CC16 polymorphisms in asthma, asthma subtypes, and asthma control in adults from the Agricultural Lung Health Study.

BACKGROUND: The club cell secretory protein (CC16) has anti-inflammatory and antioxidant effects and is a potential early biomarker of lung damage. The CC16 single nucleotide polymorphism (SNP) rs3741240 risk allele (A) has been inconsistently linked to asthma; other tagging SNPs in the gene have not been explored. The aim was to determine whether CC16 tagging polymorphisms are associated with adult asthma, asthma subtypes or asthma control in the Agricultural Lung Health Study (ALHS). METHODS: The ALHS is an asthma case-control study nested in the Agricultural Health Study cohort. Asthma cases were individuals with current doctor diagnosed asthma, likely undiagnosed asthma, or asthma-COPD overlap defined by questionnaire. We also examined asthma subtypes and asthma control. Five CC16 tagging SNPs were imputed to 1000 Genomes Integrated phase 1 reference panel. Logistic regression was used to estimate associations between CC16 SNPs and asthma outcomes adjusted for covariates. RESULTS: The sample included 1120 asthma cases and 1926 controls of European ancestry, with a mean age of 63 years. The frequency of the risk genotype (AA) for rs3741240 was 12.5% (n = 382). CC16 rs3741240 was not associated with adult asthma outcomes. A tagging SNP in the CC16 gene, rs12270961 was associated with uncontrolled asthma (n = 208, ORadj= 1.4, 95% CI 1.0, 1.9; p = 0.03). CONCLUSION: This study, the largest study to investigate associations between CC16 tagging SNPs and asthma phenotypes in adults, did not confirm an association of rs3741240 with adult asthma. A tagging SNP in CC16 suggests a potential relationship with asthma control.

DNA methylation signature of smoking in lung cancer is enriched for exposure signatures in newborn and adult blood.

Smoking impacts DNA methylation genome-wide in blood of newborns from maternal smoking during pregnancy and adults from personal smoking. We compared smoking-related DNA methylation in lung adenocarcinoma (61 never smokers, 91 current smokers, and 238 former smokers) quantified with the Illumina450k BeadArray in The Cancer Genome Atlas with published large consortium meta-analyses of newborn and adult blood. We assessed whether CpG sites related to smoking in blood from newborns and adults were enriched in the lung adenocarcinoma methylation signal. Testing CpGs differentially methylated by smoke exposure, we identified 296 in lung adenocarcinoma meeting a P < 10-4 cutoff, while previous meta-analyses identified 3,042 in newborn blood, and 8,898 in adult blood meeting the same P < 10-4 cutoff. Lung signals were highly enriched for those seen in newborn (24 overlapping CpGs, Penrichment = 1.2 × 10-18) and adult blood (66 overlapping CpGs, Penrichment = 1.2 × 10-48). The 105 genes annotated to CpGs differentially methylated in lung tumors, but not blood, were enriched for RNA processing ontologies. Some epigenetic alterations associated with cigarette smoke exposure are tissue specific, but others are common across tissues. These findings support the value of blood-based methylation biomarkers for assessing exposure effects in target tissues.

Maternal levels of perfluoroalkyl substances (PFASs) during pregnancy and childhood allergy and asthma related outcomes and infections in the Norwegian Mother and Child (MoBa) cohort.

INTRODUCTION: Prenatal exposure to perfluoroalkyl substances (PFASs) has been inconsistently associated with asthma and allergic diseases and increased number of infections in early childhood. We examined the association of PFASs measured in pregnancy with childhood asthma, allergies and common infectious diseases in a prospective pregnancy cohort followed to age 7 years. MATERIAL AND METHODS: Six PFASs (out of 19 measured) with at least 80% of measurements above the limit of quantification (LOQ) in maternal plasma during pregnancy in two subcohorts of the Norwegian Mother and Child Cohort Study (MoBa) were analyzed in relation to health outcomes: perfluorooctane sulfonic acid (PFOS), acid (PFOA), perfluorohexane sulfonic acid (PFHxS), perfluorononanoic acid (PFNA), perfluoroundecanoic acid (PFUnDA), and perfluoroheptane sulfonic acid (PFHpS). Follow-up questionnaires were completed at 3 years by 1270 women and at 7 years by 972 women among the 1943 with pregnancy questionnaire and PFAS measures. Health outcomes included parent reports of child's symptoms or doctor diagnosed asthma and allergic conditions at age 7 years and parent-reported frequency of various infections at 3 and 7 years of age. Logistic and Poisson regression were used. The false discovery rate was controlled at 5%. Sensitivity analyses on gender were performed. RESULTS: Among the allergy and asthma outcomes, a statistically significant inverse association was seen between PFUnDA concentrations and ever having atopic eczema in girls. PFUnDA also tended to be inversely associated with both wheeze and asthma. For infections from 0 to 3 and 6 to 7 years, 11 significant positive associations were seen between PFASs and airways infections (bronchitis/pneumonia, throat infection, pseudocroup), ear infection and gastric flu/diarrhea; whereas 6 inverse associations were seen for pseudocroup, ear infections and urinary tract infections. The majority of the findings with respect to infectious diseases were found in girls only. DISCUSSION: With the exception of an inverse association between PFUnDA and eczema, and a tendency of a similar association for wheeze and asthma, maternal PFAS levels during pregnancy showed little association with asthma or allergy related outcomes. Findings from the present study suggest immunosuppressive effects of PFASs on airways infections, such as bronchitis/pneumonia and throat infections, as well as diarrhea/gastric flu. Our results indicate a possible role of gender in the PFAS-health outcome associations.

Prediction of gestational age based on genome-wide differentially methylated regions.

BACKGROUND: We explored the association between gestational age and cord blood DNA methylation at birth and whether DNA methylation could be effective in predicting gestational age due to limitations with the presently used methods. We used data from the Norwegian Mother and Child Birth Cohort study (MoBa) with Illumina HumanMethylation450 data measured for 1753 newborns in two batches: MoBa 1, n = 1068; and MoBa 2, n = 685. Gestational age was computed using both ultrasound and the last menstrual period. We evaluated associations between DNA methylation and gestational age and developed a statistical model for predicting gestational age using MoBa 1 for training and MoBa 2 for predictions. The prediction model was additionally used to compare ultrasound and last menstrual period-based gestational age predictions. Furthermore, both CpGs and associated genes detected in the training models were compared to those detected in a published prediction model for chronological age. RESULTS: There were 5474 CpGs associated with ultrasound gestational age after adjustment for a set of covariates, including estimated cell type proportions, and Bonferroni-correction for multiple testing. Our model predicted ultrasound gestational age more accurately than it predicted last menstrual period gestational age. CONCLUSIONS: DNA methylation at birth appears to be a good predictor of gestational age. Ultrasound gestational age is more strongly associated with methylation than last menstrual period gestational age. The CpGs linked with our gestational age prediction model, and their associated genes, differed substantially from the corresponding CpGs and genes associated with a chronological age prediction model.

Lung function, respiratory symptoms and venous thromboembolism risk: the Atherosclerosis Risk in Communities Study.

Essentials The association of lung function with venous thromboembolism (VTE) is unclear. Chronic obstructive pulmonary disease (COPD) patterns were associated with a higher risk of VTE. Symptoms were also associated with a higher risk of VTE, but a restrictive pattern was not. COPD may increase the risk of VTE and respiratory symptoms may be a novel risk marker for VTE. SUMMARY: Background The evidence for the association between chronic obstructive pulmonary disease (COPD) and venous thromboembolism (VTE) is limited. There is no study investigating the association between restrictive lung disease (RLD) and respiratory symptoms with VTE. Objectives To investigate prospectively the association of lung function and respiratory symptoms with VTE. Patients/Methods In 1987-1989, we assessed lung function by using spirometry, and obtained information on respiratory symptoms (cough, phlegm, and dyspnea) in 14 654 participants aged 45-64 years, without a history of VTE or anticoagulant use, and followed them through 2011. Participants were classified into four mutually exclusive groups: 'COPD' (forced expiratory volume in 1 s [FEV1 ]/forced vital capacity [FVC] below the lower limit of normal [LLN]), 'RLD' (FEV1 /FVC ≥ LLN and FVC < LLN), 'respiratory symptoms with normal spirometic results' (without RLD or COPD), and 'normal' (without respiratory symptoms, RLD, or COPD). Results We documented 639 VTEs (238 unprovoked and 401 provoked VTEs). After adjustment for VTE risk factors, VTE risk was increased for individuals with either respiratory symptoms with normal spirometric results (hazard ratio [HR] 1.40, 95% confidence interval [CI] 1.12-1.73) or COPD (HR 1.33, 95% CI 1.07-1.67) but not for those with RLD (HR 1.15, 95% CI 0.82-1.60). These elevated risks of VTE were derived from both unprovoked and provoked VTE. Moreover, FEV1 and FEV1 /FVC showed dose-response relationships with VTE. COPD was more strongly associated with pulmonary embolism than with deep vein thrombosis. Conclusions Obstructive spirometric patterns were associated with an increased risk of VTE, suggesting that COPD may increase the risk of VTE. Respiratory symptoms may represent a novel risk marker for VTE.

25-Hydroxyvitamin D in pregnancy and genome wide cord blood DNA methylation in two pregnancy cohorts (MoBa and ALSPAC).

The aim of the study was to investigate whether maternal mid-pregnancy 25-hydroxyvitamin D concentrations are associated with cord blood DNA methylation. DNA methylation was assessed using the Illumina HumanMethylation450 BeadChip, and maternal plasma 25-hydroxyvitamin D was measured in 819 mothers/newborn pairs participating in the Norwegian Mother and Child Cohort (MoBa) and 597 mothers/newborn pairs participating in the Avon Longitudinal Study of Parents and Children (ALSPAC). Across 473,731CpG DNA methylation sites in cord blood DNA, none were strongly associated with maternal 25-hydroxyvitamin D after adjusting for multiple tests (false discovery rate (FDR)>0.5; 473,731 tests). A meta-analysis of the results from both cohorts, using the Fisher method for combining p-values, also did not strengthen findings (FDR>0.2). Further exploration of a set of CpG sites in the proximity of four a priori defined candidate genes (CYP24A1, CYP27B1, CYP27A1 and CYP2R1) did not result in any associations with FDR<0.05 (56 tests). In this large genome wide assessment of the potential influence of maternal vitamin D status on DNA methylation, we did not find any convincing associations in 1416 newborns. If true associations do exist, their identification might require much larger consortium studies, expanded genomic coverage, investigation of alternative cell types or measurements of 25-hydroxyvitamin D at different gestational time points.

Gender difference in interactions between MAOA promoter uVNTR polymorphism and negative familial stressors on body mass index among Chinese adolescents.

OBJECTIVES: Monoamine oxidase A (MAOA) modulates metabolism of serotonin and dopamine metabolism, neurotransmitters involved in regulation of appetite and food intake. The gene coding for MAOA contains a 30-bp tandem repeat (uVNTR) polymorphism in its promoter region that has been previously identified to be associated with obesity with mixed findings in the literature. Our goals were to replicate the population effects of this functional polymorphism on obesity risk, and to further explore gender differences and interaction effects with negative stressors. METHODS: Analyses were conducted with data on genotypes, measured weight and height, and self-reported behavioural characteristics among 1101 Chinese adolescents 11-15 years old living in Wuhan, China. RESULTS: Girls with the high-activity allele had significantly lower body mass index (BMI; ß = -0.25 ± 0.98, P = 0.011) compared to those with the low activity allele. Experience of negative familial stressors (e.g., death or illness of family members, hit or scolded by parents and increased quarrelling with parents, parents argued frequently) significantly weakened this protective genetic effect on BMI (P for interaction = 0.043). Stratified analyses showed a significant protective genetic effect on BMI only within the stratum of low stress level (ß = -0.44 ± 0.14, P = 0.002). No similar effect was observed among boys. CONCLUSIONS: Our findings confirm the genetic effects of MAOA uVNTR polymorphism on BMI in a Chinese adolescent population and suggest potential genetic interactions with negative familial stressors.

Food allergens in mattress dust in Norwegian homes - a potentially important source of allergen exposure.

BACKGROUND: Sensitization to food allergens and food allergic reactions are mostly caused by ingesting the allergen, but can also occur from exposure via the respiratory tract or the skin. Little is known about exposure to food allergens in the home environment. OBJECTIVE: The objective of this study was firstly to describe the frequency of detection of allergens from fish, egg, milk, and peanut in mattress dust collected from homes of 13-year-old adolescents and secondly to identify home characteristics associated with the presence of food allergen contamination in dust. METHODS: Food allergens were measured by dot blot analysis in mattress dust from 143 homes in Oslo, Norway. We analysed associations between home characteristics (collected by parental questionnaires and study technicians) and food allergens by multivariate regression models. RESULTS: Fish allergen was detected in 46%, peanut in 41%, milk in 39%, and egg allergen in 22% of the mattress dust samples; only three samples contained none of these allergens. All four food allergens were more frequently detected in mattresses in small dwellings (< 100 m(2)) than larger dwellings (≥ 130 m(2)); 63-71% of the small dwellings (n = 24) had milk, peanut, and fish allergens in the samples compared with 33-44% of the larger dwellings (n = 95). Milk, peanut, and egg allergens were more frequently detected in homes with bedroom and kitchen on the same floor as compared with different floors, with odds ratios of 2.5 (95% confidence interval (CI): 1.1, 5.6) for milk, 2.4 (95% CI: 1.0, 6.1) for peanut, and 3.1 (95% CI: 1.3, 7.5) for egg allergens. CONCLUSIONS AND CLINICAL RELEVANCE: Food allergens occurred frequently in beds in Norwegian homes, with dwelling size and proximity of kitchen and bedroom as the most important determinants. Due to the amount of time children spent in the bedroom, mattress dust may be an important source of exposure to food allergens.

Adhesion molecules, endothelin-1 and lung function in seven population-based cohorts.

CONTEXT: Endothelial function is abnormal in chronic obstructive pulmonary disease (COPD); whether endothelial dysfunction causes COPD is unknown. OBJECTIVE: Test associations of endothelial biomarkers with FEV1 using instrumental variables. METHODS: Among 26 907 participants with spirometry, ICAM-1, P-selectin, E-selectin and endothelin-1 were measured in subsets. RESULTS: ICAM-1 and P-selectin were inversely associated with FEV1 among European-Americans (-29 mL and -34 mL per standard deviation of log-transformed biomarker, p < 0.001), as was endothelin-1 among African-Americans (-22 mL, p = 0.008). Genetically-estimated ICAM-1 and P-selectin were not significantly associated with FEV1. The instrumental variable for endothelin-1 was non-informative. CONCLUSION: Although ICAM-1, P-selectin and endothelin-1 were inversely associated with FEV1, associations for ICAM-1 and P-selectin do not appear causal.

Triclosan exposure and allergic sensitization in Norwegian children.

BACKGROUND: Exposure to the synthetic antimicrobial chemical, triclosan, used in personal care products, has been hypothesized to lead to allergic disease. We investigated whether triclosan exposure was associated with allergic sensitization and symptoms in 10-year-old Norwegian children. METHODS: Urinary concentrations of triclosan were measured in one first morning void from 623 children, collected during 2001-2004. Logistic regression models, controlling for urine specific gravity, parental allergic disease, maternal education, and household income, were fitted for allergic sensitization (either skin prick test positivity or serum-specific IgE ≥ 0.35 kU/l to at least one of 15 evaluated inhalant and food allergens), current rhinitis, and current asthma (questionnaire and exercise challenge test). RESULTS: The adjusted odds ratio (aOR) for allergic sensitization among those in the fourth quartile of triclosan concentration was 2.0 [95% confidence interval (CI): 1.1, 3.4] compared with the reference group (

Traffic exposure and incident venous thromboembolism in the Atherosclerosis Risk in Communities (ARIC) Study.

BACKGROUND: Two recent case-control studies in Italy reported that long-term exposure to particulate air pollution or living near major traffic roads was associated with an increased risk of deep vein thrombosis (DVT). No prospective evidence exists on the possible association between long-term traffic-related air pollution and incident venous thromboembolism (VTE). OBJECTIVES: To examine the association between long-term traffic exposure and incident VTE in a population-based prospective cohort study. METHODS: We studied 13,143 middle-aged men and women in the Atherosclerosis Risk in Communities Study without a history of DVT or pulmonary embolism at baseline examination (1987-1989). The Geographical Information System-mapped traffic density and distance to major roads in the four study communities served as measures of traffic exposure. We examined the association between traffic exposure and incident VTE with proportional hazards regression models. RESULTS: A total of 405 subjects developed VTE in 2005. Traffic density was not significantly associated with VTE. Relative to those in the lowest quartile of traffic density, the adjusted hazard ratios across increasing quartiles were 1.18 (95% confidence interval [CI] 0.88-1.57), 0.99 (95% CI 0.74-1.34) and 1.14 (95% CI 0.86-1.51) (P-value for trend across quartiles = 0.64). For residents living within 150 m of major roads, as compared with subjects living further away, the adjusted hazard ratio was 1.16 (95% CI 0.95-1.42, P = 0.14). CONCLUSIONS: This first prospective study in the general population does not support an association between air pollution exposure or traffic proximity and risk of DVT. More data may be needed to clarify whether traffic or air pollution influences the risk of VTE.

Part 5. Public health and air pollution in Asia (PAPA): a combined analysis of four studies of air pollution and mortality.

BACKGROUND: In recent years, Asia has experienced rapid economic growth and a deteriorating environment caused by the increasing use of fossil fuels. Although the deleterious effects of air pollution from fossil-fuel combustion have been demonstrated in many Western nations, few comparable studies have been conducted in Asia. Time-series studies of daily mortality in Asian cities can contribute important new information to the existing body of knowledge about air pollution and health. Not only can these studies verify important health effects of air pollution in local regions in Asia, they can also help determine the relevance of existing air pollution studies to mortality and morbidity for policymaking and environmental controls. In addition, the studies can help identify factors that might modify associations between air pollution and health effects in various populations and environmental conditions. Collaborative multicity studies in Asia-especially when designed, conducted, and analyzed using a common protocol-will provide more robust air pollution effect estimates for the region as well as relevant, supportable estimates of local adverse health effects needed by environmental and public-health policymakers. SPECIFIC OBJECTIVES: The Public Health and Air Pollution in Asia (PAPA*) project, sponsored by the Health Effects Institute, consisted of four studies designed to assess the effects of air pollution on mortality in four large Asian cities, namely Bangkok, in Thailand, and Hong Kong, Shanghai, and Wuhan, in China. In the PAPA project, a Common Protocol was developed based on methods developed and tested in NMMAPS, APHEA, and time-series studies in the literature to help ensure that the four studies could be compared with each other and with previous studies by following an established protocol. The Common Protocol (found at the end of this volume) is a set of prescriptive instructions developed for the studies and used by the investigators in each city. It is flexible enough to allow for adjustments in methods to optimize the fit of health-effects models to each city's data set. It provides the basis for generating reproducible results in each city and for meta-estimates from combined data. By establishing a common methodology, factors that might influence the differences in results from previous studies can more easily be explored. Administrative support was provided to ensure that the highest quality data were used in the analysis. It is anticipated that the PAPA results will contribute to the international scientific discussion of how to conduct and interpret time-series studies of air pollution and will stimulate the development of high-quality routine systems for recording daily deaths and hospital admissions for time-series analysis. METHODS: Mortality data were retrieved from routine databases with underlying causes of death coded using the World Health Organization (WHO) International Classification of Diseases, 9th revision or 10th revision (ICD-9, ICD-10). Air quality measurements included nitrogen dioxide (NO2), sulfur dioxide (SO2), particulate matter with aerodynamic diameter < or = 10 microm (PM10), and ozone (O3) and were obtained from several fixed-site air monitoring stations that were located throughout the metropolitan areas of the four cities and that met the standards of procedures for quality assurance and quality control carried out by local government units in each city. Using the Common Protocol, an optimized core model was established for each city to assess the effects of each of the four air pollutants on daily mortality using generalized linear modeling with adjustments for time trend, seasonality, and other time-varying covariates by means of a natural-spline smoothing function. The models were adjusted to suit local situations by correcting for influenza activity, autocorrelation, and special weather conditions. Researchers in Hong Kong, for example, used influenza activity based on frequency of respiratory mortality; researchers in Hong Kong and Shanghai used autoregressive terms for daily outcomes at lag days; and researchers in Wuhan used additional smoothing for periods with extreme weather conditions. RESULTS AND DISCUSSION: For mortality due to all natural (nonaccidental) causes at all ages, the effects of air pollutants per 10-microg/m3 increase in concentration was found to be higher in Bangkok than in the three Chinese cities, with the exception of the effect of NO2 in Wuhan. The magnitude of the effects for cardiovascular and respiratory mortality were generally higher than for all natural mortality at all ages. In addition, the effects associated with PM10 and O3 in all natural, cardiovascular; and respiratory mortality were found to be higher in Bangkok than in the three Chinese cities. The explanation for these three findings might be related to consistently higher daily mean temperatures in Bangkok, variations in average time spent outdoors by the susceptible populations, and the fact that less air conditioning is available and used in Bangkok than in the other cities. However, when pollutant concentrations were incorporated into the excess risk estimates through the use of interquartile range (IQR), the excess risk was more comparable across the four cities. We found that the increases in effects among older age groups were greater in Bangkok than in the other three cities. After excluding data on extremely high concentrations of PM10 in Bangkok, the effect estimate associated with PM10 concentrations decreased in Bangkok (suggesting a convex relationship between risk and PM10, where risk levels off at high concentrations) instead of increasing, as it did in the other cities. This leveling off of effect estimates at high concentrations might be related to differences in vulnerability and exposure of the population to air pollution as well as to the sources of the air pollutant. IMPLICATIONS OF THE STUDY: The PAPA project is the first coordinated Asian multicity air pollution study ever published; this signifies the beginning of an era of cooperation and collaboration in Asia, with the development of a common protocol for coordination, data management, and analysis. The results of the study demonstrated that air pollution in Asia is a significant public health burden, especially given the high concentrations of pollutants and high-density populations in major cities. When compared with the effect estimates reported in the research literature of North America and Western Europe, the study's effect estimates for PM10 were generally similar and the effect estimates for gaseous pollutants were relatively higher. In Bangkok, however, a tropical city where total exposures to outdoor pollution might be higher than in most other cities, the observed effects were greater than those reported in the previous (i.e., Western) studies. In general, the results suggested that, even though social and environmental conditions across Asia might vary, it is still generally appropriate to apply to Asia the effect estimates for other health outcomes from previous studies in the West. The results also strongly support the adoption of the global air quality guidelines recently announced by WHO.

Prenatal and postnatal parental smoking and acute otitis media in early childhood.

AIM: To explore the associations between acute otitis media in early childhood and prenatal and postnatal tobacco smoke exposure. METHODS: Subjects were 32 077 children born between 2000 and 2005 in the Norwegian Mother and Child Study with questionnaire data on tobacco smoke exposure and acute otitis media up to 18 months of age. Multivariate regression models were used to obtain adjusted relative risks for acute otitis media. RESULTS: Acute otitis media was slightly more common in children exposed to parental smoking. The incidence from 0 to 6 months was 4.7% in unexposed children and 6.0% in children exposed both prenatally and postnatally. After adjusting for postnatal exposure and covariates, the relative risk for acute otitis media 0-6 months when exposed to maternal smoking in pregnancy was 1.34, 95% confidence interval: 1.06-1.69. Maternal smoking in pregnancy was associated with acute otitis media up to 12 months of age. Compared with non-exposed children, there was a slightly increased risk of recurrent acute otitis media for children exposed both prenatally and postnatally with a relative risk of 1.24, 95% confidence interval: 1.01-1.52. CONCLUSION: Even in a cohort with relatively low exposure levels of parental smoking, maternal smoking in pregnancy was associated with an increased risk of acute otitis media in early childhood.

Pesticide use and adult-onset asthma among male farmers in the Agricultural Health Study.

Although specific pesticides have been associated with wheeze in farmers, little is known about pesticides and asthma. Data from 19,704 male farmers in the Agricultural Health Study were used to evaluate lifetime use of 48 pesticides and prevalent adult-onset asthma, defined as doctor-diagnosed asthma after the age of 20 yrs. Asthma cases were categorised as allergic (n = 127) and nonallergic (n = 314) based on their history of eczema or hay fever. Polytomous logistic regression, controlling for age, state, smoking and body mass, was used to assess pesticide associations. High pesticide exposure events were associated with a doubling of both allergic and nonallergic asthma. For ever-use, 12 individual pesticides were associated with allergic asthma and four with nonallergic asthma. For allergic asthma, coumaphos (OR 2.34; 95% CI 1.49-3.70), heptachlor (OR 2.01; 95% CI 1.30-3.11), parathion (OR 2.05; 95% CI 1.21-3.46), 80/20 mix (carbon tetrachloride/carbon disulfide) (OR 2.15; 95% CI 1.23-3.76) and ethylene dibromide (OR 2.07; 95% CI 1.02-4.20) all showed ORs of >2.0 and significant exposure-response trends. For nonallergic asthma, DDT (dichlorodiphenyltrichloroethane) showed the strongest association (OR 1.41; 95% CI 1.09-1.84), but with little evidence of increasing asthma with increasing use. Current animal handling and farm activities did not confound these results. There was little evidence that allergy alone was driving these associations. In conclusion, pesticides may be an overlooked contributor to asthma risk among farmers.

Genetic variation in ORM1-like 3 (ORMDL3) and gasdermin-like (GSDML) and childhood asthma.

BACKGROUND: A genome-wide association study identified ORM1-like 3 (orosomucoid 1-like 3, ORMDL3) as an asthma candidate gene. Single nucleotide polymorphisms (SNPs) in the region including ORMDL3 on chromosome 17q21 were related to childhood asthma risk and ORMDL3 expression levels in Europeans. OBJECTIVE: We examined whether polymorphisms in ORMDL3 and the adjacent gasdermin-like (GSDML) gene associated with asthma in the genome-wide association study are related to childhood asthma and atopy in a Mexico City population. METHODS: We genotyped rs4378650 in ORMDL3 and rs7216389 in GSDML in 615 nuclear families consisting of asthmatic children aged 4-17 years and their parents. Atopy was determined by skin prick tests to 25 aeroallergens. RESULTS: Individuals carrying the C allele of rs4378650 or the T allele of rs7216389 had increased risk of asthma [relative risk (RR) = 1.73, 95% confidence interval (CI) 1.19-2.53, P = 0.003 for one or two copies of rs4378650 C, and RR = 1.64, 95% CI 1.12-2.38, P = 0.009 for one or two copies of rs7216389 T). Linkage disequilibrium between the two SNPs was high (r(2) = 0.92). Neither of the SNPs was associated with the degree of atopy. A meta-analysis of five published studies on rs7216389 in nine populations gave an odds ratio for asthma of 1.44 (95% CI, 1.35-1.54, P < 0.00001). CONCLUSIONS: Our results and the meta-analysis provide evidence to confirm the finding from a recent genome-wide association study that polymorphisms in ORMDL3 and the adjacent GSDML may contribute to childhood asthma.

Folic acid supplements in pregnancy and early childhood respiratory health.

BACKGROUND: Folate supplementation is recommended for pregnant women to reduce the risk of congenital malformations. Maternal intake of folate supplements during pregnancy might also influence childhood immune phenotypes via epigenetic mechanisms. OBJECTIVE: To investigate the relationship between folate supplements in pregnancy and risk of lower respiratory tract infections and wheeze in children up to 18 months of age. METHODS: In the Norwegian Mother and Child Cohort Study, questionnaire data collected at several time points during pregnancy and after birth on 32,077 children born between 2000 and 2005 were used to assess the effects of folate supplements during pregnancy on respiratory outcomes up to 18 months of age, while accounting for other supplements in pregnancy and supplementation in infancy. RESULTS: Folate supplements in the first trimester were associated with increased risk of wheeze and respiratory tract infections up to 18 months of age. Adjusting for exposure later in pregnancy and in infancy, the relative risk for wheeze for children exposed to folic acid supplements in the first trimester was 1.06 (95% CI 1.03 to 1.10), the relative risk for lower respiratory tract infections was 1.09 (95% CI 1.02 to 1.15) and the relative risk for hospitalisations for lower respiratory tract infections was 1.24 (95% CI 1.09 to 1.41). CONCLUSIONS: Folic acid supplements in pregnancy were associated with a slightly increased risk of wheeze and lower respiratory tract infections up to 18 months of age. The results suggest that methyl donors in the maternal diet during pregnancy may influence respiratory health in children consistent with epigenetic mechanisms.

Lack of association between genetic variation in G-protein-coupled receptor for asthma susceptibility and childhood asthma and atopy.

G-protein-coupled receptor for asthma susceptibility (GPRA or GPR154) was identified as an asthma and atopy candidate gene by positional cloning. Some subsequent studies suggest associations of GPRA single nucleotide polymorphisms (SNPs) and haplotypes with asthma or atopy susceptibility. However, the associated SNPs or haplotypes vary among studies. The role of GPRA genetic variation in asthma and atopy remains unsolved. Published data on GRPA variants and asthma come exclusively from Caucasian and Asian populations. We examined whether GPRA SNPs and haplotypes are associated with asthma and atopy in a Mexican population. We genotyped and analyzed 27 GPRA SNPs in 589 nuclear families consisting of asthmatic children aged 4-17 years of age and their parents in Mexico City. Atopy was determined by skin prick tests to 25 aeroallergens. The 27 SNPs examined provided excellent coverage of the GPRA gene. GPRA SNPs and haplotypes were not associated with childhood asthma and the degree of atopy to aeroallergens in a Mexican population. Our review of studies of GPRA variants in relation to asthma phenotypes shows considerable heterogeneity. Accordingly, our results suggest that GPRA variants are not an important contributor to childhood asthma and atopy susceptibility in a Mexican population.

Childhood exposure to environmental tobacco smoke and chronic respiratory symptoms in non-smoking adults: the Singapore Chinese Health Study.

BACKGROUND: Childhood exposure to environmental tobacco smoke has been extensively associated with childhood respiratory illness; fewer studies have addressed the effects on adults. METHODS: Childhood environmental tobacco smoke exposure in relation to chronic cough, phlegm, and asthma diagnosis was studied in never smokers from a cohort of Singaporeans of Chinese ethnicity aged 45-74 years at enrollment from 1993 to 1998. From 1999 to 2004 subjects were interviewed regarding environmental tobacco smoke exposure before and after the age of 18 and the presence and duration of current symptoms of chronic cough and phlegm production and asthma diagnosis. RESULTS: Among 35,000 never smokers, fewer had smoking mothers (19%) than fathers (48%). Although few subjects currently lived (20%) or worked (4%) with smokers, 65% reported living with a daily smoker before the age of 18 years. Living with a smoker before the age of 18 increased the odds of chronic dry cough (149 cases, odds ratio 2.1, 95% CI 1.4 to 3.3) and, to a lesser extent, phlegm, after adjustment for age, sex, dialect group, and current and past exposure to smokers at home and at work after the age of 18. Associations strengthened with higher numbers of smokers in childhood. There was no association with asthma or chronic bronchitis. There was evidence to suggest a stronger association among subjects with a lower adult intake of fibre which has previously been found to be protective for respiratory symptoms. CONCLUSIONS: In this large study of non-smokers, living with a smoker in childhood was associated with chronic dry cough and phlegm in adulthood, independent of later exposures to environmental tobacco smoke.

Genetic polymorphism of GSTM1 and antioxidant supplementation influence lung function in relation to ozone exposure in asthmatic children in Mexico City.

BACKGROUND: We recently reported that antioxidant supplementation with vitamins C and E mitigated ozone related decline in forced expiratory flow (FEF(25-75)) in 158 asthmatic children in an area with high ozone exposure in Mexico City. METHODS: A study was undertaken to determine whether deletion of glutathione S-transferase M1 (GSTM1 null genotype), a gene involved in response to oxidative stress, influences ozone related decline in FEF(25-75) and the benefit of antioxidant supplementation. RESULTS: GSTM1 null children receiving placebo had significant ozone related decrements in FEF(25-75) (percentage change per 50 ppb of ozone 2.9 (95% CI -5.2 to -0.6), p=0.01); GSTM1 positive children did not. Conversely, the effect of antioxidants was stronger in children with the GSTM1 null genotype. CONCLUSIONS: Asthmatic children with a genetic deficiency of GSTM1 may be more susceptible to the deleterious effects of ozone on the small airways and might derive greater benefit from antioxidant supplementation.