating both history and anatomical findings for a screening scheme of pediatric OSA.

Perfluoroalkyl and polyfluoroalkyl substances (PFASs), as well as polymers of PFASs, have been widely used in commercial applications and have been detected in humans and the environment. Previous epidemiological studies have shown associations between particular PFAS chemicals and serum lipid concentrations in adults, particularly perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA). There exists, however, limited information concerning the effect of PFASs have on serum lipids among children. In the present cross-sectional study, 225 Taiwanese children (12-15 years of age) were recruited to determine the relationship between serum level PFASs and lipid concentration. Results showed that eight out of ten particular PFASs were detected in the serum of >94% of the participants. Serum PFOS and perfluorotetradecanoic acid (PFTA) levels were at an order of magnitude higher than the other PFASs, with arithmetical means of 32.4 and 30.7 ng/ml in boys and 34.2 and 27.4 ng/ml in girls, respectively. However, the variation in serum PFTA concentration was quite large. Following covariate adjustment, linear regression models revealed that PFOS, PFOA, and perfluorononanoic acid (PFNA) were positively associated with total cholesterol (TC), low-density lipoprotein (LDL) and triglycerides (TG), particularly for PFOS and PFTA. Quartile analysis, with the lowest exposure quartile as a reference, yielded associations between serum PFTA and elevations in TC (p=0.002) and LDL (p=0.004). Though not statistically significant, high-density lipoprotein (HDL) appeared to decrease linearly across quartiles for PFOS and PFOA exposure. In conclusion, a significant association was observed between serum PFASs and lipid level in Taiwanese children. These findings for PFTA are novel, and emphasize the need to investigate the exposure route and toxicological evidence of PFASs beyond PFOS and PFOA.

Background A limited number of studies have reported an association between long-term exposure to ambient air pollutants and lung function growth among children, with inconclusive results. Objectives To assess the relationship between air pollutant exposure and lung function growth, and to examine potential sex differences in the susceptibility of lung function growth to air pollution. Methods We conducted a two-year prospective cohort study of Taiwanese children aged 12 at baseline who were followed from October 1, 2007 to November 31, 2009. The study population comprised 2941 non-smoking children who completed pulmonary function tests at both baseline and follow-up surveys. We applied spatial modeling for individual-level exposure assessment to capture relevant exposures and also attempted to eliminate potential community-level confounding. The exposure parameters were annual averages and values calculated from 24-hourly PM 2.5 and 8-hourly ozone (O 3 ) concentrations, corresponding to the residential addresses over the study period. The effect estimates were presented as lung function growth deficits per interquartile range (IQR) for PM 2.5 and O 3 . Results In a multiple linear mixed effect model, adjusted for confounding, growth deficits in the forced vital capacity (FVC), forced expiration volume in 1 s (FEV 1 ), and forced expiratory flow between the 25th and 75th percentiles of the FVC were associated with increased exposure to PM 2.5 and O 3 . For example, greater exposure to PM 2.5 (IQR, 17.92 μg/m 3 ) was associated with an annual deficit in FVC growth of 75 mL in boys and 61 mL in girls ( p for interaction 3 . Conclusions The study provides evidence that long-term exposure to PM 2.5 and O 3 may have a detrimental effect on the development of lung function in children. The estimated deficits were generally larger in boys, compared to girls.

Background Air pollution influences the development of limb defects in animals. There is little epidemiologic evidence on the effect of prenatal air pollution exposure on the risk of limb defects. Objective To assess the relations between exposure to ambient air pollutants and the risk of limb defects. Methods We conducted a matched-pairs case-control study in Taiwan from 2001 through 2007. The case group consisted of 1687 limb defects and the control group was density-sampling matched one to ten based on the month and year of conception from 1510,064 live singleton newborns in 2001–2007. Adjusted conditional logistic regression models were used to estimate odds ratios per 10 ppb change for O3, NO2, 1 ppb change for SO2, 10 µg/m3 change for PM10, and 100 ppb change for CO during the first trimester and first three gestational months. Results Of the specific limb defects, reduction deformities of limbs (adjusted OR=1.024, 95% CI: 1.000, 1.048) was associated with a 1 ppb increase in SO2 during weeks of 9–12 of gestation as well as the first trimester. Reduction deformities of limbs was also associated with a 10 ppb increase in O3 during weeks of 1–4 of gestation (adjusted OR=1.391, 95% CI: 1.064, 1.818) among preterm births. Conclusion The present study provides evidence that exposure to outdoor air SO2 during the first trimester of pregnancy may increase the risk of limb defects. Exposure to O3 was associated with reduction deformities of limbs among preterm births. Similar levels of SO2 and O3 are encountered globally by large numbers of pregnant women.

Aims Obesity and early puberty have been reported to be mutually causative. We investigated the causal relationship between adiposity and early puberty by performing bidirectional Mendelian randomization (MR) and longitudinal data analyses. Methods We used information from the Taiwan Children Health Study (3109 adolescents aged 11–12 years) with 17 body mass index (BMI)- and 10 puberty-related single-nucleotide polymorphisms (SNPs) to produce genetic instrumental variables (IVs). The two-stage least squares (2SLS) method, MR sensitivity analysis, and survival analysis were used to explore and confirm causality. Results Regression estimates from IVs revealed that significantly increased association of BMI with early puberty was noted (coefficients: 0.13, 0.10, and 0.09; 95% CI: 0.07–0.19, 0.02–0.19, and 0.02–0.16 for all participants, male adolescents, and female adolescents, respectively). Genetic IVs for puberty were not associated with BMI. MR sensitivity and two-sample MR analyses produced similar results. Longitudinal analysis results revealed that prepubertal overweight and obesity could predict early onset of puberty. However, after excluding children with a history of overweight and obesity at the age of 7–12 years, early puberty was not found to trigger new-onset of overweight and obesity at the age of 18 years in either sex. Conclusions Higher adiposity may lead to early puberty. However, the causal effects of early puberty on adiposity accumulation were not supported by our data. Targeted interventions to reduce childhood obesity are strongly recommended to prevent obesity-related comorbidities, as well as early puberty onset.

The characteristics of the formation of conversion coatings on an AZ91D Mg alloy were detailed. Because the galvanic effect prevailed around the eutectic α + β, alkaline stannate conversion coatings nucleated first near the β phase where plenty Mg2+ were present. Conversely, the formation of cerium conversion coatings largely relied on an increase in the interfacial pH. Intense dissolution of the primary α phase in acid cerium nitrate solution caused hydrogen bubble evolution, which, in turn, resulted in blisters. It is evident that the galvanic corrosion routes on the AZ91D depend on the pH of the conversion coating solution.

Introduction Environmental tobacco smoke (ETS) is a hazardous component of indoor air, and may increase the risk of respiratory diseases, atherosclerosis and otitis media in children. In this study, we explored the relationship between time inside the house, ETS exposure and urinary cotinine level, and also determined the association of time inside the house on asthma phenotypes when children exposed to ETS. Methods A total of 222 asthmatic children and 205 non-asthmatic controls were recruited in the Genetic and Biomarker study for Childhood Asthma (GBCA). Structured questionnaires and time–location pattern questionnaires were administered by face-to-face interview. Urinary cotinine was measured by liquid chromatography tandem mass spectrometry (LC/MS/MS). The level of household ETS exposure was assessed using the cotinine/creatinine ratio (CCR). Results In general, urinary cotinine and CCR were higher in subjects exposed to household ETS than those who never had ETS at home. A significant positive relationship was found between average time inside the house and urinary CCR in asthmatic children with current ETS at home (β=0.278, p=0.02). After adjustment for age and gender, average time inside the house was positively related to severe wheeze in asthmatic children with household ETS within 1 month (OR: 1.26, 95%: 1.02–1.64). Conclusions Our study suggests that the major source of ETS exposure for children is due to longer period of exposures among children living with adult smokers at home. Home-smoking restrictions that effectively prevent children from being exposed to ETS would be worthwhile.

Objective The study investigates the association between area-level socioeconomic status (SES) and children's lung function. Methods Participants were 3994 seventh grade students from the Taiwan Children Health Study living in 14 communities in Taiwan and were recruited in 2007. Area-level SES predictors were population size, occupation type, income and education level. Hierarchical linear models (HLM) were used to examine the effects of area-level SES on lung function, after accounting for area air pollution and individual SES (parental education and family income). Results Areas with high income were independently associated with lower child lung function. The coefficients for log transformation of area tax per person in HLM were − 47.8 (95% confidence interval (CI): − 80.9, − 14.8) in FEV 1 , − 43.8 (95% CI: − 75.2, − 12.5) in FVC, − 93.4 (95% CI: − 179.3, − 7.5) in FEF 25-75 and − 203.2 (95% CI: − 349.1, − 57.2) in PEF. All SES predictors influenced in the same direction and affected males more. The interaction of area tax per person with parental educational level was significant on PEF, suggesting significant association of greater parental education with lower lung function in children. Conclusion High area SES was inversely associated with lung function in Taiwanese children.

We aim to explore the relationships between exposure to dampness, pets, and environmental tobacco smoke (ETS) early in life and asthma in Taiwanese children, and to discuss their links to early- and late-onset asthma. We conducted a 1:2 matched case-control study from the Taiwan Children Health Study, which was a nationwide study that recruited 12-to-14 year-old school children in 14 communities. The 579 mothers of the participants were interviewed by telephone about their children's environmental exposures before they were 5 years old, including the in-utero period. Childhood asthma was associated with exposure to early life environmental factors, such as cockroaches (OR=2.16; 95% CI, 1.15-4.07), visible mould (OR=1.75; 95% CI, 1.15-2.67), mildewy odors (OR=5.04; 95% CI, 2.42-10.50), carpet (OR=2.36; 95% CI, 1.38-4.05), pets (OR=2.11; 95% CI, 1.20-3.72), and more than one hour of ETS per day (OR=1.93; 95% CI, 1.16-3.23). The ORs for mildewy odors, feather pillows, and ETS during early childhood were greater among children with late-onset asthma. Cockroaches, carpet, pets, and in-utero exposures to ETS affected the timing of early-onset asthma. Exposure to these factors led to dose-responsiveness in the risk of asthma. And the earlier exposures may trigger the earlier onset. Interventions in avoiding these environmental exposures are necessary for early-prevention of childhood asthma.

Literature has shown adverse effects of ambient air pollution exposure on various asthma related outcomes in childhood. However, the associated evidence on pulmonary function effects is still inconsistent. We conducted a population-based study comprised of seventh-grade children in 14 Taiwanese communities. Pulmonary function tests and questionnaires were completed on 3957 subjects. We evaluated the effects of ambient air pollution exposures based on the data collected in 2005–2007 by existing air monitoring stations. Multiple linear mixed effect models were fitted to estimate the relationship between community pollutant levels and pulmonary function indices. After adjustment for individual-level confounders, pulmonary function differed only slightly between communities with different levels of air pollution. We found greater effects of ambient air pollutants on pulmonary function for boys than for girls. Among boys, traffic-related pollutants CO, NOx, NO 2 , and NO were generally associated with chronic adverse effects on FVC and FEV 1 , and subchronic adverse effects mainly on maximal mid-expiratory flow (MMEF) and peak expiratory flow rate. Among girls, only NOx and NO 2 showed subchronic adverse effects on MMEF. Although effect estimates of SO 2 , PM 10 , and PM 2.5 were generally negative for boys, none achieved statistical significance. Our data suggests that ambient traffic-related pollution had chronic adverse effects on pulmonary function in schoolchildren, especially for boys.

Background Epidemiologic studies indicate that exposure to air pollution caused by traffic may have an association with an increased risk of childhood asthma. Some studies report an association between the polymorphisms of the microsomal epoxide hydroxylase ( EPHX1 ) gene and enzyme activity. We investigated the associations of EPHX1 Tyr113His and His139Arg polymorphisms with asthma and wheezing outcomes, and focused on the functional genetic change in different ambient nitrogen dioxide (NO 2 ) levels on glutathione S-transferase p1 ( GSTP1 ) and glutathione S-transferase m1 ( GSTM1 ) genotypes. Methods A total of 3,741 children were enrolled in the Taiwan Children Health Study from 14 communities. We examined the associations of EPHX1 Tyr113His and His139Arg genotypes and diplotypes with asthma and wheezing outcomes under different ambient NO 2 exposures. Results Children with the EPHX1 Arg/His or Arg/Arg genotypes at codon 139 were significantly associated with increased risks of lifetime asthma (adjusted OR [aOR] = 1.3; 95% CI, 1.1-1.7; and aOR=1.5; 95% CI, 1.1-2.1, respectively). The EPHX1 diplotypes showed significant associations with lifetime asthma (global P value=.01) and early-onset asthma (global P value=.01). The risk of EPHX1 139Arg allele and 113Tyr-139Arg diplotype were of greater magnitude in higher compared with lower NO 2 communities. The increase of the effect from the EPHX1 139Arg allele with higher NO 2 exposure was most marked in the GSTP1 Val allele and GSTM1 present genotype. Conclusions Children with high EPHX1 activity may have increase risk of asthma and wheezing outcomes, and can be mediated through airway oxidative stress generation.