Kuan-Yen Tung

Serum polyfluoroalkyl concentrations, asthma outcomes, and immunological markers in a case-control study of Taiwanese children.

Background: Perfluorinated compounds (PFCs) are ubiquitous pollutants. Experimental data suggest that they may be associated with adverse health outcomes, including asthma. However, there is little supporting epidemiological evidence. Methods: A total of 231 asthmatic children and 225 nonasthmatic controls, all from northern Taiwan, were recruited in the Genetic and Biomarkers study for Childhood Asthma. Structure questionnaires were administered by face-to-face interview. Serum concentrations of 11 PFCs and levels of immunological markers were also measured. Associations of PFC quartiles with concentrations of immunological markers and asthma outcomes were estimated using multivariable regression models. Results: Nine PFCs were detectable in most children (≥ 84.4%), of which perfluorooctane sulfonate (PFOS) was the most abundant (median serum concentrations of 33.9 ng/mL in asthmatics and 28.9 ng/mL in controls). Adjusted odds ratios for asthma among those with the highest versus lowest quartile of PFC exposure ranged from 1.81 (95% CI: 1.02, 3.23) for the perfluorododecanoic acid (PFDoA) to 4.05 (95% CI: 2.21, 7.42) for perfluorooctanic acid (PFOA). PFOS, PFOA, and subsets of the other PFCs were positively associated with serum IgE concentrations, absolute eosinophil counts (AEC), eosinophilic cationic protein (ECP) concentrations, and asthma severity scores among asthmatics. Conclusions: This study suggests an association between PFC exposure and juvenile asthma. Because of widespread exposure to these chemicals, these findings may be of potential public health concern.

Gene-gene and gene-environmental interactions of childhood asthma: a multifactor dimension reduction approach.

Background The importance of gene-gene and gene-environment interactions on asthma is well documented in literature, but a systematic analysis on the interaction between various genetic and environmental factors is still lacking. Methodology/Principal Findings We conducted a population-based, case-control study comprised of seventh-grade children from 14 Taiwanese communities. A total of 235 asthmatic cases and 1,310 non-asthmatic controls were selected for DNA collection and genotyping. We examined the gene-gene and gene-environment interactions between 17 single-nucleotide polymorphisms in antioxidative, inflammatory and obesity-related genes, and childhood asthma. Environmental exposures and disease status were obtained from parental questionnaires. The model-free and non-parametrical multifactor dimensionality reduction (MDR) method was used for the analysis. A three-way gene-gene interaction was elucidated between the gene coding glutathione S-transferase P (GSTP1), the gene coding interleukin-4 receptor alpha chain (IL4Ra) and the gene coding insulin induced gene 2 (INSIG2) on the risk of lifetime asthma. The testing-balanced accuracy on asthma was 57.83% with a cross-validation consistency of 10 out of 10. The interaction of preterm birth and indoor dampness had the highest training-balanced accuracy at 59.09%. Indoor dampness also interacted with many genes, including IL13, beta-2 adrenergic receptor (ADRB2), signal transducer and activator of transcription 6 (STAT6). We also used likelihood ratio tests for interaction and chi-square tests to validate our results and all tests showed statistical significance. Conclusions/Significance The results of this study suggest that GSTP1, INSIG2 and IL4Ra may influence the lifetime asthma susceptibility through gene-gene interactions in schoolchildren. Home dampness combined with each one of the genes STAT6, IL13 and ADRB2 could raise the asthma risk.

Glutathione S-transferase, incense burning and asthma in children.

Incense burning is a popular practice in many family homes and temples. However, little is known about the effects of indoor incense burning and genetic polymorphisms on asthma. This study evaluated the effects of indoor incense burning and glutathione S-transferase (GST) genetic polymorphisms on asthma and wheeze. In 2007, 3,764 seventh-grade schoolchildren (mean±sd age 12.42±0.65 yrs) were evaluated using a standard questionnaire for information about respiratory symptoms and environmental exposures. Multiple logistic regressions were performed to assess the association between GST polymorphisms and incense burning frequency on asthma and wheeze, after adjusting for potential confounders. The frequency of incense burning at home was associated with increased risk of current asthma (p = 0.05), medication use (p = 0.03) and exercise wheeze (p = 0.001). GST&thgr;1 (GSTT1) null genotypes were associated with current asthma (OR 1.43, 95% CI 1.00–2.04) and medication use (OR 1.46, 95% CI 1.01–2.22). GSTT1 showed a significant interactive effect with incense burning on current asthma, current wheeze and nocturnal wheeze. The frequency of incense burning was associated with increased risk of current asthma, medication use, lifetime wheeze, nocturnal wheeze and exercise wheeze in an exposure–response manner among children with GSTT1 null genotype (p<0.05). Incense burning is a risk factor for asthma and wheezing, especially in GSTT1 genetically susceptible children.

Microsomal Epoxide Hydroxylase Genotypes/Diplotypes, Traffic Air Pollution, and Childhood Asthma

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 (NO₂) 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 NO₂ 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 NO₂ communities. The increase of the effect from the EPHX1 139Arg allele with higher NO₂ 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.

GSTP1 is a hub gene for gene–air pollution interactions on childhood asthma

There is growing evidence that multiple genes and air pollutants are associated with asthma. By identifying the effect of air pollution on the general population, the effects of air pollution on childhood asthma can be better understood. We conducted the Taiwan Children Health Study (TCHS) to investigate the influence of gene–air pollution interactions on childhood asthma. Complete monitoring data for the ambient air pollutants were collected from Taiwan Environmental Protection Agency air monitoring stations. Our results show a significant two‐way gene–air pollution interaction between glutathione S‐transferase P (GSTP1) and PM10 on the risk of childhood asthma. Interactions between GSTP1 and different types of air pollutants have a higher information gain than other gene–air pollutant combinations. Our study suggests that interaction between GSTP1 and PM10 is the most influential gene–air pollution interaction model on childhood asthma. The different types of air pollution combined with the GSTP1 gene may alter the susceptibility to childhood asthma. It implies that GSTP1 is an important hub gene in the anti‐oxidative pathway that buffers the harmful effects of air pollution.

Fine Particle, Ozone Exposure, and Asthma/Wheezing: Effect Modification by Glutathione S-transferase P1 Polymorphisms

Background There are limited studies on the role of interaction between exposure to ambient air pollution and glutathione-S-transferase (GST) P1 on the risk of asthma/wheezing among children, which provided suggestive, but inconclusive results. Methods To assess the joint effect of air pollutants and GSTP1 on asthma/wheezing, we conducted a nationwide cross-sectional study of 3,825 children in Taiwan Children Health Study. The studied determinants were three GSTP1 Ile105Val (rs 1695) genotypes (Ile-Ile; Ile-Val and Val-Val) and expoure to ambient air pollutants. We used routine air-pollution monitoring data for ozone (O3) and particles with an aerodynamic diameter of 2.5 µm or less (PM2.5). The effect estimates were presented as odds ratios (ORs) per interquartile changes for PM2.5 and O3. Findings In a two-stage hierarchical model adjusting for confounding, the risk of asthma was negatively associated with PM2.5 (adjusted odds ratio (OR) 0.60; 95% confidence interval (CI) 0.45, 0.82) and O3 (OR 0.74; 95% CI 0.60, 0.90) among Ile105 homozygotes, but positively associated with PM2.5 (OR 1.52; 95% CI 1.01, 2.27) and O3 (OR 1.19; 95% CI 0.91, 1.57) among those with at least one val105 allele (interaction p value = 0.001 and 0.03, respectively). A similar tendency of effect modification between PM2.5 and O3 and GSTP1 on wheezing was found. Conclusion Children who carried Ile105 variant allele and exposed to PM2.5 and O3 may be less likely to occurrence of asthma/wheezing.

Tumour necrosis factor G-308A polymorphism modifies the effect of home dampness on childhood asthma

Objectives Environmental exposure at home, such as dampness, has been shown to have adverse effects on respiratory health. However, few studies explored the association between home dampness and genetic polymorphisms on childhood asthma. The aim of the study is to evaluate the effects of home dampness and tumour necrosis factor-α gene (TNF-α) on asthma in Taiwanese children. Methods The authors investigated 3810 schoolchildren in Taiwan Children Health Study from 14 communities. Childrens exposure and disease status were measured from a parental questionnaire. Multiple logistic regression models were fitted to estimate the effects of home dampness exposure and TNF-α genotypes on the prevalence of asthma and wheeze. Results Mildewy odour at home was significantly associated with increased prevalence of lifetime wheeze (OR=1.36, 95% CI 1.05 to 1.77, p for trend=0.04). The effects of water stamp on the wall at home were associated with lifetime asthma and lifetime wheeze. Children with water stamp on the wall at home and TNF-308 A allele had increased risks on lifetime asthma, active asthma and lifetime wheeze. TNF-α showed significant interactive effects with mildewy odour on lifetime asthma (p for interaction=0.01), and with water stamp on the wall at home on lifetime wheeze (p for interaction=0.04). Under stratification by TNF-308 genotypes, we found that the frequency of water stamp on the wall was associated with increased risks of all asthma subcategories and lifetime wheeze among TNF-308 GA or AA genotypes (p for trend<0.05). Conclusions Home dampness is a risk factor for asthma and wheeze among children, especially for those with the TNF-308 A allele.

Interleukin-13 Genetic Variants, Household Carpet Use and Childhood Asthma

Interleukin (IL)-13 genetic polymorphisms have shown adverse effects on respiratory health. However, few studies have explored the interactive effects between IL-13 haplotypes and environmental exposures on childhood asthma. The aims of our study are to evaluate the effects of IL-13 genetic variants on asthma phenotypes, and explore the potential interaction between IL-13 and household environmental exposures among Taiwanese children. We investigated 3,577 children in the Taiwan Children Health Study from 14 Taiwanese communities. Data regarding childrens exposure and disease status were obtained from parents using a structured questionnaire. Four SNPs were tagged accounting for 100% of the variations in IL-13. Multiple logistic regression models with false-discovery rate (FDR) adjustments were fitted to estimate the effects of IL-13 variants on asthma phenotypes. SNP rs1800925, SNP rs20541 and SNP rs848 were significantly associated with increased risks on childhood wheeze with FDR of 0.03, 0.04 and 0.04, respectively. Children carrying two copies of h1011 haplotype showed increased susceptibility to wheeze. Compared to those without carpet use and h1011 haplotype, children carrying h1011 haplotype and using carpet at home had significantly synergistic risks of wheeze (OR, 2.5; 95% CI, 1.4–4.4; p for interaction, 0.01) and late-onset asthma (OR, 4.7; 95% CI, 2.0–10.9; p for interaction, 0.02). In conclusions, IL-13 genetic variants showed significant adverse effects on asthma phenotypes among children. The results also suggested that asthma pathogenesis might be mediated by household carpet use.

Association of time-location patterns with urinary cotinine among asthmatic children under household environmental tobacco smoke exposure.

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.

Home dampness, beta-2 adrenergic receptor genetic polymorphisms, and asthma phenotypes in children

BACKGROUND Dampness in the home is a strong risk factor for respiratory symptoms and constitutes a significant public health issue in subtropical areas. However, little is known about the effects of dampness and genetic polymorphisms on asthma. METHODS In 2007, 6078 schoolchildren were evaluated using a standard questionnaire with regard to information about respiratory symptoms and environmental exposure. Multiple logistic regression analyses were performed to assess the effects of home dampness and beta-2-adrenergic receptor (ADRB2) gene polymorphisms on the prevalence of asthma and selected indicators of severity of asthma. RESULTS The frequency of mildewy odor, the number of walls with water stamp, and the duration of water damage were all associated with being awakened at night due to wheezing. However, no other clear-cut associations were found for any of the other indicators of asthma. Children exposed to mildewy odor with ADRB2 Arg/Arg genotype were associated with being awakened at night due to wheezing (OR=1.95, 95% CI, 1.14-3.36), compared to those without exposure and with the ADRB2 Gly allele. ADRB2 Arg16Gly showed a significant interactive effect with home dampness on being awakened at night due to wheezing and current wheezing, but no significant effect on active asthma and medication use. Frequency and degree of home dampness were also associated with the prevalence of asthma and selected indicators of severity of asthma, in an exposure-response manner among children with ADRB2 Arg/Arg genotype. CONCLUSIONS Home dampness prevention is one of the important steps of asthma control, especially in children carrying ADRB2 Arg/Arg genotypes.