Childhood asthma and household exposures to nitrogen dioxide and fine particles: a triple-crossover randomized intervention trial.

OBJECTIVE: Triple-crossover randomized controlled intervention trial to test whether reduced exposure to household NO2 or fine particles results in reduced symptoms among children with persistent asthma. METHODS: Children (n = 126) aged 5-11 years with persistent asthma living in homes with gas stoves and levels of NO2 15 ppb or greater recruited in Connecticut and Massachusetts (2015-2019) participated in an intervention involving three air cleaners configured for: (1) NO2 reduction: sham particle filtration and real NO2 scrubbing; (2) particle filtration: HEPA filter and sham NO2 scrubbing; (3) control: sham particle filtration and sham NO2 scrubbing. Air cleaners were randomly assigned for 5-week treatment periods using a three-arm crossover design. Outcome was number of asthma symptom-days during final 14 days of treatment. Treatment effects were assessed using repeated measures, linear mixed models. RESULTS: Measured NO2 was lower (by 4 ppb, p < .0001) for NO2-reducing compared to control or particle-reducing treatments. NO2-reducing treatment did not reduce asthma morbidity compared to control. In analysis controlling for measured NO2, there were 1.8 (95% CI -0.3 to 3.9, p = .10) fewer symptom days out of 14 in the particle-reducing treatment compared to control. CONCLUSIONS: It remains unknown if using an air cleaner alone can achieve levels of NO2 reduction large enough to observe reductions in asthma symptoms. We observed that in small, urban homes with gas stoves, modest reductions in asthma symptoms occurred using air cleaners that remove fine particles. An intervention targeting exposures to both NO2 and fine particles is complicated and further research is warranted. REGISTRATION NUMBER: NCT02258893.

Investigating the Impact of Maternal Residential Mobility on Identifying Critical Windows of Susceptibility to Ambient Air Pollution During Pregnancy.

Identifying periods of increased vulnerability to air pollution during pregnancy with respect to the development of adverse birth outcomes can improve understanding of possible mechanisms of disease development and provide guidelines for protection of the child. Exposure to air pollution during pregnancy is typically based on the mother's residence at delivery, potentially resulting in exposure misclassification and biasing the estimation of critical windows of pregnancy. In this study, we determined the impact of maternal residential mobility during pregnancy on defining weekly exposure to particulate matter less than or equal to 10 µm in aerodynamic diameter (PM10) and estimating windows of susceptibility to term low birth weight. We utilized data sets from 4 Connecticut birth cohorts (1988-2008) that included information on all residential addresses between conception and delivery for each woman. We designed a simulation study to investigate the impact of increasing levels of mobility on identification of critical windows. Increased PM10 exposure during pregnancy weeks 16-18 was associated with an increased probability of term low birth weight. Ignoring residential mobility when defining weekly exposure had only a minor impact on the identification of critical windows for PM10 and term low birth weight in the data application and simulation study. Identification of critical pregnancy windows was robust to exposure misclassification caused by ignoring residential mobility in these Connecticut birth cohorts.

A community-based evaluation of proximity to unconventional oil and gas wells, drinking water contaminants, and health symptoms in Ohio.

Over 4 million Americans live within 1.6 km of an unconventional oil and gas (UO&G) well, potentially placing them in the path of toxic releases. We evaluated relationships between residential proximity to UO&G wells and (1) water contamination and (2) health symptoms in an exploratory study. We analyzed drinking water samples from 66 Ohio households for 13 UO&G-related volatile organic compounds (VOCs) (e.g., benzene, disinfection byproducts [DBPs]), gasoline-range organics (GRO), and diesel-range organics. We interviewed participants about health symptoms and calculated metrics capturing proximity to UO&G wells. Based on multivariable logistic regression, odds of detection of bromoform and dibromochloromethane in surface water decreased significantly as distance to nearest UO&G well increased (odds ratios [OR]: 0.28-0.29 per km). Similarly, distance to nearest well was significantly negatively correlated with concentrations of GRO and toluene in ground water (rSpearman: -0.40 to -0.44) and with concentrations of bromoform and dibromochloromethane in surface water (rSpearman: -0.48 to -0.50). In our study population, those with higher inverse-distance-squared-weighted UO&G well counts within 5 km around the home were more likely to report experiencing general health symptoms (e.g. stress, fatigue) (OR: 1.52, 95%CI: 1.02-2.26). This exploratory study, though limited by small sample size and self-reported health symptoms, suggests that those in closer proximity to multiple UO&G wells may be more likely to experience environmental health impacts. Further, presence of brominated DBPs (linked to UO&G wastewater) raises the question of whether UO&G activities are impacting drinking water sources in the region. The findings from this study support expanded studies to advance knowledge of the potential for water quality and human health impacts; such studies could include a greater number of sampling sites, more detailed chemical analyses to examine source attribution, and objective health assessments.

NIAID, NIEHS, NHLBI, and MCAN Workshop Report: The indoor environment and childhood asthma-implications for home environmental intervention in asthma prevention and management.

Environmental exposures have been recognized as critical in the initiation and exacerbation of asthma, one of the most common chronic childhood diseases. The National Institute of Allergy and Infectious Diseases; National Institute of Environmental Health Sciences; National Heart, Lung, and Blood Institute; and Merck Childhood Asthma Network sponsored a joint workshop to discuss the current state of science with respect to the indoor environment and its effects on the development and morbidity of childhood asthma. The workshop included US and international experts with backgrounds in allergy/allergens, immunology, asthma, environmental health, environmental exposures and pollutants, epidemiology, public health, and bioinformatics. Workshop participants provided new insights into the biologic properties of indoor exposures, indoor exposure assessment, and exposure reduction techniques. This informed a primary focus of the workshop: to critically review trials and research relevant to the prevention or control of asthma through environmental intervention. The participants identified important limitations and gaps in scientific methodologies and knowledge and proposed and prioritized areas for future research. The group reviewed socioeconomic and structural challenges to changing environmental exposure and offered recommendations for creative study design to overcome these challenges in trials to improve asthma management. The recommendations of this workshop can serve as guidance for future research in the study of the indoor environment and on environmental interventions as they pertain to the prevention and management of asthma and airway allergies.

Indoor microbial communities: Influence on asthma severity in atopic and nonatopic children.

BACKGROUND: Allergic and nonallergic asthma severity in children can be affected by microbial exposures. OBJECTIVE: We sought to examine associations between exposures to household microbes and childhood asthma severity stratified by atopic status. METHODS: Participants (n = 196) were selected from a cohort of asthmatic children in Connecticut and Massachusetts. Children were grouped according to asthma severity (mild with no or minimal symptoms and medication or moderate to severe persistent) and atopic status (determined by serum IgE levels). Microbial community structure and concentrations in house dust were determined by using next-generation DNA sequencing and quantitative PCR. Logistic regression was used to explore associations between asthma severity and exposure metrics, including richness, taxa identification and quantification, community composition, and concentration of total fungi and bacteria. RESULTS: Among all children, increased asthma severity was significantly associated with an increased concentration of summed allergenic fungal species, high total fungal concentrations, and high bacterial richness by using logistic regression in addition to microbial community composition by using the distance comparison t test. Asthma severity in atopic children was associated with fungal community composition (P = .001). By using logistic regression, asthma severity in nonatopic children was associated with total fungal concentration (odds ratio, 2.40; 95% CI, 1.06-5.44). The fungal genus Volutella was associated with increased asthma severity in atopic children (P = .0001, q = 0.04). The yeast genera Kondoa might be protective; Cryptococcus species might also affect asthma severity. CONCLUSION: Asthma severity among this cohort of children was associated with microbial exposure, and associations differed based on atopic status.

Spatiotemporal calibration and resolution refinement of output from deterministic models.

Spatiotemporal calibration of output from deterministic models is an increasingly popular tool to more accurately and efficiently estimate the true distribution of spatial and temporal processes. Current calibration techniques have focused on a single source of data on observed measurements of the process of interest that are both temporally and spatially dense. Additionally, these methods often calibrate deterministic models available in grid-cell format with pixel sizes small enough that the centroid of the pixel closely approximates the measurement for other points within the pixel. We develop a modeling strategy that allows us to simultaneously incorporate information from two sources of data on observed measurements of the process (that differ in their spatial and temporal resolutions) to calibrate estimates from a deterministic model available on a regular grid. This method not only improves estimates of the pollutant at the grid centroids but also refines the spatial resolution of the grid data. The modeling strategy is illustrated by calibrating and spatially refining daily estimates of ambient nitrogen dioxide concentration over Connecticut for 1994 from the Community Multiscale Air Quality model (temporally dense grid-cell estimates on a large pixel size) using observations from an epidemiologic study (spatially dense and temporally sparse) and Environmental Protection Agency monitoring stations (temporally dense and spatially sparse). Copyright © 2016 John Wiley & Sons, Ltd.

Distributions of heavy metals in maternal and cord blood and the association with infant birth weight in China.

OBJECTIVE: To measure serum levels of heavy metals in Chinese pregnant women and their newborns, and to evaluate the association of these metals with infant birth weight. STUDY DESIGN: We measured serum concentrations of lead (Pb), thallium (Tl), cadmium (Cd), selenium (Se), arsenic (As), nickle (Ni), vanadium (V), cobalt (Co), and mercury (Hg) in 81 mother-infant pairs using an inductively coupled plasma mass spectrometry method. Multiple linear regression analyses were used to evaluate the associations of these heavy metals with infant birth weight. RESULTS: Se, Pb, As, and Cd showed the highest detection rates (98.8%) in both the maternal and cord blood, followed by Tl, which was detected in 79.0% and 71.6% of the maternal and cord blood samples, respectively. Pb had the highest concentrations in both the maternal and cord blood samples of all toxic metals detected, with concentrations of 23.1 ng/g and 22.0 ng/g, respectively. No significant associations were observed between any heavy metals and birth weight. However, Tl in the maternal and cord blood was most notably inversely associated with birth weight. CONCLUSION: Se intake was low in Chinese women and their newborns, whereas Pb had the highest concentrations in both the maternal and cord blood samples of all toxic metals detected. Tl was a unique pollution source in this population, and Tl levels were shown to have the largest effect on decreasing infant birth weight in this pilot study. Further research incorporating larger sample sizes is needed to investigate the effects of prenatal exposure to heavy metals--especially Tl and Pb--on birth outcome in Chinese infants.

Polymorphisms in DNA repair genes, hair dye use, and the risk of non-Hodgkin lymphoma.

PURPOSE: Genetic polymorphisms in DNA repair genes and hair dye use may both have a role in the development of non-Hodgkin lymphoma (NHL). We aimed to examine the interaction between variants in DNA repair genes and hair dye use with risk of NHL in a population-based case-control study of Connecticut women. METHODS: We examined 24 single nucleotide polymorphisms in 16 DNA repair genes among 518 NHL cases and 597 controls and evaluated the associations between hair dye use and risk of overall NHL and common NHL subtypes, stratified by genotype, using unconditional logistic regression. RESULTS: Women who used hair dye before 1980 had a significantly increased risk of NHL, particularly for the follicular lymphoma (FL) subtype, but not for diffuse large B-cell lymphoma. The following genotypes in combination with hair dye use before 1980 were associated with FL risk: BRCA2 rs144848 AC+CC [odds ratio (OR) (95% confidence interval (CI)) 3.28(1.27-8.50)], WRN rs1346044 TT [OR(95% CI) 2.70(1.30-5.65)], XRCC3 rs861539 CT+TT [OR(95% CI) 2.76(1.32-5.77)], XRCC4 rs1805377 GG [OR(95% CI) 2.07(1.10-3.90)] and rs1056503 TT [OR(95% CI) 2.17(1.16-4.07)], ERCC1 rs3212961 CC [OR(95% CI) 1.93(1.00-3.72)], RAD23B rs1805329 CC [OR(95% CI) 2.28(1.12-4.64)], and MGMT rs12917 CC, rs2308321 AA, and rs2308327 AA genotypes [OR(95% CI) 1.96(1.06-3.63), 2.02(1.09-3.75), and 2.23(1.16-4.29), respectively]. In addition, a significant interaction with risk of overall NHL was observed between WRN rs1346044 and hair dye use before 1980 (p(interaction) = 0.032). CONCLUSIONS: Our results indicated that genetic variation in DNA repair genes modifies susceptibility to NHL in relation to hair dye use, particularly for the FL subtype and in women who began using hair dye before 1980. Further studies are needed to confirm these observations.

Role of one-carbon metabolizing pathway genes and gene-nutrient interaction in the risk of non-Hodgkin lymphoma.

PURPOSE: Genetic polymorphisms in one-carbon metabolizing pathway genes have been associated with risk of malignant lymphoma. However, the results have been inconsistent. The objectives of this study were to examine the potential relationship between gene-nutrient interactions and the risk of non-Hodgkin lymphoma (NHL). METHODS: We examined 25 polymorphisms in 16 one-carbon metabolism genes for their main effect and gene-nutrient interactions in relation to NHL risk among 518 incident cases and 597 population-based controls of Connecticut women enrolled between 1996 and 2000. RESULTS: A significantly reduced risk of NHL was associated with the homozygous TT genotype in CBS (rs234706, Ex9+33C>T) (OR = 0.51, 95 % CI 0.31-0.84), the homozygous CC genotype in MBD2 (rs603097, -2176C>T) (OR = 0.37, 95 % CI 0.17-0.79), the heterozygote AG genotype in FTHFD (rs1127717, Ex21+31A>G) (OR = 0.73, 95 % CI 0.55-0.98), and a borderline significantly reduced risk of NHL was observed for the homozygous CC genotype in MTRR (rs161870, Ex5+136T>C) (OR = 0.23, 95 % CI 0.05-1.04). The reduced risk of NHL associated with these genotypes was predominately in those with higher dietary vitamin B6 and methionine intakes, as well as with higher dietary folate intake although results were less stable. A borderline significantly increased risk of NHL was also observed for CBS (rs1801181, Ex13+41C>T), FTHFD (rs2305230, Ex10-40G>T), SHMT1 (rs1979277, Ex12+138C>T), and SHMT1 (rs1979276, Ex12+236T>C), and these associations appeared to be contingent on dietary nutrient intakes. CONCLUSION: Our results suggest that variation in several one-carbon metabolizing pathway genes may influence the risk of NHL through gene-nutrient interactions involving dietary nutrient intakes.

Household levels of nitrogen dioxide and pediatric asthma severity.

BACKGROUND: Adverse respiratory effects in children with asthma are associated with exposures to nitrogen dioxide (NO2). Levels indoors can be much higher than outdoors. Primary indoor sources of NO2 are gas stoves, which are used for cooking by one-third of U.S. households. We investigated the effects of indoor NO2 exposure on asthma severity among an ethnically and economically diverse sample of children, controlling for season and indoor allergen exposure. METHODS: Children 5-10 years of age with active asthma (n = 1,342) were recruited through schools in urban and suburban Connecticut and Massachusetts (2006-2009) for a prospective, year-long study with seasonal measurements of NO2 and asthma severity. Exposure to NO2 was measured passively for four, month-long, periods with Palmes tubes. Asthma morbidity was concurrently measured by a severity score and frequency of wheeze, night symptoms, and use of rescue medication. We used adjusted, hierarchical ordered logistic regression models to examine associations between household NO2 exposure and health outcomes. RESULTS: Every 5-fold increase in NO2 exposure above a threshold of 6 ppb was associated with a dose-dependent increase in risk of higher asthma severity score (odds ratio = 1.37 [95% confidence interval = 1.01-1.89]), wheeze (1.49 [1.09-2.03]), night symptoms (1.52 [1.16-2.00]), and rescue medication use (1.78 [1.33-2.38]). CONCLUSIONS: Asthmatic children exposed to NO2 indoors, at levels well below the U.S. Environmental Protection Agency outdoor standard (53 ppb), are at risk for increased asthma morbidity. Risks are not confined to inner city children, but occur at NO2 concentrations common in urban and suburban homes.

Cytokine polymorphisms in Th1/Th2 pathway genes, body mass index, and risk of non-Hodgkin lymphoma.

We conducted a population-based, case-control study in Connecticut women to test the hypothesis that genetic variations in Th1 and Th2 cytokine genes modify the relationship between body mass index (BMI) and risk of non-Hodgkin lymphoma (NHL). Compared with those with BMI less than 25 kg/m(2), women with BMI more than or equal to 25 kg/m(2) had 50% to 90% increased risk of NHL among women who carried IFNGR2 (rs9808753) AA, IL5 (rs2069812) CT/TT, IL7R (rs1494555) AA, and TNF (rs1799724) CC genotypes, but no increased risk among women with IFNGR2 AG/GG, IL5 CC, IL7R AG/GG, and TNF CT/TT genotypes. A significant interaction with BMI was only observed for IFNGR2 (rs9808753 P(forinteraction) = .034) and IL7R (rs1494555 P(forinteraction) = .016) for NHL overall; IL7R (rs1494555 P(forinteraction) = .016) and TNF (1799724 P(forinteraction) = .031) for B-cell lymphoma; and IL5 (rs2069812 P(forinteraction) = .034) for T-cell lymphoma. After stratification by common B-cell lymphoma subtypes, a significant interaction was observed for IFNGR2 (rs9808753 P(forinteraction) = .006), IL13 (rs20541 P(forinteraction) = .019), and IL7R (rs1494555 P(forinteraction) = .012) for marginal zone B-cell lymphoma; IL7R (rs1494555 P(forinteraction) = .017) for small lymphocytic lymphoma/chronic lymphocytic leukemia; and IL12A (rs568408 P(forinteraction) = .013) and TNF (1799724 P(forinteraction) = .04) for follicular lymphoma. The results suggest that common genetic variation in Th1/Th2 pathway genes may modify the association between BMI and NHL risk.

Polymorphisms in DNA repair pathway genes, body mass index, and risk of non-Hodgkin lymphoma.

We conducted a population-based case-control study in Connecticut women to test the hypothesis that genetic variations in DNA repair pathway genes may modify the relationship between body mass index (BMI) and risk of non-Hodgkin lymphoma (NHL). Compared to those with BMI <25, women with BMI ≥25 had significantly increased risk of NHL among women who carried BRCA1 (rs799917) CT/TT, ERCC2 (rs13181) AA, XRCC1 (rs1799782) CC, and WRN (rs1801195) GG genotypes, but no increase in NHL risk among women who carried BRCA1 CC, ERCC2 AC/CC, XRCC1 CT/TT, and WRN GT/TT genotypes. A significant interaction with BMI was only observed for WRN (rs1801195; P = 0.004) for T-cell lymphoma and ERCC2 (rs13181; P = 0.002) for diffuse large B-cell lymphoma. The results suggest that common genetic variation in DNA repair pathway genes may modify the association between BMI and NHL risk.

Assessment of children's personal and land use regression model-estimated exposure to NO2 in Springfield, Massachusetts.

Ambient nitrogen dioxide (NO2) is derived from tailpipe vehicle emission and is linked with various of health outcomes. Personal exposure monitoring is crucial for accurate assessment of the associated disease risks. This study aimed to evaluate the utility of a wearable air pollutant sampler in determining the personal NO2 exposure of school children for comparison with a model-based personal exposure assessment. We employed cost-effective, wearable passive samplers to directly measure personal exposure of 25 children (aged 12-13 years) in Springfield, MA to NO2 over a five-day period in winter 2018. NO2 levels were additionally measured at 40 outdoor sites in the same region using stationary passive samplers. A land use regression (LUR) model was developed based on the ambient NO2 measures, with a good prediction performance (R2 = 0.72) using road lengths, distance to highway, and institutional land area as predictor variables. Time-weighted averages (TWA), which incorporated the time-activity patterns of participants and LUR-derived estimates in children's primary microenvironments (homes, the school and commute paths), were calculated as an indirect measure of personal NO2 exposure. Results indicated that the conventional residence-based exposure estimate approach, often used in epidemiological studies, differed from the direct personal exposure and could overestimate the personal exposure by up to 109 %. TWA improved personal NO2 exposure estimates by accounting for the time activity patterns of individuals, a difference of 5.4 % ± 34.2 % was found for exposures compared to wristband measurements. Nevertheless, the personal wristband measurements exhibited a large variability due to the potential contributions from indoor and in-vehicle NO2 sources. The findings suggest that exposure to NO2 can be highly personalized based on individual activities and contact with pollutants in specific microenvironments, reaffirming the importance of measuring personal exposure.

Paired Indoor and Outdoor Nitrogen Dioxide Associated With Childhood Asthma Outcomes in a Mixed Rural-Urban Setting: A Feasibility Study.

INTRODUCTION: Nitrogen dioxide (NO2) is known to be a trigger for asthma exacerbation. However, little is known about the role of seasonal variation in indoor and outdoor NO2 levels in childhood asthma in a mixed rural-urban setting of North America. METHODS: This prospective cohort study, as a feasibility study, included 62 families with children (5-17 years) that had diagnosed persistent asthma residing in Olmsted County, Minnesota. Indoor and outdoor NO2 concentrations were measured using passive air samples over 2 weeks in winter and 2 weeks in summer. We assessed seasonal variation in NO2 levels in urban and rural residential areas and the association with asthma control status collected from participants' asthma diaries during the study period. RESULTS: Outdoor NO2 levels were lower (median: 2.4 parts per billion (ppb) in summer, 3.9 ppb in winter) than the Environmental Protection Agency (EPA) annual standard (53 ppb). In winter, a higher level of outdoor NO2 was significantly associated with urban residential living area (P = .014) and lower socioeconomic status (SES) (P = .027). For both seasons, indoor NO2 was significantly higher (P < .05) in rural versus urban areas and in homes with gas versus electric stoves (P < .05). Asthma control status was not associated with level of indoor or outdoor NO2 in this cohort. CONCLUSIONS: NO2 levels were low in this mixed rural-urban community and not associated with asthma control status in this small feasibility study. Further research with a larger sample size is warranted for defining a lower threshold of NO2 concentration with health effect on asthma in mixed rural-urban settings.

Effects of ambient pollen concentrations on frequency and severity of asthma symptoms among asthmatic children.

BACKGROUND: Previous studies on the associations between ambient pollen exposures and daily respiratory symptoms have produced inconsistent results. We investigated these relationships in a cohort of asthmatic children using pollen exposure models to estimate individual ambient exposures. METHODS: Daily symptoms of wheeze, night symptoms, shortness of breath, chest tightness, persistent cough, and rescue medication use were recorded in a cohort of 430 children with asthma (age 4-12 years) in Connecticut, Massachusetts, and New York. Daily ambient exposures to tree, grass, weed, and total pollen were estimated using mixed-effects models. We stratified analyses by use of asthma maintenance medication and sensitization to grass or weed pollens. Separate logistic regression analyses using generalized estimating equations were performed for each symptom outcome and pollen type. We adjusted analyses for maximum daily temperature, maximum 8-hour average ozone, fine particles (PM2.5), season, and antibiotic use. RESULTS: Associations were observed among children sensitized to specific pollens; these associations varied by use of asthma maintenance medication. Exposures to even relatively low levels of weed pollen (6-9 grains/m(3)) were associated with increased shortness of breath, chest tightness, rescue medication use, wheeze, and persistent cough, compared with lower exposure among sensitized children on maintenance medication. Grass pollen exposures ≥ 2 grains/m(3) were associated with wheeze, night symptoms, shortness of breath, and persistent cough compared with lower exposure among sensitized children who did not take maintenance medication. CONCLUSION: Even low-level pollen exposure was associated with daily asthmatic symptoms.

Dietary nitrate and nitrite intake and non-Hodgkin lymphoma survival.

Nitrate and nitrite are precursors in the formation of N-nitroso compounds. We recently found a 40% increased risk of NHL with higher dietary nitrite intake and significant increases in risk for follicular and T-cell lymphoma. It is possible that these compounds also affect NHL prognosis by enhancing cancer progression in addition to development by further impairing immune system function. To test the hypothesis that nitrate and nitrite intake affects NHL survival, we evaluated the association in study participants that have been followed post-disease diagnosis in a population-based case-control study among women in Connecticut. We did not observe a significant increasing trend of mortality for NHL overall or by subtype for nitrate or nitrite intake for deaths from NHL or death from any cause, although a borderline significant protective trend was observed for follicular lymphoma with increasing nitrate intake. We did not identify a difference in overall survival for nitrate (P = 0.39) or for nitrite (P = 0.66) or for NHL specific survival for nitrate (P = 0.96) or nitrite (P = 0.17). Thus, our null findings do not confer support for the possibility that dietary nitrate and nitrite intake impacts NHL survival by promoting immune unresponsiveness.

Association of variants in innate immune genes with asthma and eczema.

BACKGROUND: The innate immune pathway is important in the pathogenesis of asthma and eczema. However, only a few variants in these genes have been associated with either disease. We investigate the association between polymorphisms of genes in the innate immune pathway with childhood asthma and eczema. In addition, we compare individual associations with those discovered using a multivariate approach. METHODS: Using a novel method, case control based association testing (C2BAT), 569 single nucleotide polymorphisms (SNPs) in 44 innate immune genes were tested for association with asthma and eczema in children from the Boston Home Allergens and Asthma Study and the Connecticut Childhood Asthma Study. The screening algorithm was used to identify the top SNPs associated with asthma and eczema. We next investigated the interaction of innate immune variants with asthma and eczema risk using Bayesian networks. RESULTS: After correction for multiple comparisons, 7 SNPs in 6 genes (CARD25, TGFB1, LY96, ACAA1, DEFB1, and IFNG) were associated with asthma (adjusted p-value<0.02), while 5 SNPs in 3 different genes (CD80, STAT4, and IRAKI) were significantly associated with eczema (adjusted p-value < 0.02). None of these SNPs were associated with both asthma and eczema. Bayesian network analysis identified 4 SNPs that were predictive of asthma and 10 SNPs that predicted eczema. Of the genes identified using Bayesian networks, only CD80 was associated with eczema in the single-SNP study. Using novel methodology that allows for screening and replication in the same population, we have identified associations of innate immune genes with asthma and eczema. Bayesian network analysis suggests that additional SNPs influence disease susceptibility via SNP interactions. CONCLUSION: Our findings suggest that innate immune genes contribute to the pathogenesis of asthma and eczema, and that these diseases likely have different genetic determinants.

Genetic polymorphisms in IL10RA and TNF modify the association between blood transfusion and risk of non-Hodgkin lymphoma.

We conducted a population-based case-control study in Connecticut women to test the hypothesis that genetic variations in Th1 and Th2 cytokine genes may modify the association between blood transfusion and risk of non-Hodgkin lymphoma (NHL). Compared with women without blood transfusion, women with a history of transfusion had an increased risk of NHL if they carried IL10RA (rs9610) GG genotype [odds ratio (OR) = 1.9, 95% confidence interval (CI): 1.1-3.2] or TNF (rs1800629) AG/AA genotypes (OR = 1.6, 95% CI: 0.9-2.7). We also found women with a history of transfusion had a decreased risk of NHL if they carried IL10RA (rs9610) AG/AA genotypes (OR = 0.6, 95% CI: 0.4-0.9) or TNF (rs1800629) GG genotype (OR = 0.7, 95% CI: 0.5-1.0). A similar pattern was also observed for B-cell lymphoma but not for T-cell lymphoma. Statistically significant interactions with blood transfusion were observed for IL10RA (rs9610) (P(forinteraction) = 0.003) and TNF (rs1800629) (P(forinteraction) = 0.012) for NHL overall and IL10RA (rs9610) (P(forinteraction) = 0.001) and TNF (rs1800629) (P(forinteraction) = 0.019) for B-cell lymphoma. The results suggest that genetic polymorphisms in TNF and IL10RA genes may modify the association between blood transfusion and NHL risk.

Relationship between birth weight and exposure to airborne fine particulate potassium and titanium during gestation.

Airborne particles are linked to numerous health impacts, including adverse pregnancy outcomes. Most studies of particles examined total mass, although the chemical structure of particles varies widely. We investigated whether mother's exposure to potassium (K) and titanium (Ti) components of airborne fine particulate matter (PM(2.5)) during pregnancy was associated with birth weight or risk of low birth weight (<2500 g) for term infants. The study population was 76,788 infants born in four counties in Connecticut and Massachusetts, US, for August 2000-February 2004. Both K and Ti were associated with birth weight. An interquartile range (IQR) increase K was associated with an 8.75% (95% confidence interval (CI): 1.24-16.8%) increase in risk of low birth weight. An IQR increase in Ti was associated with a 12.1% (95% CI: 3.55-21.4%) increase in risk of low birth weight, with an estimate of 6.41% (95% CI: -5.80-20.2%) for males and 16.4% (95% CI: 5.13-28.9%) for females. Results were robust to sensitivity analysis of first births only, but not adjustment by co-pollutants. Disentangling the effects of various chemical components is challenging because of the covariance among some components due to similar sources. Central effect estimates for infants of African-American mothers were higher than those of white mothers, although the confidence intervals overlapped. Our results indicate that exposure to airborne potassium and titanium during pregnancy is associated with lower birth weight. Associations may relate to chemical components of sources producing K and Ti.

Household mold and dust allergens: exposure, sensitization and childhood asthma morbidity.

BACKGROUND: Few studies address concurrent exposures to common household allergens, specific allergen sensitization and childhood asthma morbidity. OBJECTIVE: To identify levels of allergen exposures that trigger asthma exacerbations in sensitized individuals. METHODS: We sampled homes for common indoor allergens (fungi, dust mites (Der p 1, Der f 1), cat (Fel d 1), dog (Can f 1) and cockroach (Bla g 1)) for levels associated with respiratory responses among school-aged children with asthma (N=1233) in a month-long study. Blood samples for allergy testing and samples of airborne fungi and settled dust were collected at enrollment. Symptoms and medication use were recorded on calendars. Combined effects of specific allergen sensitization and level of exposure on wheeze, persistent cough, rescue medication use and a 5-level asthma severity score were examined using ordered logistic regression. RESULTS: Children sensitized and exposed to any Penicillium experienced increased risk of wheeze (odds ratio [OR] 2.12 95% confidence interval [CI] 1.12, 4.04), persistent cough (OR 2.01 95% CI 1.05, 3.85) and higher asthma severity score (OR 1.99 95% CI 1.06, 3.72) compared to those not sensitized or sensitized but unexposed. Children sensitized and exposed to pet allergen were at significantly increased risk of wheeze (by 39% and 53% for Fel d 1>0.12 µg/g and Can f 1>1.2 µg/g, respectively). Increased rescue medication use was significantly associated with sensitization and exposure to Der p 1>0.10 µg/g (by 47%) and Fel d 1>0.12 µg/g (by 32%). CONCLUSION: Asthmatic children sensitized and exposed to low levels of common household allergens Penicillium, Der p 1, Fel d 1 and Can f 1 are at significant risk for increased morbidity.