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1.  Arterial Blood Pressure and Long-Term Exposure to Traffic-Related Air Pollution: An Analysis in the European Study of Cohorts for Air Pollution Effects (ESCAPE) 
Environmental Health Perspectives  2014;122(9):896-905.
Background: Long-term exposure to air pollution has been hypothesized to elevate arterial blood pressure (BP). The existing evidence is scarce and country specific.
Objectives: We investigated the cross-sectional association of long-term traffic-related air pollution with BP and prevalent hypertension in European populations.
Methods: We analyzed 15 population-based cohorts, participating in the European Study of Cohorts for Air Pollution Effects (ESCAPE). We modeled residential exposure to particulate matter and nitrogen oxides with land use regression using a uniform protocol. We assessed traffic exposure with traffic indicator variables. We analyzed systolic and diastolic BP in participants medicated and nonmedicated with BP-lowering medication (BPLM) separately, adjusting for personal and area-level risk factors and environmental noise. Prevalent hypertension was defined as ≥ 140 mmHg systolic BP, or ≥ 90 mmHg diastolic BP, or intake of BPLM. We combined cohort-specific results using random-effects meta-analysis.
Results: In the main meta-analysis of 113,926 participants, traffic load on major roads within 100 m of the residence was associated with increased systolic and diastolic BP in nonmedicated participants [0.35 mmHg (95% CI: 0.02, 0.68) and 0.22 mmHg (95% CI: 0.04, 0.40) per 4,000,000 vehicles × m/day, respectively]. The estimated odds ratio (OR) for prevalent hypertension was 1.05 (95% CI: 0.99, 1.11) per 4,000,000 vehicles × m/day. Modeled air pollutants and BP were not clearly associated.
Conclusions: In this first comprehensive meta-analysis of European population-based cohorts, we observed a weak positive association of high residential traffic exposure with BP in nonmedicated participants, and an elevated OR for prevalent hypertension. The relationship of modeled air pollutants with BP was inconsistent.
Citation: Fuks KB, Weinmayr G, Foraster M, Dratva J, Hampel R, Houthuijs D, Oftedal B, Oudin A, Panasevich S, Penell J, Sommar JN, Sørensen M, Tittanen P, Wolf K, Xun WW, Aguilera I, Basagaña X, Beelen R, Bots ML, Brunekreef B, Bueno-de-Mesquita HB, Caracciolo B, Cirach M, de Faire U, de Nazelle A, Eeftens M, Elosua R, Erbel R, Forsberg B, Fratiglioni L, Gaspoz JM, Hilding A, Jula A, Korek M, Krämer U, Künzli N, Lanki T, Leander K, Magnusson PK, Marrugat J, Nieuwenhuijsen MJ, Östenson CG, Pedersen NL, Pershagen G, Phuleria HC, Probst-Hensch NM, Raaschou-Nielsen O, Schaffner E, Schikowski T, Schindler C, Schwarze PE, Søgaard AJ, Sugiri D, Swart WJ, Tsai MY, Turunen AW, Vineis P, Peters A, Hoffmann B. 2014. Arterial blood pressure and long-term exposure to traffic-related air pollution: an analysis in the European Study of Cohorts for Air Pollution Effects (ESCAPE). Environ Health Perspect 122:896–905; http://dx.doi.org/10.1289/ehp.1307725
doi:10.1289/ehp.1307725
PMCID: PMC4154218  PMID: 24835507
2.  Long-Term Aircraft Noise Exposure and Body Mass Index, Waist Circumference, and Type 2 Diabetes: A Prospective Study 
Environmental Health Perspectives  2014;122(7):687-694.
Background: Long-term aircraft noise exposure may increase the risk of cardiovascular disease, but no study has investigated chronic effects on the metabolic system.
Objectives: The aim of this study was to investigate effects of long-term aircraft noise exposure on body mass index (BMI), waist circumference, and type 2 diabetes. Furthermore, we explored the modifying effects of sleep disturbance.
Methods: This prospective cohort study of residents of Stockholm County, Sweden, followed 5,156 participants with normal baseline oral glucose tolerance tests (OGTT) for up to 10 years. Exposure to aircraft noise was estimated based on residential history. Information on outcomes and confounders was obtained from baseline and follow-up surveys and examinations, and participants who developed prediabetes or type 2 diabetes were identified by self-reported physician diagnosis or OGTT at follow-up. Adjusted associations were assessed by linear, logistic, and random-effects models.
Results: The mean (± SD) increases in BMI and waist circumference during follow-up were 1.09 ± 1.97 kg/m2 and 4.39 ± 6.39 cm, respectively. The cumulative incidence of prediabetes and type 2 diabetes was 8% and 3%, respectively. Based on an ordinal noise variable, a 5-dB(A) increase in aircraft noise was associated with a greater increase in waist circumference of 1.51 cm (95% CI: 1.13, 1.89), fully adjusted. This association appeared particularly strong among those who did not change their home address during the study period, which may be a result of lower exposure misclassification. However, no clear associations were found for BMI or type 2 diabetes. Furthermore, sleep disturbances did not appear to modify the associations with aircraft noise.
Conclusions: Long-term aircraft noise exposure may be linked to metabolic outcomes, in particular increased waist circumference.
Citation: Eriksson C, Hilding A, Pyko A, Bluhm G, Pershagen G, Östenson CG. 2014. Long-term aircraft noise exposure and body mass index, waist circumference, and type 2 diabetes: a prospective study. Environ Health Perspect 122:687–694; http://dx.doi.org/10.1289/ehp.1307115
doi:10.1289/ehp.1307115
PMCID: PMC4080526  PMID: 24800763
3.  Mortality Related to Air Pollution with the Moscow Heat Wave and Wildfire of 2010 
Epidemiology (Cambridge, Mass.)  2014;25(3):359-364.
Supplemental Digital Content is available in the text.
Background:
Prolonged high temperatures and air pollution from wildfires often occur together, and the two may interact in their effects on mortality. However, there are few data on such possible interactions.
Methods:
We analyzed day-to-day variations in the number of deaths in Moscow, Russia, in relation to air pollution levels and temperature during the disastrous heat wave and wildfire of 2010. Corresponding data for the period 2006–2009 were used for comparison. Daily average levels of PM10 and ozone were obtained from several continuous measurement stations. The daily number of nonaccidental deaths from specific causes was extracted from official records. Analyses of interactions considered the main effect of temperature as well as the added effect of prolonged high temperatures and the interaction with PM10.
Results:
The major heat wave lasted for 44 days, with 24-hour average temperatures ranging from 24°C to 31°C and PM10 levels exceeding 300 μg/m3 on several days. There were close to 11,000 excess deaths from nonaccidental causes during this period, mainly among those older than 65 years. Increased risks also occurred in younger age groups. The most pronounced effects were for deaths from cardiovascular, respiratory, genitourinary, and nervous system diseases. Continuously increasing risks following prolonged high temperatures were apparent during the first 2 weeks of the heat wave. Interactions between high temperatures and air pollution from wildfires in excess of an additive effect contributed to more than 2000 deaths.
Conclusions:
Interactions between high temperatures and wildfire air pollution should be considered in risk assessments regarding health consequences of climate change.
doi:10.1097/EDE.0000000000000090
PMCID: PMC3984022  PMID: 24598414
4.  GSTP1 and TNF Gene Variants and Associations between Air Pollution and Incident Childhood Asthma: The Traffic, Asthma and Genetics (TAG) Study 
Environmental Health Perspectives  2014;122(4):418-424.
Background: Genetics may partially explain observed heterogeneity in associations between traffic-related air pollution and incident asthma.
Objective: Our aim was to investigate the impact of gene variants associated with oxidative stress and inflammation on associations between air pollution and incident childhood asthma.
Methods: Traffic-related air pollution, asthma, wheeze, gene variant, and potential confounder data were pooled across six birth cohorts. Parents reported physician-diagnosed asthma and wheeze from birth to 7–8 years of age (confirmed by pediatric allergist in two cohorts). Individual estimates of annual average air pollution [nitrogen dioxide (NO2), particulate matter ≤ 2.5 μm (PM2.5), PM2.5 absorbance, ozone] were assigned to each child’s birth address using land use regression, atmospheric modeling, and ambient monitoring data. Effect modification by variants in GSTP1 (rs1138272/Ala114Val and rs1695/IIe105Val) and TNF (rs1800629/G-308A) was investigated.
Results: Data on asthma, wheeze, potential confounders, at least one SNP of interest, and NO2 were available for 5,115 children. GSTP1 rs1138272 and TNF rs1800629 SNPs were associated with asthma and wheeze, respectively. In relation to air pollution exposure, children with one or more GSTP1 rs1138272 minor allele were at increased risk of current asthma [odds ratio (OR) = 2.59; 95% CI: 1.43, 4.68 per 10 μg/m3 NO2] and ever asthma (OR = 1.64; 95% CI: 1.06, 2.53) compared with homozygous major allele carriers (OR = 0.95; 95% CI: 0.68, 1.32 for current and OR = 1.20; 95% CI: 0.98, 1.48 for ever asthma; Bonferroni-corrected interaction p = 0.04 and 0.01, respectively). Similarly, for GSTP1 rs1695, associations between NO2 and current and ever asthma had ORs of 1.43 (95% CI: 1.03, 1.98) and 1.36 (95% CI: 1.08, 1.70), respectively, for minor allele carriers compared with ORs of 0.82 (95% CI: 0.52, 1.32) and 1.12 (95% CI: 0.84, 1.49) for homozygous major allele carriers (Bonferroni-corrected interaction p-values 0.48 and 0.09). There were no clear differences by TNF genotype.
Conclusions: Children carrying GSTP1 rs1138272 or rs1695 minor alleles may constitute a susceptible population at increased risk of asthma associated with air pollution.
Citation: MacIntyre EA, Brauer M, Melén E, Bauer CP, Bauer M, Berdel D, Bergström A, Brunekreef B, Chan-Yeung M, Klümper C, Fuertes E, Gehring U, Gref A, Heinrich J, Herbarth O, Kerkhof M, Koppelman GH, Kozyrskyj AL, Pershagen G, Postma DS, Thiering E, Tiesler CM, Carlsten C, TAG Study Group. 2014. GSTP1 and TNF gene variants and associations between air pollution and incident childhood asthma: the traffic, asthma and genetics (TAG) Study. Environ Health Perspect 122:418–424; http://dx.doi.org/10.1289/ehp.1307459
doi:10.1289/ehp.1307459
PMCID: PMC3984232  PMID: 24465030
5.  Expression of Genes Related to Anti-Inflammatory Pathways Are Modified Among Farmers’ Children 
PLoS ONE  2014;9(3):e91097.
Background
The hygiene hypothesis states that children exposed to higher loads of microbes such as farmers’ children suffer less from allergies later in life. Several immunological mechanisms underpinning the hygiene hypothesis have been proposed such as a shift in T helper cell balance, T regulatory cell activity, or immune regulatory mechanisms induced by the innate immunity.
Objective
To investigate whether the proposed immunological mechanisms for the hygiene hypotheses are found in farmers’ children.
Methods
We assessed gene expression levels of 64 essential markers of the innate and adaptive immunity by quantitative real-time PCR in white blood cells in 316 Swiss children of the PARSIFAL study to compare farmers’ to non-farmers’ expressions and to associate them to the prevalence of asthma and rhinoconjunctivitis, total and allergen-specific IgE in serum, and expression of Cε germ-line transcripts.
Results
We found enhanced expression of genes of the innate immunity such as IRAK-4 and RIPK1 and enhanced expression of regulatory molecules such as IL-10, TGF-β, SOCS4, and IRAK-2 in farmers’ children. Furthermore, farmers’ children expressed less of the TH1 associated cytokine IFN-γ while TH2 associated transcription factor GATA3 was enhanced. No significant associations between the assessed immunological markers and allergic diseases or sensitization to allergens were observed.
Conclusion
Farmers’ children express multiple increased innate immune response and immune regulatory molecules, which may contribute to the mechanisms of action of the hygiene hypothesis.
doi:10.1371/journal.pone.0091097
PMCID: PMC3946278  PMID: 24603716
7.  Air Pollution and Respiratory Infections during Early Childhood: An Analysis of 10 European Birth Cohorts within the ESCAPE Project 
Environmental Health Perspectives  2013;122(1):107-113.
Background: Few studies have investigated traffic-related air pollution as a risk factor for respiratory infections during early childhood.
Objectives: We aimed to investigate the association between air pollution and pneumonia, croup, and otitis media in 10 European birth cohorts—BAMSE (Sweden), GASPII (Italy), GINIplus and LISAplus (Germany), MAAS (United Kingdom), PIAMA (the Netherlands), and four INMA cohorts (Spain)—and to derive combined effect estimates using meta-analysis.
Methods: Parent report of physician-diagnosed pneumonia, otitis media, and croup during early childhood were assessed in relation to annual average pollutant levels [nitrogen dioxide (NO2), nitrogen oxide (NOx), particulate matter ≤ 2.5 μm (PM2.5), PM2.5 absorbance, PM10, PM2.5–10 (coarse PM)], which were estimated using land use regression models and assigned to children based on their residential address at birth. Identical protocols were used to develop regression models for each study area as part of the ESCAPE project. Logistic regression was used to calculate adjusted effect estimates for each study, and random-effects meta-analysis was used to calculate combined estimates.
Results: For pneumonia, combined adjusted odds ratios (ORs) were elevated and statistically significant for all pollutants except PM2.5 (e.g., OR = 1.30; 95% CI: 1.02, 1.65 per 10-μg/m3 increase in NO2 and OR = 1.76; 95% CI: 1.00, 3.09 per 10-μg/m3 PM10). For otitis media and croup, results were generally null across all analyses except for NO2 and otitis media (OR = 1.09; 95% CI: 1.02, 1.16 per 10-μg/m3).
Conclusion: Our meta-analysis of 10 European birth cohorts within the ESCAPE project found consistent evidence for an association between air pollution and pneumonia in early childhood, and some evidence for an association with otitis media.
Citation: MacIntyre EA, Gehring U, Mölter A, Fuertes E, Klümper C, Krämer U, Quass U, Hoffmann B, Gascon M, Brunekreef B, Koppelman GH, Beelen R, Hoek G, Birk M, de Jongste JC, Smit HA, Cyrys J, Gruzieva O, Korek M, Bergström A, Agius RM, de Vocht F, Simpson A, Porta D, Forastiere F, Badaloni C, Cesaroni G, Esplugues A, Fernández-Somoano A, Lerxundi A, Sunyer J, Cirach M, Nieuwenhuijsen MJ, Pershagen G, Heinrich J. 2014. Air pollution and respiratory infections during early childhood: an analysis of 10 European birth cohorts within the ESCAPE project. Environ Health Perspect 122:107–113; http://dx.doi.org/10.1289/ehp.1306755
doi:10.1289/ehp.1306755
PMCID: PMC3888562  PMID: 24149084
8.  Rule-Based Models of the Interplay between Genetic and Environmental Factors in Childhood Allergy 
PLoS ONE  2013;8(11):e80080.
Both genetic and environmental factors are important for the development of allergic diseases. However, a detailed understanding of how such factors act together is lacking. To elucidate the interplay between genetic and environmental factors in allergic diseases, we used a novel bioinformatics approach that combines feature selection and machine learning. In two materials, PARSIFAL (a European cross-sectional study of 3113 children) and BAMSE (a Swedish birth-cohort including 2033 children), genetic variants as well as environmental and lifestyle factors were evaluated for their contribution to allergic phenotypes. Monte Carlo feature selection and rule based models were used to identify and rank rules describing how combinations of genetic and environmental factors affect the risk of allergic diseases. Novel interactions between genes were suggested and replicated, such as between ORMDL3 and RORA, where certain genotype combinations gave odds ratios for current asthma of 2.1 (95% CI 1.2-3.6) and 3.2 (95% CI 2.0-5.0) in the BAMSE and PARSIFAL children, respectively. Several combinations of environmental factors appeared to be important for the development of allergic disease in children. For example, use of baby formula and antibiotics early in life was associated with an odds ratio of 7.4 (95% CI 4.5-12.0) of developing asthma. Furthermore, genetic variants together with environmental factors seemed to play a role for allergic diseases, such as the use of antibiotics early in life and COL29A1 variants for asthma, and farm living and NPSR1 variants for allergic eczema. Overall, combinations of environmental and life style factors appeared more frequently in the models than combinations solely involving genes. In conclusion, a new bioinformatics approach is described for analyzing complex data, including extensive genetic and environmental information. Interactions identified with this approach could provide useful hints for further in-depth studies of etiological mechanisms and may also strengthen the basis for risk assessment and prevention.
doi:10.1371/journal.pone.0080080
PMCID: PMC3833974  PMID: 24260339
9.  Air Pollution Exposure and Lung Function in Children: The ESCAPE Project 
Environmental Health Perspectives  2013;121(11-12):1357-1364.
Background: There is evidence for adverse effects of outdoor air pollution on lung function of children. Quantitative summaries of the effects of air pollution on lung function, however, are lacking due to large differences among studies.
Objectives: We aimed to study the association between residential exposure to air pollution and lung function in five European birth cohorts with a standardized exposure assessment following a common protocol.
Methods: As part of the European Study of Cohorts for Air Pollution Effects (ESCAPE) we analyzed data from birth cohort studies situated in Germany, Sweden, the Netherlands, and the United Kingdom that measured lung function at 6–8 years of age (n = 5,921). Annual average exposure to air pollution [nitrogen oxides (NO2, NOx), mass concentrations of particulate matter with diameters < 2.5, < 10, and 2.5–10 μm (PM2.5, PM10, and PMcoarse), and PM2.5 absorbance] at the birth address and current address was estimated by land-use regression models. Associations of lung function with estimated air pollution levels and traffic indicators were estimated for each cohort using linear regression analysis, and then combined by random effects meta-analysis.
Results: Estimated levels of NO2, NOx, PM2.5 absorbance, and PM2.5 at the current address, but not at the birth address, were associated with small decreases in lung function. For example, changes in forced expiratory volume in 1 sec (FEV1) ranged from –0.86% (95% CI: –1.48, –0.24%) for a 20-μg/m3 increase in NOx to –1.77% (95% CI: –3.34, –0.18%) for a 5-μg/m3 increase in PM2.5.
Conclusions: Exposure to air pollution may result in reduced lung function in schoolchildren.
Citation: Gehring U, Gruzieva O, Agius RM, Beelen R, Custovic A, Cyrys J, Eeftens M, Flexeder C, Fuertes E, Heinrich J, Hoffmann B, de Jongste JC, Kerkhof M, Klümper C, Korek M, Mölter A, Schultz ES, Simpson A, Sugiri D, Svartengren M, von Berg A, Wijga AH, Pershagen G, Brunekreef B. 2013. Air pollution exposure and lung function in children: the ESCAPE project. Environ Health Perspect 121:1357–1364; http://dx.doi.org/10.1289/ehp.1306770
doi:10.1289/ehp.1306770
PMCID: PMC3855518  PMID: 24076757
10.  Exposure to aircraft and road traffic noise and associations with heart disease and stroke in six European countries: a cross-sectional study 
Environmental Health  2013;12:89.
Background
Although a number of studies have found an association between aircraft noise and hypertension, there is a lack of evidence on associations with other cardiovascular disease. For road traffic noise, more studies are available but the extent of possible confounding by air pollution has not been established.
Methods
This study used data from the Hypertension and Environmental Noise near Airports (HYENA) study. Cross-sectional associations between self-reported ‘heart disease and stroke’ and aircraft noise and road traffic noise were examined using data collected between 2004 and 2006 on 4712 participants (276 cases), who lived near airports in six European countries (UK, Germany, Netherlands, Sweden, Greece, Italy). Data were available to assess potential confounding by NO2 air pollution in a subsample of three countries (UK, Netherlands, Sweden).
Results
An association between night-time average aircraft noise and ‘heart disease and stroke’ was found after adjustment for socio-demographic confounders for participants who had lived in the same place for ≥ 20 years (odds ratio (OR): 1.25 (95% confidence interval (CI) 1.03, 1.51) per 10 dB (A)); this association was robust to adjustment for exposure to air pollution in the subsample. 24 hour average road traffic noise exposure was associated with ‘heart disease and stroke’ (OR: 1.19 (95% CI 1.00, 1.41), but adjustment for air pollution in the subsample suggested this may have been due to confounding by air pollution. Statistical assessment (correlations and variance inflation factor) suggested only modest collinearity between noise and NO2 exposures.
Conclusions
Exposure to aircraft noise over many years may increase risks of heart disease and stroke, although more studies are needed to establish how much the risks associated with road traffic noise may be explained by air pollution.
doi:10.1186/1476-069X-12-89
PMCID: PMC4015897  PMID: 24131577
Air pollutants; Angina pectoris; Cardiovascular diseases; Myocardial infarction; Noise; Transportation; Stroke
11.  Interaction between air pollution exposure and genes in relation to levels of inflammatory markers and risk of myocardial infarction 
BMJ Open  2013;3(9):e003058.
Objectives
Air pollution exposure induces cardiovascular effects, possibly via systemic inflammation and coagulation misbalance. Genetic variation may determine individual susceptibility. Our aim was to investigate effect modification by inflammation (Interleukin6 (IL6), tumour necrosis factor-α (TNF-α)) and coagulation (fibrinogen Bβ, plasminogen activator inhibitor-1 (PAI-1)) gene variants on the effect of long-term or short-term air pollution exposure on both blood marker levels and non-fatal myocardial infarction (MI) risk.
Design
Population-based case–control study with a nested case-crossover study. Gene-environment interactions for short-term and long-term air pollution on blood marker levels were studied in population controls, for long-term exposure on MI risk using case–control design, and for short-term exposure on MI onset using case-crossover design.
Setting
The Stockholm Heart Epidemiology Programme (SHEEP) conducted in 1992–1994 in Stockholm, Sweden. Spatial modelling was used to assess long-term (up to 30 years retrospectively) air pollution exposure to traffic-NO2 and heating-SO2 emissions at home addresses. Urban background NO2, SO2, PM10 and O3 measurements were used to estimate short-term (up to 5 days) air pollution exposure.
Participants
1192 MI cases and 1506 population controls aged 45–70 years.
Outcomes
The levels of blood markers of inflammation (IL-6, TNF-α) and coagulation (fibrinogen, PAI-1) and MI risk.
Results
We observed gene–environment interaction for several IL6 and TNF SNPs in relation to inflammation blood marker levels. One-year traffic-NO2 exposure was associated with higher IL-6 levels with each additional IL6-174C allele, and 1-year heating-SO2 exposure with higher levels of TNF-α in TNF-308AA homozygotes versus −308G carriers. Short-term air pollution exposure also interacted with IL6 and TNF in relation to marker levels. The risk of MI followed the effect on blood markers in each genotype group.
Conclusions
Genetic variants in IL6 and TNF may modify effects of long-term and short-term air pollution exposure on inflammatory marker levels and MI risk.
doi:10.1136/bmjopen-2013-003058
PMCID: PMC3780315  PMID: 24056475
Air pollution; Gene-environment interaction; inflammation; IL6; TNF
12.  A genome-wide association study of atopic dermatitis identifies loci with overlapping effects on asthma and psoriasis 
Human Molecular Genetics  2013;22(23):4841-4856.
Atopic dermatitis (AD) is the most common dermatological disease of childhood. Many children with AD have asthma and AD shares regions of genetic linkage with psoriasis, another chronic inflammatory skin disease. We present here a genome-wide association study (GWAS) of childhood-onset AD in 1563 European cases with known asthma status and 4054 European controls. Using Illumina genotyping followed by imputation, we generated 268 034 consensus genotypes and in excess of 2 million single nucleotide polymorphisms (SNPs) for analysis. Association signals were assessed for replication in a second panel of 2286 European cases and 3160 European controls. Four loci achieved genome-wide significance for AD and replicated consistently across all cohorts. These included the epidermal differentiation complex (EDC) on chromosome 1, the genomic region proximal to LRRC32 on chromosome 11, the RAD50/IL13 locus on chromosome 5 and the major histocompatibility complex (MHC) on chromosome 6; reflecting action of classical HLA alleles. We observed variation in the contribution towards co-morbid asthma for these regions of association. We further explored the genetic relationship between AD, asthma and psoriasis by examining previously identified susceptibility SNPs for these diseases. We found considerable overlap between AD and psoriasis together with variable coincidence between allergic rhinitis (AR) and asthma. Our results indicate that the pathogenesis of AD incorporates immune and epidermal barrier defects with combinations of specific and overlapping effects at individual loci.
doi:10.1093/hmg/ddt317
PMCID: PMC3820131  PMID: 23886662
13.  Interaction between Retinoid Acid Receptor-Related Orphan Receptor Alpha (RORA) and Neuropeptide S Receptor 1 (NPSR1) in Asthma 
PLoS ONE  2013;8(4):e60111.
Retinoid acid receptor-related Orphan Receptor Alpha (RORA) was recently identified as a susceptibility gene for asthma in a genome-wide association study. To investigate the impact of RORA on asthma susceptibility, we performed a genetic association study between RORA single nucleotide polymorphisms (SNPs) in the vicinity of the asthma-associated SNP (rs11071559) and asthma-related traits. Because the regulatory region of a previously implicated asthma susceptibility gene, Neuropeptide S receptor 1 (NPSR1), has predicted elements for RORA binding, we hypothesized that RORA may interact biologically and genetically with NPSR1. 37 RORA SNPs and eight NPSR1 SNPs were genotyped in the Swedish birth cohort BAMSE (2033 children) and the European cross-sectional PARSIFAL study (1120 children). Seven RORA SNPs confined into a 49 kb region were significantly associated with physician-diagnosed childhood asthma. The most significant association with rs7164773 (T/C) was driven by the CC genotype in asthma cases (OR = 2.0, 95%CI 1.36–2.93, p = 0.0003 in BAMSE; and 1.61, 1.18–2.19, p = 0.002 in the combined BAMSE-PARSIFAL datasets, respectively), and strikingly, the risk effect was dependent on the Gln344Arg mutation in NPSR1. In cell models, stimulation of NPSR1 activated a pathway including RORA and other circadian clock genes. Over-expression of RORA decreased NPSR1 promoter activity further suggesting a regulatory loop between these genes. In addition, Rora mRNA expression was lower in the lung tissue of Npsr1 deficient mice compared to wildtype littermates during the early hours of the light period. We conclude that RORA SNPs are associated with childhood asthma and show epistasis with NPSR1, and the interaction between RORA and NPSR1 may be of biological relevance. Combinations of common susceptibility alleles and less common functional polymorphisms may modify the joint risk effects on asthma susceptibility.
doi:10.1371/journal.pone.0060111
PMCID: PMC3615072  PMID: 23565190
14.  DNA Methylation in the Neuropeptide S Receptor 1 (NPSR1) Promoter in Relation to Asthma and Environmental Factors 
PLoS ONE  2013;8(1):e53877.
Asthma and allergy are complex disorders influenced by both inheritance and environment, a relationship that might be further clarified by epigenetics. Neuropeptide S Receptor 1 (NPSR1) has been associated with asthma and allergy and a study suggested modulation of the genetic risk by environmental factors. We aimed to study DNA methylation in the promoter region of NPSR1 in relation to asthma and environmental exposures. Electrophoretic Mobility Shift Assay (EMSA) was used to investigate potential functional roles of both genotypes and methylation status in the NPSR1 promoter. DNA methylation was analysed using EpiTYPER in blood samples from two well-characterized cohorts; the BIOAIR study of severe asthma in adults and the Swedish birth cohort BAMSE. We observed that DNA methylation and genetic variants in the promoter influenced the binding of nuclear proteins to DNA, suggesting functional relevance. Significant, although small, differences in methylation were related to both adult severe asthma (p = 0.0001) and childhood allergic asthma (p = 0.01). Furthermore, DNA methylation was associated with exposures such as current smoking in adults for two CpG sites (p = 0.005 and 0.04), parental smoking during infancy in the children (p = 0.02) and in which month the sample was taken (p = 0.01). In summary, DNA methylation levels in the promoter of NPSR1 showed small but significant associations with asthma, both in adults and in children, and to related traits such as allergy and certain environmental exposures. Both genetic variation and the methylated state of CpG sites seem to have an effect on the binding of nuclear proteins in the regulatory region of NPSR1 suggesting complex regulation of this gene in asthma and allergy.
doi:10.1371/journal.pone.0053877
PMCID: PMC3553086  PMID: 23372674
15.  Differential DNA Methylation in Purified Human Blood Cells: Implications for Cell Lineage and Studies on Disease Susceptibility 
PLoS ONE  2012;7(7):e41361.
Methylation of cytosines at CpG sites is a common epigenetic DNA modification that can be measured by a large number of methods, now even in a genome-wide manner for hundreds of thousands of sites. The application of DNA methylation analysis is becoming widely popular in complex disorders, for example, to understand part of the “missing heritability”. The DNA samples most readily available for methylation studies are derived from whole blood. However, blood consists of many functionally and developmentally distinct cell populations in varying proportions. We studied whether such variation might affect the interpretation of methylation studies based on whole blood DNA. We found in healthy male blood donors there is important variation in the methylation profiles of whole blood, mononuclear cells, granulocytes, and cells from seven selected purified lineages. CpG methylation between mononuclear cells and granulocytes differed for 22% of the 8252 probes covering the selected 343 genes implicated in immune-related disorders by genome-wide association studies, and at least one probe was differentially methylated for 85% of the genes, indicating that whole blood methylation results might be unintelligible. For individual genes, even if the overall methylation patterns might appear similar, a few CpG sites in the regulatory regions may have opposite methylation patterns (i.e., hypo/hyper) in the main blood cell types. We conclude that interpretation of whole blood methylation profiles should be performed with great caution and for any differences implicated in a disorder, the differences resulting from varying proportions of white blood cell types should be considered.
doi:10.1371/journal.pone.0041361
PMCID: PMC3405143  PMID: 22848472
16.  Thymic stromal lymphopoietin (TSLP) is associated with allergic rhinitis in children with asthma 
Background
Allergic rhinitis (AR) affects up to 80% of children with asthma and increases asthma severity. Thymic stromal lymphopoietin (TSLP) is a key mediator of allergic inflammation. The role of the TSLP gene (TSLP) in the pathogenesis of AR has not been studied.
Objective
To test for associations between variants in TSLP, TSLP-related genes, and AR in children with asthma.
Methods
We genotyped 15 single nucleotide polymorphisms (SNPs) in TSLP, OX40L, IL7R, and RXRα in three independent cohorts: 592 asthmatic Costa Rican children and their parents, 422 nuclear families of North American children with asthma, and 239 Swedish children with asthma. We tested for associations between these SNPs and AR. As we previously reported sex-specific effects for TSLP, we performed overall and sex-stratified analyses. We additionally performed secondary analyses for gene-by-gene interactions.
Results
Across the three cohorts, the T allele of TSLP SNP rs1837253 was undertransmitted in boys with AR and asthma as compared to boys with asthma alone. The SNP was associated with reduced odds for AR (odds ratios ranging from 0.56 to 0.63, with corresponding Fisher's combined P value of 1.2 × 10-4). Our findings were significant after accounting for multiple comparisons. SNPs in OX40L, IL7R, and RXRα were not consistently associated with AR in children with asthma. There were nominally significant interactions between gene pairs.
Conclusions
TSLP SNP rs1837253 is associated with reduced odds for AR in boys with asthma. Our findings support a role for TSLP in the pathogenesis of AR in children with asthma.
doi:10.1186/1476-7961-9-1
PMCID: PMC3032752  PMID: 21244681
17.  MMP12, Lung Function, and COPD in High-Risk Populations 
The New England journal of medicine  2009;361(27):2599-2608.
BACKGROUND
Genetic variants influencing lung function in children and adults may ultimately lead to the development of chronic obstructive pulmonary disease (COPD), particularly in high-risk groups.
METHODS
We tested for an association between single-nucleotide polymorphisms (SNPs) in the gene encoding matrix metalloproteinase 12 (MMP12) and a measure of lung function (prebronchodilator forced expiratory volume in 1 second [FEV1]) in more than 8300 subjects in seven cohorts that included children and adults. Within the Normative Aging Study (NAS), a cohort of initially healthy adult men, we tested for an association between SNPs that were associated with FEV1 and the time to the onset of COPD. We then examined the relationship between MMP12 SNPs and COPD in two cohorts of adults with COPD or at risk for COPD.
RESULTS
The minor allele (G) of a functional variant in the promoter region of MMP12 (rs2276109 [−82A→G]) was positively associated with FEV1 in a combined analysis of children with asthma and adult former and current smokers in all cohorts (P=2×10−6). This allele was also associated with a reduced risk of the onset of COPD in the NAS cohort (hazard ratio, 0.65; 95% confidence interval [CI], 0.46 to 0.92; P = 0.02) and with a reduced risk of COPD in a cohort of smokers (odds ratio, 0.63; 95% CI, 0.45 to 0.88; P = 0.005) and among participants in a family-based study of early-onset COPD (P = 0.006).
CONCLUSIONS
The minor allele of a SNP in MMP12 (rs2276109) is associated with a positive effect on lung function in children with asthma and in adults who smoke. This allele is also associated with a reduced risk of COPD in adult smokers.
doi:10.1056/NEJMoa0904006
PMCID: PMC2904064  PMID: 20018959
18.  Air Pollution Exposure—A Trigger for Myocardial Infarction? 
The association between ambient air pollution exposure and hospitalization for cardiovascular events has been reported in several studies with conflicting results. A case-crossover design was used to investigate the effects of air pollution in 660 first-time myocardial infarction cases in Stockholm in 1993–1994, interviewed shortly after diagnosis using a standard protocol. Air pollution data came from central urban background monitors. No associations were observed between the risk for onset of myocardial infarction and two-hour or 24-hour air pollution exposure. No evidence of susceptible subgroups was found. This study provides no support that moderately elevated air pollution levels trigger first-time myocardial infarction.
doi:10.3390/ijerph7041486
PMCID: PMC2872334  PMID: 20617041
air pollution; myocardial infarction; trigger; onset; case cross-over design
19.  Saliva Cortisol and Exposure to Aircraft Noise in Six European Countries 
Environmental Health Perspectives  2009;117(11):1713-1717.
Background
Several studies show an association between exposure to aircraft or road traffic noise and cardiovascular effects, which may be mediated by a noise-induced release of stress hormones.
Objective
Our objective was to assess saliva cortisol concentration in relation to exposure to aircraft noise.
Method
A multicenter cross-sectional study, HYENA (Hypertension and Exposure to Noise near Airports), comprising 4,861 persons was carried out in six European countries. In a subgroup of 439 study participants, selected to enhance the contrast in exposure to aircraft noise, saliva cortisol was assessed three times (morning, lunch, and evening) during 1 day.
Results
We observed an elevation of 6.07 nmol/L [95% confidence interval (CI), 2.32–9.81 nmol/L] in morning saliva cortisol level in women exposed to aircraft noise at an average 24-hr sound level (LAeq,24h) > 60 dB, compared with women exposed to LAeq,24h ≤ 50 dB, corresponding to an increase of 34%. Employment status appeared to modify the response. We found no association between noise exposure and saliva cortisol levels in men.
Conclusions
Our results suggest that exposure to aircraft noise increases morning saliva cortisol levels in women, which could be of relevance for noise-related cardiovascular effects.
doi:10.1289/ehp.0900933
PMCID: PMC2801169  PMID: 20049122
cardiovascular disease; gender differences
20.  Interactions between Glutathione S-Transferase P1, Tumor Necrosis Factor, and Traffic-Related Air Pollution for Development of Childhood Allergic Disease 
Environmental Health Perspectives  2008;116(8):1077-1084.
Background
Air pollutants may induce airway inflammation and sensitization due to generation of reactive oxygen species. The genetic background to these mechanisms could be important effect modifiers.
Objective
Our goal was to assess interactions between exposure to air pollution and single nucleotide polymorphisms (SNPs) in the β2-adrenergic receptor (ADRB2), glutathione S-transferase P1 (GSTP1), and tumor necrosis factor (TNF) genes for development of childhood allergic disease.
Methods
In a birth cohort originally of 4,089 children, we assessed air pollution from local traffic using nitrogen oxides (traffic NOx) as an indicator based on emission databases and dispersion modeling and estimated individual exposure through geocoding of home addresses. We measured peak expiratory flow rates and specific IgE for inhalant and food allergens at 4 years of age, and selected children with asthma symptoms up to 4 years of age (n = 542) and controls (n = 542) for genotyping.
Results
Interaction effects on allergic sensitization were indicated between several GSTP1 SNPs and traffic NOx exposure during the first year of life (pnominal < 0.001–0.06). Children with Ile105Val/Val105Val genotypes were at increased risk of sensitization to any allergen when exposed to elevated levels of traffic NOx (for a difference between the 5th and 95th percentile of exposure: odds ratio = 2.4; 95% confidence interval, 1.0–5.3). In children with TNF-308 GA/AA genotypes, the GSTP1–NOx interaction effect was even more pronounced. We observed no conclusive interaction effects for ADRB2.
Conclusion
The effect of air pollution from traffic on childhood allergy appears to be modified by GSTP1 and TNF variants, supporting a role of genes controlling the antioxidative system and inflammatory response in allergy.
doi:10.1289/ehp.11117
PMCID: PMC2516580  PMID: 18709160
ADRB2; air pollution; allergy; asthma; genetics; GSTP1; interaction; nitrogen oxides; polymorphism; TNF
21.  Hypertension and Exposure to Noise Near Airports: the HYENA Study 
Environmental Health Perspectives  2007;116(3):329-333.
Background
An increasing number of people are exposed to aircraft and road traffic noise. Hypertension is an important risk factor for cardiovascular disease, and even a small contribution in risk from environmental factors may have a major impact on public health.
Objectives
The HYENA (Hypertension and Exposure to Noise near Airports) study aimed to assess the relations between noise from aircraft or road traffic near airports and the risk of hypertension.
Methods
We measured blood pressure and collected data on health, socioeconomic, and lifestyle factors, including diet and physical activity, via questionnaire at home visits for 4,861 persons 45–70 years of age, who had lived at least 5 years near any of six major European airports. We assessed noise exposure using detailed models with a resolution of 1 dB (5 dB for United Kingdom road traffic noise), and a spatial resolution of 250 × 250 m for aircraft and 10 × 10 m for road traffic noise.
Results
We found significant exposure–response relationships between night-time aircraft as well as average daily road traffic noise exposure and risk of hypertension after adjustment for major confounders. For night-time aircraft noise, a 10-dB increase in exposure was associated with an odds ratio (OR) of 1.14 [95% confidence interval (CI), 1.01–1.29]. The exposure–response relationships were similar for road traffic noise and stronger for men with an OR of 1.54 (95% CI, 0.99–2.40) in the highest exposure category (> 65 dB; ptrend = 0.008).
Conclusions
Our results indicate excess risks of hypertension related to long-term noise exposure, primarily for night-time aircraft noise and daily average road traffic noise.
doi:10.1289/ehp.10775
PMCID: PMC2265027  PMID: 18335099
aircraft; blood pressure; hypertension; noise; road traffic
22.  Molecular Fingerprinting of the Fecal Microbiota of Children Raised According to Different Lifestyles▿ †  
In this population-based study, 90 children from three European countries were examined to determine the impact of lifestyle on the fecal microbiota. The study was designed to assess the impact of two extreme lifestyles that we hypothesized could impact the microbial composition in the gut: i.e., an anthroposophic lifestyle (restricted use of antibiotics, greater consumption of fermented vegetables, etc.) versus living on a farm (greater consumption of farm milk, contact with animals, etc.). In previous studies, these lifestyles correlated with lower prevalence of allergies. Terminal restriction fragment length polymorphism (T-RFLP) was used to assess the bacterial composition in fecal samples since recent studies have shown that the majority of this community cannot be cultivated. The T-RFLP data were used to calculate richness and evenness of the fecal microbiota. Children that were attending Steiner schools (anthroposophic children) had a significantly higher diversity of microbes in their feces than farm children, who in turn also had lower diversity than the control groups. Specific primers were also used to focus on the Lactobacillus-like community (lactic acid bacteria [LAB]). Large differences were found in the LAB subpopulations in the sampled groups. In some children, the LAB subpopulation was dominated by a species that has not yet been cultivated.
doi:10.1128/AEM.02223-06
PMCID: PMC1855685  PMID: 17293501
23.  Hypertension and Exposure to Noise near Airports (HYENA): Study Design and Noise Exposure Assessment 
Environmental Health Perspectives  2005;113(11):1473-1478.
An increasing number of people live near airports with considerable noise and air pollution. The Hypertension and Exposure to Noise near Airports (HYENA) project aims to assess the impact of airport-related noise exposure on blood pressure (BP) and cardiovascular disease using a cross-sectional study design. We selected 6,000 persons (45–70 years of age) who had lived at least 5 years near one of six major European airports. We used modeled aircraft noise contours, aiming to maximize exposure contrast. Automated BP instruments are used to reduce observer error. We designed a standardized questionnaire to collect data on annoyance, noise disturbance, and major confounders. Cortisol in saliva was collected in a subsample of the study population (n = 500) stratified by noise exposure level. To investigate short-term noise effects on BP and possible effects on nighttime BP dipping, we measured 24-hr BP and assessed continuous night noise in another sub-sample (n = 200). To ensure comparability between countries, we used common noise models to assess individual noise exposure, with a resolution of 1 dB(A). Modifiers of individual exposure, such as the orientation of living and bedroom toward roads, window-opening habits, and sound insulation, were assessed by the questionnaire. For four airports, we estimated exposure to air pollution to explore modifying effects of air pollution on cardiovascular disease. The project assesses exposure to traffic-related air pollutants, primarily using data from another project funded by the European Union (APMoSPHERE, Air Pollution Modelling for Support to Policy on Health and Environmental Risks in Europe).
doi:10.1289/ehp.8037
PMCID: PMC1310905  PMID: 16263498
air pollution; aircraft; blood pressure; hypertension; noise; road traffic
24.  Research priorities in environmental health  
BMJ : British Medical Journal  1999;318(7199):1636-1637.
PMCID: PMC1116005  PMID: 10373150
25.  Mortality in a region surrounding an arsenic emitting plant 
The purpose of the investigation is to study whether an increased mortality from certain causes exists in an area around the Rönnskärsverken smelter works in northern Sweden. Founded in 1928, this metallurgical plant processing mainly nonferrous metals has since its initial operations been using ore with a high arsenic content. This has resulted in environmental pollution to air and water of arsenic, as well as other metals and sulfur dioxide.
The causes of death for the population of two parishes in the vicinity of the plant were listed from the National Sedish Register on Death Causes. A reference area in the same part of Sweden with similar degree of urbanization, occupational profile, and age distribution was chosen. The causes of death for the two populations were followed during a period of 14 yr. A significantly higher mortality rate for lung cancer was noted in men in the exposed area. However, this increase was no longer significant when the occupationally exposed at Rönnskärsverken were excluded. The latter showed a highly significant excess mortality due to primary respiratory cancer.
A continuation of this investigation in the form of a cohort study of both the mortality and cancer incidence is currently under way.
PMCID: PMC1637390  PMID: 908290

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