Asthma has been hypothesized to be associated with lung cancer (LC) risk. We conducted a pooled analysis of 16 studies in the International Lung Cancer Consortium (ILCCO) to quantitatively assess this association and compared the results with 36 previously published studies. In total, information from 585 444 individuals was used. Study-specific measures were combined using random effects models. A meta-regression and subgroup meta-analyses were performed to identify sources of heterogeneity. The overall LC relative risk (RR) associated with asthma was 1.28 [95% confidence intervals (CIs) = 1.16–1.41] but with large heterogeneity (I2 = 73%, P < 0.001) between studies. Among ILCCO studies, an increased risk was found for squamous cell (RR = 1.69, 95%, CI = 1.26–2.26) and for small-cell carcinoma (RR = 1.71, 95% CI = 0.99–2.95) but was weaker for adenocarcinoma (RR = 1.09, 95% CI = 0.88–1.36). The increased LC risk was strongest in the 2 years after asthma diagnosis (RR = 2.13, 95% CI = 1.09–4.17) but subjects diagnosed with asthma over 10 years prior had no or little increased LC risk (RR = 1.10, 95% CI = 0.94–1.30). Because the increased incidence of LC was chiefly observed in small cell and squamous cell lung carcinomas, primarily within 2 years of asthma diagnosis and because the association was weak among never smokers, we conclude that the association may not reflect a causal effect of asthma on the risk of LC.
Atopy and plasma IgE concentration are genetically complex traits, and the specific genetic risk factors that lead to IgE dysregulation and clinical atopy are an area of active investigation.
To ascertain the genetic risk factors which lead to IgE dysregulation.
A genome wide association study (GWAS) was performed in 6,819 participants from the Framingham Heart Study (FHS). Seventy of the top SNPs were selected based on p-values and linkage disequilibrium among neighboring SNPs and evaluated in a meta-analysis with five independent populations from the KORA, B58C, and CAMP cohorts.
Thirteen SNPs located in the region of three genes, FCER1A, STAT6, and IL-13, were found to have genome-wide significance in the FHS GWAS. The most significant SNPs from the three regions were rs2251746 (FCER1A, p-value 2.11×10-12), rs1059513 (STAT6, p-value 2.87×10-08), and rs1295686 (IL-13, p-value 3.55×10-08). Four additional gene regions - HLA-G, HLA-DQA2, HLA-A, and DARC - reached genome-wide statistical significance in meta-analysis combining FHS and replication cohorts, although the DARC association did not appear independent of SNPs in the nearby FCER1A gene.
This GWAS of the FHS has identified genetic loci in HLA genes that may have a role in the pathogenesis of IgE dysregulation and atopy. It also confirmed the association of known susceptibility loci, FCER1A, STAT6, and IL-13, for the dysregulation of total IgE.
total IgE; atopy; asthma; GWAS
Environmental exposures during pregnancy and early life may have adverse health effects. Single birth cohort studies often lack statistical power to tease out such effects reliably. To improve the use of existing data and to facilitate collaboration among these studies, an inventory of the environmental exposure and health data in these studies was made as part of the ENRIECO (Environmental Health Risks in European Birth Cohorts) project. The focus with regard to exposure was on outdoor air pollution, water contamination, allergens and biological organisms, metals, pesticides, smoking and second hand tobacco smoke (SHS), persistent organic pollutants (POPs), noise, radiation, and occupational exposures. The review lists methods and data on environmental exposures in 37 European birth cohort studies. Most data is currently available for smoking and SHS (N=37 cohorts), occupational exposures (N=33), outdoor air pollution, and allergens and microbial agents (N=27). Exposure modeling is increasingly used for long-term air pollution exposure assessment; biomonitoring is used for assessment of exposure to metals, POPs and other chemicals; and environmental monitoring for house dust mite exposure assessment. Collaborative analyses with data from several birth cohorts have already been performed successfully for outdoor air pollution, water contamination, allergens, biological contaminants, molds, POPs and SHS. Key success factors for collaborative analyses are common definitions of main exposure and health variables. Our review emphasizes that such common definitions need ideally be arrived at in the study design phase. However, careful comparison of methods used in existing studies also offers excellent opportunities for collaborative analyses. Investigators can use this review to evaluate the potential for future collaborative analyses with respect to data availability and methods used in the different cohorts and to identify potential partners for a specific research question.
Environment; Europe; Exposure assessment; Birth cohort; Review
Genetic case-control association studies often include data on clinical covariates, such as body mass index (BMI), smoking status, or age, that may modify the underlying genetic risk of case or control samples. For example, in type 2 diabetes, odds ratios for established variants estimated from low–BMI cases are larger than those estimated from high–BMI cases. An unanswered question is how to use this information to maximize statistical power in case-control studies that ascertain individuals on the basis of phenotype (case-control ascertainment) or phenotype and clinical covariates (case-control-covariate ascertainment). While current approaches improve power in studies with random ascertainment, they often lose power under case-control ascertainment and fail to capture available power increases under case-control-covariate ascertainment. We show that an informed conditioning approach, based on the liability threshold model with parameters informed by external epidemiological information, fully accounts for disease prevalence and non-random ascertainment of phenotype as well as covariates and provides a substantial increase in power while maintaining a properly controlled false-positive rate. Our method outperforms standard case-control association tests with or without covariates, tests of gene x covariate interaction, and previously proposed tests for dealing with covariates in ascertained data, with especially large improvements in the case of case-control-covariate ascertainment. We investigate empirical case-control studies of type 2 diabetes, prostate cancer, lung cancer, breast cancer, rheumatoid arthritis, age-related macular degeneration, and end-stage kidney disease over a total of 89,726 samples. In these datasets, informed conditioning outperforms logistic regression for 115 of the 157 known associated variants investigated (P-value = 1×10−9). The improvement varied across diseases with a 16% median increase in χ2 test statistics and a commensurate increase in power. This suggests that applying our method to existing and future association studies of these diseases may identify novel disease loci.
This work describes a new methodology for analyzing genome-wide case-control association studies of diseases with strong correlations to clinical covariates, such as age in prostate cancer and body mass index in type 2 diabetes. Currently, researchers either ignore these clinical covariates or apply approaches that ignore the disease's prevalence and the study's ascertainment strategy. We take an alternative approach, leveraging external prevalence information from the epidemiological literature and constructing a statistic based on the classic liability threshold model of disease. Our approach not only improves the power of studies that ascertain individuals randomly or based on the disease phenotype, but also improves the power of studies that ascertain individuals based on both the disease phenotype and clinical covariates. We apply our statistic to seven datasets over six different diseases and a variety of clinical covariates. We found that there was a substantial improvement in test statistics relative to current approaches at known associated variants. This suggests that novel loci may be identified by applying our method to existing and future association studies of these diseases.
Although the negative health consequences of the exposure to second hand tobacco smoke during childhood are already known, evidence on the economic consequences is still rare. The aim of this study was to estimate excess healthcare costs of exposure to tobacco smoke in German children.
The study is based on data from two birth cohort studies of 3,518 children aged 9-11 years with information on healthcare utilisation and tobacco smoke exposure: the GINIplus study (German Infant Study On The Influence Of Nutrition Intervention Plus Environmental And Genetic Influences On Allergy Development) and the LISAplus study (Influence of Life-Style Factors On The Development Of The Immune System And Allergies In East And West Germany Plus The Influence Of Traffic Emissions And Genetics). Direct medical costs were estimated using a bottom-up approach (base year 2007). We investigated the impact of tobacco smoke exposure in different environments on the main components of direct healthcare costs using descriptive analysis and a multivariate two-step regression analysis.
Descriptive analysis showed that average annual medical costs (physician visits, physical therapy and hospital treatment) were considerably higher for children exposed to second-hand tobacco smoke at home (indoors or on patio/balcony) compared with those who were not exposed. Regression analysis confirmed these descriptive trends: the odds of positive costs and the amount of total costs are significantly elevated for children exposed to tobacco smoke at home after adjusting for confounding variables. Combining the two steps of the regression model shows smoking attributable total costs per child exposed at home of €87 [10–165] (patio/balcony) and €144 [6–305] (indoors) compared to those with no exposure. Children not exposed at home but in other places showed only a small, but not significant, difference in total costs compared to those with no exposure.
This study shows adverse economic consequences of second-hand smoke in children depending on proximity of exposure. Tobacco smoke exposure seems to affect healthcare utilisation in children who are not only exposed to smoke indoors but also if parents reported exclusively smoking on patio or balcony. Preventing children from exposure to second-hand tobacco smoke might thus be desirable not only from a health but also from an economic perspective.
Elevated cholesterol levels in children can be a risk factor for cardiovascular diseases in later life. In adults, it has been shown that blood lipid levels are strongly influenced by polymorphisms in the fatty acid desaturase (FADS) gene cluster in addition to nutritional and other exogenous and endogenous determinants. Our aim was to investigate whether lipid levels are determined by the FADS genotype already in children and whether this association interacts with dietary intake of n-3 fatty acids.
The analysis was based on data of 2006 children from two German prospective birth cohort studies. Total cholesterol, HDL, LDL and triglycerides were measured at 10 years of age. Six single nucleotide polymorphisms (SNPs) of the FADS gene cluster were genotyped. Dietary n-3 fatty acid intake was assessed by food frequency questionnaire. Linear regression modeling was used to assess the association between lipid levels, n-3 fatty acid intake and FADS genotype.
Individuals carrying the homozygous minor allele had lower levels of total cholesterol [means ratio (MR) ranging from 0.96 (p = 0.0093) to 0.98 (p = 0.2949), depending on SNPs] and LDL [MR between 0.94 (p = 0.0179) and 0.97 (p = 0.2963)] compared to homozygous major allele carriers. Carriers of the heterozygous allele showed lower HDL levels [β between −0.04 (p = 0.0074) to −0.01 (p = 0.3318)] and higher triglyceride levels [MR ranging from 1.06 (p = 0.0065) to 1.07 (p = 0.0028)] compared to homozygous major allele carriers. A higher n-3 PUFA intake was associated with higher concentrations of total cholesterol, LDL, HDL and lower triglyceride levels, but these associations did not interact with the FADS1 FADS2 genotype.
Total cholesterol, HDL, LDL and triglyceride concentrations may be influenced by the FADS1 FADS2 genotype already in 10 year old children. Genetically determined blood lipid levels during childhood might differentially predispose individuals to the development of cardiovascular diseases later in life.
Rationale: Genomic loci are associated with FEV1 or the ratio of FEV1 to FVC in population samples, but their association with chronic obstructive pulmonary disease (COPD) has not yet been proven, nor have their combined effects on lung function and COPD been studied.
Objectives: To test association with COPD of variants at five loci (TNS1, GSTCD, HTR4, AGER, and THSD4) and to evaluate joint effects on lung function and COPD of these single-nucleotide polymorphisms (SNPs), and variants at the previously reported locus near HHIP.
Methods: By sampling from 12 population-based studies (n = 31,422), we obtained genotype data on 3,284 COPD case subjects and 17,538 control subjects for sentinel SNPs in TNS1, GSTCD, HTR4, AGER, and THSD4. In 24,648 individuals (including 2,890 COPD case subjects and 13,862 control subjects), we additionally obtained genotypes for rs12504628 near HHIP. Each allele associated with lung function decline at these six SNPs contributed to a risk score. We studied the association of the risk score to lung function and COPD.
Measurements and Main Results: Association with COPD was significant for three loci (TNS1, GSTCD, and HTR4) and the previously reported HHIP locus, and suggestive and directionally consistent for AGER and TSHD4. Compared with the baseline group (7 risk alleles), carrying 10–12 risk alleles was associated with a reduction in FEV1 (β = –72.21 ml, P = 3.90 × 10−4) and FEV1/FVC (β = –1.53%, P = 6.35 × 10−6), and with COPD (odds ratio = 1.63, P = 1.46 × 10−5).
Conclusions: Variants in TNS1, GSTCD, and HTR4 are associated with COPD. Our highest risk score category was associated with a 1.6-fold higher COPD risk than the population average score.
FEV1; FVC; genome-wide association study; modeling risk
Transient receptor potential (TRP) vanilloid and ankyrin cation channels are activated by various noxious chemicals and may play an important role in the pathogenesis of cough. The aim was to study the influence of single nucleotide polymorphisms (SNPs) in TRP genes and irritant exposures on cough.
Nocturnal, usual, and chronic cough, smoking, and job history were obtained by questionnaire in 844 asthmatic and 2046 non-asthmatic adults from the Epidemiological study on the Genetics and Environment of Asthma (EGEA) and the European Community Respiratory Health Survey (ECRHS). Occupational exposures to vapors, gases, dusts, and/or fumes were assessed by a job-exposure matrix. Fifty-eight tagging SNPs in TRPV1, TRPV4, and TRPA1 were tested under an additive model.
Statistically significant associations of 6 TRPV1 SNPs with cough symptoms were found in non-asthmatics after correction for multiple comparisons. Results were consistent across the eight countries examined. Haplotype-based association analysis confirmed the single SNP analyses for nocturnal cough (7-SNP haplotype: p-global = 4.8 × 10-6) and usual cough (9-SNP haplotype: p-global = 4.5 × 10-6). Cough symptoms were associated with exposure to irritants such as cigarette smoke and occupational exposures (p < 0.05). Four polymorphisms in TRPV1 further increased the risk of cough symptoms from irritant exposures in asthmatics and non-asthmatics (interaction p < 0.05).
TRPV1 SNPs were associated with cough among subjects without asthma from two independent studies in eight European countries. TRPV1 SNPs may enhance susceptibility to cough in current smokers and in subjects with a history of workplace exposures.
Asthma; Gene-environment interaction; Irritant exposure; Smoking; TRP channel
Previous studies suggested potential priming effects of gestational weight gain (GWG) on offspring’s body composition in later life. However, consistency of these effects in normal weight, overweight and obese mothers is less clear.
We combined the individual data of three German cohorts and assessed associations of total and excessive GWG (as defined by criteria of the Institute of Medicine) with offspring’s mean body mass index (BMI) standard deviation scores (SDS) and overweight at the age of 5–6 years (total: n = 6,254). Quantile regression was used to examine potentially different effects on different parts of the BMI SDS distribution. All models were adjusted for birth weight, maternal age and maternal smoking during pregnancy and stratified by maternal pre-pregnancy weight status.
In adjusted models, positive associations of total and excessive GWG with mean BMI SDS and overweight were observed only in children of non- overweight mothers. For example, excessive GWG was associated with a mean increase of 0.08 (95% CI: 0.01, 0.15) units of BMI SDS (0.13 (0.02, 0.24) kg/m2 of ‘real’ BMI) in children of normal-weight mothers. The effects of total and excessive GWG on BMI SDS increased for higher- BMI children of normal-weight mothers.
Increased GWG is likely to be associated with overweight in offspring of non-overweight mothers.
Tracking of fatty acid (FA) contribution to plasma or serum lipids over time was shown in children and adults. However, the potential role of FADS gene variants has not been investigated.
Methods and Principal Findings
Serum GP FA composition of 331 children aged 2 and 6 years, participating in an ongoing birth cohort study, was analyzed. Correlation coefficients were estimated to describe FA tracking over 4 years and to assess the influence of FADS variants on tracking. We found low to moderate tracking (r = 0.12–0.49) of FA compositions and concentration between 2 and 6 years. Concentration changes of total monounsaturated FA and total saturated FA over time correlated closely (r = 0.79) but percentage values were unrelated (r = −0.02). Tracking for n-6 long chain polyunsaturated fatty acid (LC-PUFA) concentrations was lower in subjects homozygous for the major allele of FADS variants and higher in carriers of at least one minor allele, whereas for total n-3 LC-PUFA concentrations and compositions this was vice versa. For individual n-3 PUFA inconsistent results were found.
Conclusions and Significance
Serum GP FA composition shows low to moderate tracking over 4 years with a higher tracking for LC-PUFA metabolites than for their precursor FA. Serum PUFA levels and their tracking seem to be more influenced by lipid and lipoprotein metabolism than by FA specific pathways.
Several studies showed that blood pressure and lung function are associated. Additionally, a potential effect of antihypertensive medication, especially beta-blockers, on lung function has been discussed. However, side effects of beta-blockers have been investigated mainly in patients with already reduced lung function. Thus, aim of this analysis is to determine whether hypertension and antihypertensive medication have an adverse effect on lung function in a general adult population.
Within the population-based KORA F4 study 1319 adults aged 40-65 years performed lung function tests and blood pressure measurements. Additionally, information on anthropometric measurements, medical history and use of antihypertensive medication was available. Multivariable regression models were applied to study the association between blood pressure, antihypertensive medication and lung function.
High blood pressure as well as antihypertensive medication were associated with lower forced expiratory volume in one second (p = 0.02 respectively p = 0.05; R2: 0.65) and forced vital capacity values (p = 0.01 respectively p = 0.05, R2: 0.73). Furthermore, a detailed analysis of antihypertensive medication pointed out that only the use of beta-blockers was associated with reduced lung function, whereas other antihypertensive medication had no effect on lung function. The adverse effect of beta-blockers was significant for forced vital capacity (p = 0.04; R2: 0.65), while the association with forced expiratory volume in one second showed a trend toward significance (p = 0.07; R2: 0.73). In the same model high blood pressure was associated with reduced forced vital capacity (p = 0.01) and forced expiratory volume in one second (p = 0.03) values, too.
Our analysis indicates that both high blood pressure and the use of beta-blockers, but not the use of other antihypertensive medication, are associated with reduced lung function in a general adult population.
The fetal immune system is characterized by a Th2 bias but it is unclear how the Th2 predominance is established. Natural killer T (NKT) cells are a rare subset of T cells with immune regulatory functions and are already activated in utero. To test the hypothesis that NKT cells are part of the regulatory network that sets the fetal Th2 predominance, percentages of Vα24+Vβ11+ NKT cells expressing Th1/Th2-related chemokine receptors (CKR) were assessed in cord blood. Furthermore, IL-4 and IFN-γ secreting NKT cells were quantified within the single CKR+ subsets.
Cord blood NKT cells expressed the Th2-related CCR4 and CCR8 at significantly higher frequencies compared to peripheral blood NKT cells from adults, while CXCR3+ and CCR5+ cord blood NKT cells (Th1-related) were present at lower percentages. Within CD4negCD8neg (DN) NKT cells, the frequency of IL-4 producing NKT cells was significantly higher in cord blood, while frequencies of IFN-γ secreting DN NKT cells tended to be lower. A further subanalysis showed that the higher percentage of IL-4 secreting DN NKT cells was restricted to CCR3+, CCR4+, CCR5+, CCR6+, CCR7+, CCR8+ and CXCR4+ DN subsets in cord blood. This resulted in significantly decreased IFN-γ /IL-4 ratios of CCR3+, CCR6+ and CCR8+ cord blood DN NKT cells. Sequencing of VA24AJ18 T cell receptor (TCR) transcripts in sorted cord blood Vα24Vβ11 cells confirmed the invariant TCR alpha-chain ruling out the possibility that these cells represent an unusual subset of conventional T cells.
Despite the heterogeneity of cord blood NKT cells, we observed a clear Th2-bias at the phenotypic and functional level which was mainly found in the DN subset. Therefore, we speculate that NKT cells are important for the initiation and control of the fetal Th2 environment which is needed to maintain tolerance towards self-antigens as well as non-inherited maternal antigens.
Association of genetic-variants in the FADS1-FADS2-gene-cluster with fatty-acid-composition in blood of adult-populations is well established. We analyze this genetic-association in two children-cohort-studies. In addition, the association between variants in the FADS-gene-cluster and blood-fatty-acid-composition with eczema was studied.
Methods and Principal Findings
Data of two population-based-birth-cohorts in the Netherlands and Germany (KOALA, LISA) were pooled (n = 879) and analyzed by (logistic) regression regarding the mutual influence of single-nucleotide-polymorphisms (SNPs) in the FADS-gene-cluster (rs174545, rs174546, rs174556, rs174561, rs3834458), on polyunsaturated fatty acids (PUFA) in blood and parent-reported eczema until the age of 2 years. All SNPs were highly significantly associated with all PUFAs except for alpha-linolenic-acid and eicosapentaenoic-acid, also after correction for multiple-testing. All tested SNPs showed associations with eczema in the LISA-study, but not in the KOALA-study. None of the PUFAs was significantly associated with eczema neither in the pooled nor in the analyses stratified by study-cohort.
Conclusions and Significance
PUFA-composition in young children's blood is under strong control of the FADS-gene-cluster. Inconsistent results were found for a link between these genetic-variants with eczema. PUFA in blood was not associated with eczema. Thus the hypothesis of an inflammatory-link between PUFA and eczema by the metabolic-pathway of LC-PUFAs as precursors for inflammatory prostaglandins and leukotrienes could not be confirmed by these data.
Studies of the relationships between low socio-economic status and impaired lung function were conducted mainly in Western European countries and North America. East–West differences remain unexplored. Associations between parental education and lung function were explored using data on 24,010 school-children from eight cross-sectional studies conducted in North America, Western and Eastern Europe. Parental education was defined as low and high using country-specific classifications. Country-specific estimates of effects of low parental education on volume and flow parameters were obtained using linear and logistic regression, controlling for early life and other individual risk factors. Meta-regressions were used for assessment of heterogeneity between country-specific estimates. The association between low parental education and lung function was not consistent across the countries, but showed a more pronounced inverse gradient in the Western countries. The most consistent decrease associated with low parental education was found for peak expiratory flow (PEF), ranging from −2.80 to −1.14%, with statistically significant associations in five out of eight countries. The mean odds ratio for low PEF (<75% of predicted) was 1.34 (95% CI 1.06–1.70) after all adjustments. Although social gradients were attenuated after adjusting for known risk factors, these risk factors could not completely explain the social gradient in lung function.
Lung function; Parental education; Combined analysis; East–West differences; PATY study; Children
Identification of the risk factors for bronchial hyperresponsiveness (BHR) would increase the understanding of the causes of asthma. The relationship between physical activity and BHR in men and women aged 28.0–56.5 years randomly selected from 24 centres in 11 countries participating in the European Community Respiratory Health Survey II was investigated.
5158 subjects answered questionnaires about physical activity and performed BHR tests. Participants were asked about the frequency and duration of usual weekly exercise resulting in breathlessness or sweating. BHR was defined as a decrease in forced expiratory volume in 1 s of at least 20% of its post‐saline value for a maximum methacholine dose of 2 mg.
Both frequency and duration of physical activity were inversely related to BHR. The prevalence of BHR in subjects exercising ⩽1, 2–3 and ⩾4 times a week was 14.5%, 11.6% and 10.9%, respectively (p<0.001). The corresponding odds ratios were 1.00, 0.78 (95% CI 0.62 to 0.99) and 0.69 (95% CI 0.50 to 0.94) after controlling for potential confounding factors. The frequency of BHR in subjects exercising <1 h, 1–3 h and ⩾4 h a week was 15.9%, 10.9% and 10.7%, respectively (p<0.001). The corresponding adjusted odds ratios were 1.00, 0.70 (95% CI 0.57 to 0.87) and 0.67 (95% CI 0.50 to 0.90). Physical activity was associated with BHR in all studied subgroups.
These results suggest that BHR is strongly and independently associated with decreased physical activity. Further studies are needed to determine the mechanisms underlying this association.
Meta-analyses of population-based genome-wide association studies (GWAS) in adults have recently led to the detection of new genetic loci for obesity. Here we aimed to discover additional obesity loci in extremely obese children and adolescents. We also investigated if these results generalize by estimating the effects of these obesity loci in adults and in population-based samples including both children and adults. We jointly analysed two GWAS of 2,258 individuals and followed-up the best, according to lowest p-values, 44 single nucleotide polymorphisms (SNP) from 21 genomic regions in 3,141 individuals. After this DISCOVERY step, we explored if the findings derived from the extremely obese children and adolescents (10 SNPs from 5 genomic regions) generalized to (i) the population level and (ii) to adults by genotyping another 31,182 individuals (GENERALIZATION step). Apart from previously identified FTO, MC4R, and TMEM18, we detected two new loci for obesity: one in SDCCAG8 (serologically defined colon cancer antigen 8 gene; p = 1.85×10−8 in the DISCOVERY step) and one between TNKS (tankyrase, TRF1-interacting ankyrin-related ADP-ribose polymerase gene) and MSRA (methionine sulfoxide reductase A gene; p = 4.84×10−7), the latter finding being limited to children and adolescents as demonstrated in the GENERALIZATION step. The odds ratios for early-onset obesity were estimated at ∼1.10 per risk allele for both loci. Interestingly, the TNKS/MSRA locus has recently been found to be associated with adult waist circumference. In summary, we have completed a meta-analysis of two GWAS which both focus on extremely obese children and adolescents and replicated our findings in a large followed-up data set. We observed that genetic variants in or near FTO, MC4R, TMEM18, SDCCAG8, and TNKS/MSRA were robustly associated with early-onset obesity. We conclude that the currently known major common variants related to obesity overlap to a substantial degree between children and adults.
Genome-wide association studies (GWAS) have successfully contributed to the detection of genetic variants involved in body-weight regulation. We jointly analysed two GWAS for early-onset extreme obesity in 2,258 individuals of European origin and followed-up the findings in 3,141 individuals. Evidence for association of markers in two new genetic loci was shown (SDCCAG8 on chromosome 1q43–q44 and between TNKS/MSRA on chromosome 8p23.1). We also re-identified variants in or near FTO, MC4R, and TMEM18 to be associated with extreme obesity. In addition, we assessed the effect of the markers in 31,182 obese, lean, normal weight, and unselected individuals from population-based samples and showed that the variants near FTO, MC4R, TMEM18, and SDCCAG8 were consistently associated with obesity. For variants of TNKS/MSRA, the obesity association was limited to children and adolescents. In summary, we detected two new obesity loci and confirmed that the currently known major common variants related to obesity overlap to a substantial degree between children and adults.
Little is known about the influencing potential of specific characteristics on lung function in different populations. The aim of this analysis was to determine whether lung function determinants differ between subpopulations within Germany and whether prediction equations developed for one subpopulation are also adequate for another subpopulation.
Within three studies (KORA C, SHIP-I, ECRHS-I) in different areas of Germany 4059 adults performed lung function tests. The available data consisted of forced expiratory volume in one second, forced vital capacity and peak expiratory flow rate. For each study multivariate regression models were developed to predict lung function and Bland-Altman plots were established to evaluate the agreement between predicted and measured values.
The final regression equations for FEV1 and FVC showed adjusted r-square values between 0.65 and 0.75, and for PEF they were between 0.46 and 0.61. In all studies gender, age, height and pack-years were significant determinants, each with a similar effect size. Regarding other predictors there were some, although not statistically significant, differences between the studies. Bland-Altman plots indicated that the regression models for each individual study adequately predict medium (i.e. normal) but not extremely high or low lung function values in the whole study population.
Simple models with gender, age and height explain a substantial part of lung function variance whereas further determinants add less than 5% to the total explained r-squared, at least for FEV1 and FVC. Thus, for different adult subpopulations of Germany one simple model for each lung function measures is still sufficient.
Prenatal and postnatal tobacco exposure have been reported to be associated with behavioral problems. However, the magnitude of the association with tobacco exposure at specific periods of exposure is unclear.
We assessed the relative risk of behavioral problems in children who had been exposed to tobacco smoke in utero and postnatally.
We analyzed data from a prospective birth cohort study in two cities in Germany: the German Infant Nutrition Intervention. Our sample included 5,991 children born between 1995 and 1998 as well as their parents. We measured behavioral problems using the Strength and Difficulties Questionnaire (SDQ) at follow-up 10 years after birth. According to prespecified SDQ cutoff values, children were classified as “normal,” “borderline,” or “abnormal” according to the subscales “emotional symptoms,” “conduct problems,” “hyperactivity/inattention,” “peer-relationship problems,” and a total difficulties score. Smoke exposure and further covariates were assessed using parent questionnaires.
Compared with children not exposed to tobacco smoke, children exposed both pre- and postnatally to tobacco smoke had twice the estimated risk [95% confidence interval (CI), 1.4–3.1] of being classified as abnormal according to the total difficulties score of the SDQ at 10 years of age. Children who were only prenatally exposed had a 90% higher relative risk (95% CI, 0.9–4.0), whereas children who were only postnatally exposed had a 30% higher relative risk (95% CI, 0.9–1.9). These results could not be explained by confounding by parental education, father’s employment, child’s time spent in front of computer or television screen, being a single father or mother, or mother’s age.
Prenatal exposure to tobacco smoke is associated with behavioral problems in school-age children. Although our findings do not preclude the influence of postnatal exposure, prenatal exposure seems to be more important.
adolescent health; behavioral problems; cohort study; environmental tobacco smoke exposure; strengths and difficulties questionnaire
Asthma and atopy are complex phenotypes with shared genetic component. In this study we attempt to identify genes related to these traits performing a two-stage DNA pooling genome-wide analysis in order to reduce costs. First, we assessed all markers in a subset of subjects using DNA pooling, and in a second stage we evaluated the most promising markers at an individual level.
For the genome-wide analysis, we constructed DNA pools from 75 subjects with atopy and asthma, 75 subjects with atopy and without asthma and 75 control subjects without atopy or asthma. In a second stage, the most promising regions surrounding significant markers after correction for false discovery rate were replicated with individual genotyping of samples included in the pools and an additional set of 429 atopic subjects and 222 controls from the same study centres.
Homo sapiens protein kinase-like protein SgK493 (SGK493) was found to be associated with atopy. To lesser extent mitogen-activated protein kinase 5 (MAP3K5), collagen type XVIII alpha 1 (COL18A1) and collagen type XXIX alpha 1 (COL29A1) were also found to be associated with atopy. Functional evidences points out a role for MAP3K5, COL18A1 and COL29A1 but the function of SGK493 is unknown.
In this analysis we have identified new candidate regions related to atopy and suggest SGK493 as an atopy locus, although these results need further replication.
Background The association of long-term air pollution and lung function has not been studied across adult European multi-national populations before. The aim of this study was to determine the association between long-term urban background air pollution and lung function levels, as well as change in lung function among European adults.
Methods Forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and the ratio thereof (FEV1/FVC) were assessed at baseline and after 9 years of follow-up in adults from 21 European centres (followed-up sample 5610). Fine particles (PM2.5) were measured in 2000/2001 using central monitors.
Results Despite sufficient statistical power no significant associations were found between city-specific annual mean PM2.5 and average lung function levels. The findings also do not support an effect on change in lung function, albeit statistical power was insufficient to significantly detect such an association.
Conclusions The inability to refuse the null hypothesis may reflect (i) no effect of urban air pollution on lung function or (ii) inherent biases due to the study design. Examples of the latter are lack of individual-level air quality assignment, not quantified within-city contrasts in traffic-related pollution, or the heterogeneity of the studied populations and their urban environments. Future studies on long-term effects of air pollution on lung function could increase statistical power and reduce potential misclassification and confounding by characterizing exposure on the level of individuals, capturing contrasts due to local sources, in particular traffic.
PM2.5; FEV1; FVC; adults; longitudinal; multilevel
Traffic-related air pollution is related with asthma, and this association may be modified by genetic factors.
We investigated the role of genetic polymorphisms potentially modifying the association between home outdoor levels of modeled nitrogen dioxide and asthma.
Adults from 13 cities of the second European Community Respiratory Health Survey (ECRHS II) were included (n = 2,920), for whom both DNA and outdoor NO2 estimates were available. Home addresses were geocoded and linked to modeled outdoor NO2 estimates, as a marker of local traffic-related pollution. We examined asthma prevalence and evaluated polymorphisms in genes involved in oxidative stress pathways [gluthatione S-transferases M1 (GSTM1), T1 (GSTT1), and P1 (GSTP1) and NAD(P)H:quinine oxidoreductase (NQO1)], inflammatory response [tumor necrosis factor α (TNFA)], immunologic response [Toll-like receptor 4 (TLR4)], and airway reactivity [adrenergic receptor β2 (ADRB2)].
The association between modeled NO2 and asthma prevalence was significant for carriers of the most common genotypes of NQO1 rs2917666 [odds ratio (OR) = 1.54; 95% confidence interval (CI), 1.10–2.24], TNFA rs2844484 (OR = 2.02; 95% CI, 1.30–3.27). For new-onset asthma, the effect of NO2 was significant for the most common genotype of NQO1 rs2917666 (OR = 1.52; 95% CI, 1.09–2.16). A significant interaction was found between NQO1 rs2917666 and NO2 for asthma prevalence (p = 0.02) and new-onset asthma (p = 0.04).
Genetic polymorphisms in the NQO1 gene are related to asthma susceptibility among persons exposed to local traffic-related air pollution. This points to the importance of antioxidant pathways in the protection against the effects of air pollution on asthma.
air pollution; asthma; gene polymorphisms; genetics; nitrogen dioxide; oxidative stress; traffic pollution
Growing evidence indicates that ambient air pollution is associated with exacerbation of chronic diseases like chronic pulmonary disease. A prospective panel study was conducted to investigate short-term changes of blood markers of inflammation and coagulation in response to daily changes in air pollution in Erfurt, Germany. 12 clinical visits were scheduled and blood parameters were measured in 38 male patients with chronic pulmonary disease during winter 2001/2002. Additive mixed models with random patient intercept were applied, adjusting for trend, weekday, and meteorological parameters. Hourly data on ultrafine particles (UFP, 0.01-0.1 μm), accumulation mode particles (ACP, 0.1-1.0 μm), PM10 (particulate matter <10 μm in diameter), elemental (EC) and organic carbon (OC), gaseous pollutants (nitrogen monoxide [NO], nitrogen dioxide [NO2], carbon monoxide [CO], and sulphur dioxide [SO2]) were collected at a central monitoring site and meteorological data were received from an official network. For each person and visit the individual 24-hour average of pollutants immediately preceding the blood withdrawal (lag 0) up to day 5 (lag1-4) and 5-day running means were calculated.
Increased levels of fibrinogen were observed for an increase in one interquartile range of UFP, PM10, EC, OC, CO, and NO revealing the strongest effect for lag 3. E-selectin increased in association with ACP and PM10 with a delay of one day. The ACP effect was also seen with the 5-day-mean. The pattern found for D-dimer was inconsistent. Prothrombin fragment 1+2 decreased with lag 4 consistently for all particulate pollutants. Von Willebrand factor antigen (vWF) showed a consistent decrease in association with almost all air pollutants with all lags except for lag 0. No associations were found for C-reactive protein, soluble intercellular adhesion molecule 1, serum amyloid A and factor VII.
These results suggest that elevated concentrations of air pollution are associated with changes in some blood markers of inflammation and coagulation in patients with chronic pulmonary disease. The clinical implications of these findings need further investigation.
Epidemiological studies on health effects of outdoor air pollution are largely based on single monitoring site for estimating the exposure of people living in urban areas. For such an approach two aspects are important: the temporal correlation and the spatial variation of the absolute levels of concentrations measured at different sites in an urban area. Whereas many studies have shown small spatial variability of fine particles in urban areas, little is known on how well a single monitoring station could represent the temporal and spatial variation of ultrafine particles across urban areas.
In our study we investigated the temporal and spatial variation of particle number concentration (PNC) at four background sites in Augsburg, Germany. Two of them were influenced by traffic, one was placed in the outskirts of the city.
The average PNC levels at two urban background sites with traffic impact were 16,943 cm−3 and 20,702 cm−3, respectively, compared to 11,656 cm−3 at the urban background site without traffic impact (ratio 1.2 to 1.8). The Spearman correlation coefficients between the monitoring sites were high (r>0.80).
The pronounced differences in absolute PNC levels suggest that the use of a single monitoring station in long-term epidemiological studies must be insufficient to attribute accurate exposure levels of PNC to all study subjects. On the other hand, the high temporal correlations of PNC across the city area of Augsburg implicate that in epidemiological time-series studies the use of one single ambient monitoring site is an adequate approach for characterizing exposure to ultrafine particles.
particle number concentration (PNC); spatial variation; correlation coefficients; wind direction; epidemiological studies
Studies relying on outdoor pollutants measures have reported associations between air pollutants and birth weight.
Our aim was to assess the relation between maternal personal exposure to airborne benzene during pregnancy and fetal growth.
We recruited pregnant women in two French maternity hospitals in 2005–2006 as part of the EDEN mother–child cohort. A subsample of 271 nonsmoking women carried a diffusive air sampler for a week during the 27th gestational week, allowing assessment of benzene exposure. We estimated head circumference of the offspring by ultrasound measurements during the second and third trimesters of pregnancy and at birth.
Median benzene exposure was 1.8 μg/m3 (5th, 95th percentiles, 0.5, 7.5 μg/m3). Log-transformed benzene exposure was associated with a gestational age–adjusted decrease of 68 g in mean birth weight [95% confidence interval (CI), −135 to −1 g] and of 1.9 mm in mean head circumference at birth (95% CI, −3.8 to 0.0 mm). It was associated with an adjusted decrease of 1.9 mm in head circumference assessed during the third trimester (95% CI, −4.0 to 0.3 mm) and of 1.5 mm in head circumference assessed at the end of the second trimester of pregnancy (95% CI, −3.1 to 0 mm).
Our prospective study among pregnant women is one of the first to rely on personal monitoring of exposure; a limitation is that exposure was assessed during 1 week only. Maternal benzene exposure was associated with decreases in birth weight and head circumference during pregnancy and at birth. This association could be attributable to benzene and a mixture of associated traffic-related air pollutants.
atmospheric pollution; benzene; birth weight; cohort; fetal growth; head circumference; personal monitoring; sensitivity analysis; ultrasonography
Adverse effects have been reported of prenatal and/or postnatal passive exposure to smoking on children's health. Uncertainties remain about the relative importance of smoking at different periods in the child's life. We investigate this in a pooled analysis, on 53 879 children from 12 cross‐sectional studies—components of the PATY study (Pollution And The Young).
Effects were estimated, within each study, of three exposures: mother smoked during pregnancy, parental smoking in the first two years, current parental smoking. Outcomes were: wheeze, asthma, “woken by wheeze”, bronchitis, nocturnal cough, morning cough, “sensitivity to inhaled allergens” and hay fever. Logistic regressions were used, controlling for individual risk factors and study area. Heterogeneity between study‐specific results, and mean effects (allowing for heterogeneity) were estimated using meta‐analytical tools.
There was strong evidence linking parental smoking to wheeze, asthma, bronchitis and nocturnal cough, with mean odds ratios all around 1.15, with independent effects of prenatal and postnatal exposures for most associations.
Adverse effects of both pre‐ and postnatal parental smoking on children's respiratory health were confirmed. Asthma was most strongly associated with maternal smoking during pregnancy, but postnatal exposure showed independent associations with a range of other respiratory symptoms. All tobacco smoke exposure has serious consequences for children's respiratory health and needs to be reduced urgently.
tobacco smoke; fetus; child; respiratory symptoms; asthma