Showing papers by "Joachim Heinrich published in 2012"
Utrecht University1, Imperial College London2, Karolinska Institutet3, Vytautas Magnus University4, Flemish Institute for Technological Research5, University of Hasselt6, National and Kapodistrian University of Athens7, University of California, Berkeley8, Swiss Tropical and Public Health Institute9, University of Basel10, National Institutes of Health11, University of Manchester12, Norwegian Institute of Public Health13, University of Duisburg-Essen14, ARPA-E15, University of Washington16
TL;DR: Careful selection of monitoring sites, examination of influential observations and skewed variable distributions were essential for developing stable LUR models, which are used to estimate air pollution concentrations at the home addresses of participants in the health studies involved in ESCAPE.
Abstract: Land Use Regression (LUR) models have been used increasingly for modeling small-scale spatial variation in air pollution concentrations and estimating individual exposure for participants of cohort studies. Within the ESCAPE project, concentrations of PM(2.5), PM(2.5) absorbance, PM(10), and PM(coarse) were measured in 20 European study areas at 20 sites per area. GIS-derived predictor variables (e.g., traffic intensity, population, and land-use) were evaluated to model spatial variation of annual average concentrations for each study area. The median model explained variance (R(2)) was 71% for PM(2.5) (range across study areas 35-94%). Model R(2) was higher for PM(2.5) absorbance (median 89%, range 56-97%) and lower for PM(coarse) (median 68%, range 32- 81%). Models included between two and five predictor variables, with various traffic indicators as the most common predictors. Lower R(2) was related to small concentration variability or limited availability of predictor variables, especially traffic intensity. Cross validation R(2) results were on average 8-11% lower than model R(2). Careful selection of monitoring sites, examination of influential observations and skewed variable distributions were essential for developing stable LUR models. The final LUR models are used to estimate air pollution concentrations at the home addresses of participants in the health studies involved in ESCAPE.
861 citations
Utrecht University1, Swiss Tropical and Public Health Institute2, University of Basel3, University of Washington4, University of Augsburg5, Imperial College London6, University of Manchester7, Vytautas Magnus University8, National Technical University of Athens9, University of Düsseldorf10, University of Crete11, National and Kapodistrian University of Athens12, National Institutes of Health13, Norwegian Institute of Public Health14, ARPA-E15, University of Ulm16
TL;DR: The ESCAPE study as discussed by the authors investigated the relationship between long-term exposure to outdoor air pollution and health using cohort studies across Europe, and found substantial variability in spatial patterns of PM2.5, PM10 and PMcoarse.
371 citations
University of Pennsylvania1, Erasmus University Rotterdam2, University of Bristol3, University of Duisburg-Essen4, Pasteur Institute5, University of Western Australia6, University College London7, University of Copenhagen8, Imperial College London9, University of Southern California10, University of Helsinki11, University of Marburg12, VU University Amsterdam13, University of Oxford14, University of Tartu15, University College Dublin16, Queen's University Belfast17, University of Zaragoza18, University of Oulu19, University of Turku20, University of Tampere21, Wellcome Trust Sanger Institute22, Pompeu Fabra University23, Harvard University24, University of Cambridge25, McMaster University26
TL;DR: A North American, Australian and European collaborative meta-analysis of 14 studies consisting of 5,530 cases and 8,318 controls of European ancestry observed two loci that yielded genome-wide significant combined P values near OLFM4 at 13q14 and within HOXB5 at 17q21, which yielded directionally consistent associations.
Abstract: Multiple genetic variants have been associated with adult obesity and a few with severe obesity in childhood; however, less progress has been made in establishing genetic influences on common early-onset obesity. We performed a North American, Australian and European collaborative meta-analysis of 14 studies consisting of 5,530 cases (≥95th percentile of body mass index (BMI)) and 8,318 controls (<50th percentile of BMI) of European ancestry. Taking forward the eight newly discovered signals yielding association with P < 5 × 10(-6) in nine independent data sets (2,818 cases and 4,083 controls), we observed two loci that yielded genome-wide significant combined P values near OLFM4 at 13q14 (rs9568856; P = 1.82 × 10(-9); odds ratio (OR) = 1.22) and within HOXB5 at 17q21 (rs9299; P = 3.54 × 10(-9); OR = 1.14). Both loci continued to show association when two extreme childhood obesity cohorts were included (2,214 cases and 2,674 controls). These two loci also yielded directionally consistent associations in a previous meta-analysis of adult BMI(1).
347 citations
01 Jan 2012
TL;DR: The ESCAPE study as discussed by the authors investigated the relationship between long-term exposure to outdoor air pollution and health using cohort studies across Europe, and found substantial variability was found in spatial patterns of PM 2.5, PM2.5 absorbance, PM 10 and PM coarse.
Abstract: Abstract The ESCAPE study (European Study of Cohorts for Air Pollution Effects) investigates relationships between long-term exposure to outdoor air pollution and health using cohort studies across Europe. This paper analyses the spatial variation of PM 2.5 , PM 2.5 absorbance, PM 10 and PM coarse concentrations between and within 20 study areas across Europe. We measured NO 2 , NO x , PM 2.5 , PM 2.5 absorbance and PM 10 between October 2008 and April 2011 using standardized methods. PM coarse was determined as the difference between PM 10 and PM 2.5 . In each of the twenty study areas, we selected twenty PM monitoring sites to represent the variability in important air quality predictors, including population density, traffic intensity and altitude. Each site was monitored over three 14-day periods spread over a year, using Harvard impactors. Results for each site were averaged after correcting for temporal variation using data obtained from a reference site, which was operated year-round. Substantial concentration differences were observed between and within study areas. Concentrations for all components were higher in Southern Europe than in Western and Northern Europe, but the pattern differed per component with the highest average PM 2.5 concentrations found in Turin and the highest PM coarse in Heraklion. Street/urban background concentration ratios for PM coarse (mean ratio 1.42) were as large as for PM 2.5 absorbance (mean ratio 1.38) and higher than those for PM 2.5 (1.14) and PM 10 (1.23), documenting the importance of non-tailpipe emissions. Correlations between components varied between areas, but were generally high between NO 2 and PM 2.5 absorbance (average R 2 = 0.80). Correlations between PM 2.5 and PM coarse were lower (average R 2 = 0.39). Despite high correlations, concentration ratios between components varied, e.g. the NO 2 /PM 2.5 ratio varied between 0.67 and 3.06. In conclusion, substantial variability was found in spatial patterns of PM 2.5 , PM 2.5 absorbance, PM 10 and PM coarse . The highly standardized measurement of particle concentrations across Europe will contribute to a consistent assessment of health effects across Europe.
334 citations
University of Augsburg1, Utrecht University2, National Institutes of Health3, Imperial College London4, University of Manchester5, National and Kapodistrian University of Athens6, National Technical University of Athens7, Umeå University8, University of Düsseldorf9, University of Crete10, Swiss Tropical and Public Health Institute11, University of Basel12, Norwegian Institute of Public Health13, University of Duisburg-Essen14, ARPA-E15, University of Washington16, University of Pavia17
TL;DR: The ESCAPE study as mentioned in this paper investigated the long-term effects of exposure to air pollution on human health in Europe and found significant contrasts in annual average NO2 and NOx concentrations between and especially within 36 study areas across Europe.
301 citations
University of Bristol1, Hannover Medical School2, University of Copenhagen3, Erasmus University Rotterdam4, QIMR Berghofer Medical Research Institute5, Imperial College London6, Technische Universität München7, University of Kiel8, University of Pennsylvania9, University of Western Australia10, University of Basel11, University of Manchester12, VU University Amsterdam13, Karolinska Institutet14, University of Geneva15, Wellcome Trust Sanger Institute16, University of Oulu17, University of the East18, University of Washington19, University of Melbourne20, Ludwig Maximilian University of Munich21, University of Bonn22, Aarhus University23, Tartu University Hospital24, Statens Serum Institut25, University of Iowa26, Children's Hospital of Philadelphia27, King's College London28, Telethon Institute for Child Health Research29, Children's Medical Research Institute30, Swiss Tropical and Public Health Institute31, Norwegian Institute of Public Health32, Manchester Academic Health Science Centre33, Utrecht University34, Copenhagen University Hospital35, Karolinska University Hospital36, Sahlgrenska University Hospital37, Ontario Institute for Cancer Research38, St George's, University of London39, Medical Research Council40
TL;DR: A genome-wide association meta-analysis of affected individuals and controls and the ten most strongly associated new susceptibility loci examined underline the importance of both epidermal barrier function and immune dysregulation in atopic dermatitis pathogenesis.
Abstract: Atopic dermatitis (AD) is a commonly occurring chronic skin disease with high heritability. Apart from filaggrin (FLG), the genes influencing atopic dermatitis are largely unknown. We conducted a genome-wide association meta-analysis of 5,606 affected individuals and 20,565 controls from 16 population-based cohorts and then examined the ten most strongly associated new susceptibility loci in an additional 5,419 affected individuals and 19,833 controls from 14 studies. Three SNPs reached genome-wide significance in the discovery and replication cohorts combined, including rs479844 upstream of OVOL1 (odds ratio (OR) = 0.88, P = 1.1 × 10(-13)) and rs2164983 near ACTL9 (OR = 1.16, P = 7.1 × 10(-9)), both of which are near genes that have been implicated in epidermal proliferation and differentiation, as well as rs2897442 in KIF3A within the cytokine cluster at 5q31.1 (OR = 1.11, P = 3.8 × 10(-8)). We also replicated association with the FLG locus and with two recently identified association signals at 11q13.5 (rs7927894; P = 0.008) and 20q13.33 (rs6010620; P = 0.002). Our results underline the importance of both epidermal barrier function and immune dysregulation in atopic dermatitis pathogenesis.
294 citations
01 Jan 2012
293 citations
University of Bristol1, Hannover Medical School2, University of Copenhagen3, Erasmus University Rotterdam4, QIMR Berghofer Medical Research Institute5, Imperial College London6, University of Kiel7, Technische Universität München8, University of Pennsylvania9, University of Western Australia10, University of Basel11, University of Manchester12, VU University Amsterdam13, Karolinska Institutet14, Wellcome Trust Sanger Institute15, University of Geneva16, University of Oulu17, University of the East18, University of Washington19, University of Melbourne20, Ludwig Maximilian University of Munich21, University of Bonn22, Aarhus University23, Tartu University Hospital24, Statens Serum Institut25, University of Iowa26, Children's Hospital of Philadelphia27, King's College London28, Telethon Institute for Child Health Research29, Children's Medical Research Institute30, Swiss Tropical and Public Health Institute31, Norwegian Institute of Public Health32, Manchester Academic Health Science Centre33, Utrecht University34, Copenhagen University Hospital35, Karolinska University Hospital36, Sahlgrenska University Hospital37, Ontario Institute for Cancer Research38, St George's, University of London39, Medical Research Council40
TL;DR: This paper conducted a genome-wide association meta-analysis of 5,606 affected individuals and 20,565 controls from 16 population-based cohorts and then examined the ten most strongly associated new susceptibility loci in an additional 5,419 affected individuals from 14 studies.
Abstract: Atopic dermatitis (AD) is a commonly occurring chronic skin disease with high heritability. Apart from filaggrin (FLG), the genes influencing atopic dermatitis are largely unknown. We conducted a genome-wide association meta-analysis of 5,606 affected individuals and 20,565 controls from 16 population-based cohorts and then examined the ten most strongly associated new susceptibility loci in an additional 5,419 affected individuals and 19,833 controls from 14 studies. Three SNPs reached genome-wide significance in the discovery and replication cohorts combined, including rs479844 upstream of OVOL1 (odds ratio (OR) = 0.88, P = 1.1 × 10(-13)) and rs2164983 near ACTL9 (OR = 1.16, P = 7.1 × 10(-9)), both of which are near genes that have been implicated in epidermal proliferation and differentiation, as well as rs2897442 in KIF3A within the cytokine cluster at 5q31.1 (OR = 1.11, P = 3.8 × 10(-8)). We also replicated association with the FLG locus and with two recently identified association signals at 11q13.5 (rs7927894; P = 0.008) and 20q13.33 (rs6010620; P = 0.002). Our results underline the importance of both epidermal barrier function and immune dysregulation in atopic dermatitis pathogenesis.
272 citations
TL;DR: The results indicate that metabolic profiles are age dependent and might reflect different aging processes, such as incomplete mitochondrial fatty acid oxidation.
Abstract: Understanding the complexity of aging is of utmost importance. This can now be addressed by the novel and powerful approach of metabolomics. However, to date, only a few metabolic studies based on large samples are available. Here, we provide novel and specific information on age-related metabolite concentration changes in human homeostasis. We report results from two population-based studies: the KORA F4 study from Germany as a discovery cohort, with 1038 female and 1124 male participants (32-81 years), and the TwinsUK study as replication, with 724 female participants. Targeted metabolomics of fasting serum samples quantified 131 metabolites by FIA-MS/MS. Among these, 71/34 metabolites were significantly associated with age in women/men (BMI adjusted). We further identified a set of 13 independent metabolites in women (with P values ranging from 4.6 × 10(-04) to 7.8 × 10(-42) , α(corr) = 0.004). Eleven of these 13 metabolites were replicated in the TwinsUK study, including seven metabolite concentrations that increased with age (C0, C10:1, C12:1, C18:1, SM C16:1, SM C18:1, and PC aa C28:1), while histidine decreased. These results indicate that metabolic profiles are age dependent and might reflect different aging processes, such as incomplete mitochondrial fatty acid oxidation. The use of metabolomics will increase our understanding of aging networks and may lead to discoveries that help enhance healthy aging.
264 citations
TL;DR: Maternal smoking during pregnancy appears to increase the risk of wheeze and asthma among children who are not exposed to maternal smoking after birth, particularly among preschool-age children.
Abstract: Rationale: Although epidemiological studies suggest that exposure to maternal smoking during fetal and early life increases the risk of childhood wheezing and asthma, previous studies were not able to differentiate the effects of prenatal from postnatal exposure. Objectives: To assess the effect of exposure to maternal smoking only during pregnancy on wheeze and asthma among preschool-age children. Methods: A pooled analysis was performed based on individual participant data from eight European birth cohorts. Cohort-specific effects of maternal smoking during pregnancy, but not during the first year, on wheeze and asthma at 4 to 6 years of age were estimated using logistic regression and then combined using a random effects model. Adjustments were made for sex, parental education, parental asthma, birth weight, and siblings. Measurements and Main Results: Among the 21,600 children included in the analysis, 735 children (3.4%) were exposed to maternal smoking exclusively during pregnancy but not in the first year after birth. In the pooled analysis, maternal smoking only during pregnancy was associated with wheeze and asthma at 4 to 6 years of age, with adjusted odds ratios of 1.39 (95% confidence interval, 1.08-1.77) and 1.65 (95% confidence interval, 1.18-2.31), respectively. The likelihood to develop wheeze and asthma increased statistically significantly in a linear dose-dependent manner in relation to maternal daily cigarette consumption during the first trimester of pregnancy. Conclusions: Maternal smoking during pregnancy appears to increase the risk of wheeze and asthma among children who are not exposed to maternal smoking after birth.
230 citations
TL;DR: This study shows that female sex is an independent risk factor for non-allergic asthma, and stresses the need for more careful assessment of possible non- allergic asthma in clinical practice, in men and women.
Abstract: Background Although women with severe non-allergic asthma may represent a substantial proportion of adults with asthma in clinical practice, gender differences in the incidence of allergic and non-allergic asthma have been little investigated in the general population. Methods Gender differences in asthma prevalence, reported diagnosis and incidence were investigated in 9091 men and women randomly selected from the general population and followed up after 8–10 years as part of the European Community Respiratory Health Survey. The protocol included assessment of bronchial responsiveness, IgE specific to four common allergens and skin tests to nine allergens. Results Asthma was 20% more frequent in women than in men over the age of 35 years. Possible under-diagnosis of asthma appeared to be particularly frequent among non-atopic individuals, but was as frequent in women as in men. The follow-up of subjects without asthma at baseline showed a higher incidence of asthma in women than in men (HR 1.94; 95% CI 1.40 to 2.68), which was not explained by differences in smoking, obesity or lung function. More than 60% of women and 30% of men with new-onset asthma were non-atopic. The incidence of non-allergic asthma was higher in women than in men throughout all the reproductive years (HR 3.51; 95% CI 2.21 to 5.58), whereas no gender difference was observed for the incidence of allergic asthma. Conclusions This study shows that female sex is an independent risk factor for non-allergic asthma, and stresses the need for more careful assessment of possible non-allergic asthma in clinical practice, in men and women.
United States Department of Health and Human Services1, Research Triangle Park2, University of Leicester3, University of Washington4, University of Nottingham5, University of Virginia6, Erasmus University Rotterdam7, Swiss Tropical and Public Health Institute8, University of Basel9, University of Greifswald10, University of Bristol11, University of Iceland12, University of Groningen13, University of New Mexico14, Cornell University15, National Institutes of Health16, Brigham and Women's Hospital17, Memorial University of Newfoundland18, King's College London19, Medical Research Council20, Harvard University21, Columbia University22, Imperial College London23, University of Texas Health Science Center at Houston24, Uppsala University25, University of Oxford26, University of North Carolina at Chapel Hill27, Wake Forest University28, Broad Institute29, Veterans Health Administration30, Ghent University31, Boston University32, United States Department of Veterans Affairs33, Cedars-Sinai Medical Center34, Florida International University35, University of Auckland36, Technische Universität München37, University Medical Center Groningen38, University of Geneva39, Group Health Research Institute40, University of Tennessee Health Science Center41, University of Cambridge42, University of Oulu43, St George's, University of London44
TL;DR: In this paper, the authors conducted genome-wide joint meta-analyses (JMA) of single nucleotide polymorphism (SNP) and SNP-by-smoking (ever-smoking or pack-years) associations on spirometic measures of pulmonary function, forced expiratory volume in one second (FEV(1)), and its ratio to forced vital capacity(FEV (1)/FVC).
Abstract: Genome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function, forced expiratory volume in one second (FEV(1)), and its ratio to forced vital capacity (FEV(1)/FVC). Given that cigarette smoking adversely affects pulmonary function, we conducted genome-wide joint meta-analyses (JMA) of single nucleotide polymorphism (SNP) and SNP-by-smoking (ever-smoking or pack-years) associations on FEV(1) and FEV(1)/FVC across 19 studies (total N = 50,047). We identified three novel loci not previously associated with pulmonary function. SNPs in or near DNER (smallest P(JMA = )5.00×10(-11)), HLA-DQB1 and HLA-DQA2 (smallest P(JMA = )4.35×10(-9)), and KCNJ2 and SOX9 (smallest P(JMA = )1.28×10(-8)) were associated with FEV(1)/FVC or FEV(1) in meta-analysis models including SNP main effects, smoking main effects, and SNP-by-smoking (ever-smoking or pack-years) interaction. The HLA region has been widely implicated for autoimmune and lung phenotypes, unlike the other novel loci, which have not been widely implicated. We evaluated DNER, KCNJ2, and SOX9 and found them to be expressed in human lung tissue. DNER and SOX9 further showed evidence of differential expression in human airway epithelium in smokers compared to non-smokers. Our findings demonstrated that joint testing of SNP and SNP-by-environment interaction identified novel loci associated with complex traits that are missed when considering only the genetic main effects.
TL;DR: The data identify two loci associated with head size, with the inversion at 17q21 also likely to be involved in attaining maximal brain size.
Abstract: During aging, intracranial volume remains unchanged and represents maximally attained brain size, while various interacting biological phenomena lead to brain volume loss. Consequently, intracranial volume and brain volume in late life reflect different genetic influences. Our genome-wide association study (GWAS) in 8,175 community-dwelling elderly persons did not reveal any associations at genome-wide significance (P < 5 × 10(-8)) for brain volume. In contrast, intracranial volume was significantly associated with two loci: rs4273712 (P = 3.4 × 10(-11)), a known height-associated locus on chromosome 6q22, and rs9915547 (P = 1.5 × 10(-12)), localized to the inversion on chromosome 17q21. We replicated the associations of these loci with intracranial volume in a separate sample of 1,752 elderly persons (P = 1.1 × 10(-3) for 6q22 and 1.2 × 10(-3) for 17q21). Furthermore, we also found suggestive associations of the 17q21 locus with head circumference in 10,768 children (mean age of 14.5 months). Our data identify two loci associated with head size, with the inversion at 17q21 also likely to be involved in attaining maximal brain size.
TL;DR: This article performed a meta-analysis of seven genome-wide association studies (GWAS) (N = 10,768 individuals of European ancestry enrolled in pregnancy and/or birth cohorts) and followed up three lead signals in six replication studies (combined N = 19,089).
Abstract: To identify genetic variants associated with head circumference in infancy, we performed a meta-analysis of seven genome-wide association studies (GWAS) (N = 10,768 individuals of European ancestry enrolled in pregnancy and/or birth cohorts) and followed up three lead signals in six replication studies (combined N = 19,089). rs7980687 on chromosome 12q24 (P = 8.1 × 10(-9)) and rs1042725 on chromosome 12q15 (P = 2.8 × 10(-10)) were robustly associated with head circumference in infancy. Although these loci have previously been associated with adult height, their effects on infant head circumference were largely independent of height (P = 3.8 × 10(-7) for rs7980687 and P = 1.3 × 10(-7) for rs1042725 after adjustment for infant height). A third signal, rs11655470 on chromosome 17q21, showed suggestive evidence of association with head circumference (P = 3.9 × 10(-6)). SNPs correlated to the 17q21 signal have shown genome-wide association with adult intracranial volume, Parkinson's disease and other neurodegenerative diseases, indicating that a common genetic variant in this region might link early brain growth with neurological disease in later life.
TL;DR: A genome-wide association study (GWAS) was performed in 6819 participants from the Framingham Heart Study (FHS) as discussed by the authors, where the top SNPs were selected based on P values and linkage disequilibrium among neighboring SNPs and evaluated in a meta-analysis with 5 independent populations from the Cooperative Health Research in the Region of Augsburg cohort, the British 1958 Birth Cohort, and the Childhood Asthma Management Program cohort.
Abstract: Background 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. Objective We sought to ascertain the genetic risk factors that lead to IgE dysregulation. Methods A genome-wide association study (GWAS) was performed in 6819 participants from the Framingham Heart Study (FHS). Seventy of the top single nucleotide polymorphisms (SNPs) were selected based on P values and linkage disequilibrium among neighboring SNPs and evaluated in a meta-analysis with 5 independent populations from the Cooperative Health Research in the Region of Augsburg cohort, the British 1958 Birth Cohort, and the Childhood Asthma Management Program cohort. Results Thirteen SNPs located in the region of 3 genes, FCER1A , signal transducer and activator of transcription 6 (STAT6) , and IL13 , were found to have genome-wide significance in the FHS cohort GWAS. The most significant SNPs from the 3 regions were rs2251746 ( FCER1A , P = 2.11 × 10 −12 ), rs1059513 ( STAT6 , P = 2.87 × 10 −8 ), and rs1295686 ( IL13 , P = 3.55 × 10 −8 ). Four additional gene regions, HLA-G , HLA-DQA2 , HLA-A , and Duffy blood group, chemokine receptor (DARC) , reached genome-wide statistical significance in a meta-analysis combining the FHS and replication cohorts, although the DARC association did not appear independent of SNPs in the nearby FCER1A gene. Conclusion This GWAS of the FHS cohort has identified genetic loci in HLA genes that might have a role in the pathogenesis of IgE dysregulation and atopy. It also confirmed the association of the known susceptibility loci FCER1A , STAT6 , and IL13 for the dysregulation of total IgE.
Swiss Tropical and Public Health Institute1, University of Basel2, Fondation Jean Dausset Centre d'Etude du Polymorphisme Humain3, Paris Diderot University4, French Institute of Health and Medical Research5, Imperial College London6, Wellcome Trust Centre for Human Genetics7, Research Triangle Park8, National Institutes of Health9, Boston University10, University Medical Center Groningen11, Joseph Fourier University12, University of Paris-Sud13, University of North Carolina at Chapel Hill14, University of Cologne15, Innsbruck Medical University16, French Alternative Energies and Atomic Energy Commission17, St George's, University of London18
TL;DR: The results suggest that genetic determinants of longitudinal and cross-sectional lung function differ and vary by asthma status, and genetic heterogeneity of lung function might be extensive.
Abstract: Background Genome-wide association studies have identified determinants of chronic obstructive pulmonary disease, asthma, and lung function level; however, none have addressed decline in lung function. Objective We conducted the first genome-wide association study on the age-related decrease in FEV 1 and its ratio to forced vital capacity (FVC) stratified a priori by asthma status. Methods Discovery cohorts included adults of European ancestry (1,441 asthmatic and 2,677 nonasthmatic participants: the Epidemiological Study on the Genetics and Environment of Asthma, the Swiss Cohort Study on Air Pollution and Lung and Heart Disease in Adults, and the European Community Respiratory Health Survey). The associations of FEV 1 and FEV 1 /FVC ratio decrease with 2.5 million single nucleotide polymorphisms (SNPs) were estimated. Thirty loci were followed up by in silico replication (1,160 asthmatic and 10,858 nonasthmatic participants: Atherosclerosis Risk in Communities, the Framingham Heart Study, the British 1958 Birth Cohort, and the Dutch Asthma Study). Results Main signals identified differed between asthmatic and nonasthmatic participants. None of the SNPs reached genome-wide significance. The association between the height-related gene DLEU7 and FEV 1 decrease suggested for nonasthmatic participants in the discovery phase was replicated (discovery, P = 4.8 × 10 −6 ; replication, P = .03), and additional sensitivity analyses point to a relation to growth. The top ranking signal, TUSC3 , which is associated with FEV 1 /FVC ratio decrease in asthmatic participants ( P = 5.3 × 10 −8 ), did not replicate. SNPs previously associated with cross-sectional lung function were not prominently associated with decline. Conclusions Genetic heterogeneity of lung function might be extensive. Our results suggest that genetic determinants of longitudinal and cross-sectional lung function differ and vary by asthma status.
TL;DR: Evidence is added that long-term exposure to outdoor air pollution, characterised by the concentration of PM10, is associated with increased respiratory symptoms, and PM10 was not associated with lung function across all studies combined.
Abstract: Studies of the impact of long-term exposure to outdoor air pollution on the prevalence of respiratory symptoms and lung function in children have yielded mixed results, partly related to differences in study design, exposure assessment, confounder selection and data analysis. We assembled respiratory health and exposure data for >45,000 children from comparable cross-sectional studies in 12 countries. 11 respiratory symptoms were selected, for which comparable questions were asked. Spirometry was performed in about half of the children. Exposure to air pollution was mainly characterised by annual average concentrations of particulate matter with a 50% cut-off aerodynamic diameter of 10 μm (PM(10)) measured at fixed sites within the study areas. Positive associations were found between the average PM(10) concentration and the prevalence of phlegm (OR per 10 μg · m(-3) 1.15, 95% CI 1.02-1.30), hay fever (OR 1.20, 95% CI 0.99-1.46), bronchitis (OR 1.08, 95% CI 0.98-1.19), morning cough (OR 1.15, 95% CI 1.02-1.29) and nocturnal cough (OR 1.13, 95% CI 0.98-1.29). There were no associations with diagnosed asthma or asthma symptoms. PM(10) was not associated with lung function across all studies combined. Our study adds to the evidence that long-term exposure to outdoor air pollution, characterised by the concentration of PM(10), is associated with increased respiratory symptoms.
01 Jan 2012
TL;DR: A meta-analysis of genome-wide association studies and lead signals showed suggestive evidence of association with head circumference in infancy, indicating that a common genetic variant in this region might link early brain growth with neurological disease in later life.
University of Paris-Sud1, French Institute of Health and Medical Research2, Fondation Jean Dausset Centre d'Etude du Polymorphisme Humain3, Paris Diderot University4, Joseph Fourier University5, Centre Hospitalier Universitaire de Grenoble6, National Institutes of Health7, Uppsala University8, French Alternative Energies and Atomic Energy Commission9, Pompeu Fabra University10
TL;DR: TRPV1 SNPs were associated with cough among subjects without asthma from two independent studies in eight European countries and may enhance susceptibility to cough in current smokers and in subjects with a history of workplace exposures.
Abstract: Background: 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. Methods: 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. Results: 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 )a nd 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). Conclusions: 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.
Harvard University1, Massachusetts Institute of Technology2, Brigham and Women's Hospital3, University of Manchester4, University of Göttingen5, Wake Forest University6, University of Liverpool7, Lund University8, National Institute of Occupational Health9, University of Southern California10, University of Aberdeen11, University of Hawaii12, National Institutes of Health13, Heidelberg University14, German Cancer Research Center15, University of Cambridge16, University of Sheffield17, Nuffield Orthopaedic Centre18
TL;DR: It is shown 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.
Abstract: 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-controlcovariate 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 falsepositive 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=1610 29 ). The improvement varied across diseases with a 16% median increase in x 2 test statistics and a commensurate increase in power. This suggests that applying our method to
TL;DR: Increased consumption of high-sugar products and lower diet quality are associated with a higher likelihood of emotional symptoms in children.
Abstract: Background/Aims: To assess the association between food intake and diet quality and behavioral problems at the 10-year follow-up of the two population-based birth
Swiss Institute of Allergy and Asthma Research1, Centre national de la recherche scientifique2, Ghent University3, Oslo University Hospital4, University of Helsinki5, Ludwig Maximilian University of Munich6, University of Paris-Sud7, French Institute of Health and Medical Research8, Charité9, National Institutes of Health10, University Medical Center Groningen11, Medical University of Vienna12, University of Arizona13, Joseph Fourier University14, Utrecht University15, Leiden University Medical Center16, Pompeu Fabra University17, Pierre-and-Marie-Curie University18, University of Valencia19, University of Toulouse20, University of Crete21, World Health Organization22, Paris Descartes University23, University of Paris24, Medical University of Łódź25, Biomax Informatics AG26, Bradford Royal Infirmary27, Boston Children's Hospital28
TL;DR: In this article, a review of current knowledge on the IgE-related phenotypes and how a multidisciplinary effort could result in a new integrative translational approach is presented.
Abstract: Mechanisms of the Development of Allergy (MeDALL), a Seventh Framework Program European Union project, aims to generate novel knowledge on the mechanisms of initiation of allergy. Precise phenotypes of IgE-mediated allergic diseases will be defined in MeDALL. As part of MeDALL, a scientific seminar was held on January 24, 2011, to review current knowledge on the IgE-related phenotypes and to explore how a multidisciplinary effort could result in a new integrative translational approach. This article provides a summary of the meeting. It develops challenges in IgE-related phenotypes and new clinical and epidemiologic approaches to the investigation of allergic phenotypes, including cluster analysis, scale-free models, candidate biomarkers, and IgE microarrays; the particular case of severe asthma was reviewed. Then novel approaches to the IgE-associated phenotypes are reviewed from the individual mechanisms to the systems, including epigenetics, human in vitro immunology, systems biology, and animal models. The last chapter deals with the understanding of the population-based IgE-associated phenotypes in children and adolescents, including age effect in terms of maturation, observed effects of early-life exposures and shift of focus from early life to pregnancy, gene-environment interactions, cohort effects, and time trends in patients with allergic diseases. This review helps to define phenotypes of allergic diseases in MeDALL.
University of Göttingen1, International Agency for Research on Cancer2, University of Toronto3, Pennsylvania State University4, Mayo Clinic5, Ludwig Maximilian University of Munich6, Nofer Institute of Occupational Medicine7, Curie Institute8, Russian Academy9, Charles University in Prague10, Carol Davila University of Medicine and Pharmacy11, Wayne State University12, University of California, Los Angeles13, University of Michigan14, University of California, San Francisco15, University of Liverpool16, University of Hawaii at Manoa17, Dartmouth College18, National Institutes of Health19, Memorial Sloan Kettering Cancer Center20, Icahn School of Medicine at Mount Sinai21, University of Strathclyde22
TL;DR: It is concluded that the association of asthma with lung cancer risk may not reflect a causal effect of asthma on the risk of LC, and the association was weak among never smokers.
Abstract: 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 (I(2) = 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.
TL;DR: FADS gene cluster modulates the effect of breastfeeding on asthma and results from the GINIplus and LISAplus studies are published.
Abstract: To cite this article: Standl M, Sausenthaler S, Lattka E, Koletzko S, Bauer C-P, Wichmann H-E, von Berg A, Berdel D, Kramer U, Schaaf B, Lehmann I, Herbarth O, Klopp N, Koletzko B, Heinrich J FADS gene cluster modulates the effect of breastfeeding on asthma Results from the GINIplus and LISAplus studies Allergy 2012; 67: 83–90
Abstract
Background: The protective effect of breastfeeding (BF) on the development of asthma has been widely recognized, even if not all results have been consistent Gene variants of the FADS gene cluster have a major impact on fatty acid composition in blood and in breast milk Therefore, we evaluated the influence of the FADS1 FADS2 gene cluster polymorphisms on the association between BF and asthma
Methods: The analysis was based on data (N = 2245) from two German prospective birth cohort studies Information on asthma and BF during the first 6 months was collected using questionnaires completed by the parents Logistic regression modelling was used to analyse the association between exclusive BF and ever having asthma stratified by genotype
Results: In the stratified analyses, BF for 3 or 4 months after birth had a protective effect for heterozygous and homozygous carriers of the minor allele (adjusted odds ratio between 037 (95% CI: 018–080) and 042 (95% CI: 020–088) Interaction terms of BF with genotype were significant and ranged from −117 (P-value: 0015) to −133 (00066) Moreover, heterozygous and homozygous carriers of the minor allele who were exclusively breastfed for 5 or 6 months after birth had a reduced risk of asthma [032 (018–057) to 047 (027–081)] in the stratified analyses For individuals carrying the homozygous major allele, BF showed no significant effect on the development of asthma
Conclusions: The association between exclusive BF and asthma is modified by the genetic variants of FADS genotypes in children
TL;DR: 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.
Abstract: Background: 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. Methods: 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. Results: 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 [b between 20.04 (p=0.0074) to 20.01 (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. Conclusion: 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.
TL;DR: The finding that utilization and costs are considerably higher in moderate but not in mild COPD highlights the economic importance of prevention and of interventions aiming at early diagnosis and delayed disease progression.
TL;DR: Growth velocity during infancy and onset of asthma in school‐aged children and Allergy 2012; 67: 257–264.
Abstract: To cite this article: Flexeder C, Thiering E, Bruske I, Koletzko S, Bauer C-P, Wichmann H-E, Mansmann U, von Berg A, Berdel D, Kramer U, Schaaf B, Lehmann I, Herbarth O, Heinrich J Growth velocity during infancy and onset of asthma in school-aged children Allergy 2012; 67: 257–264
Abstract
Background: Growth velocities during infancy might affect the risk of asthma in childhood This study examines the association between peak height and weight velocities during the first 2 years of life and onset of asthma and wheeze up to 10 years of age
Methods: Data from 9086 children who participated in the GINIplus and LISAplus birth cohorts were analyzed Information on asthma was requested annually from 1 to 10 years and information on wheeze at 1, 2, 4, 6, and 10 years Peak height and weight velocities were calculated using height and weight measurements obtained between birth and 2 years of age Cox proportional hazards models and generalized linear mixed models were calculated after adjustment for potential confounding factors including birth weight and body mass index at 10 years of age
Results: Per interquartile range increase in peak weight velocity (PWV), the risk of asthma increased significantly (adjHR: 122; CI: 102–147) The relationship between peak height velocity (PHV) and onset of asthma was nonsignificant (adjHR: 108; CI: 088–131) Wheeze was not significantly associated with PHV or with PWV (adjOR: 107; CI: 064–177 and adjOR: 111; CI: 068–179, respectively)
Conclusions: Weight gain during infancy is positively associated with physician-diagnosed asthma in school-aged children
TL;DR: In this article, the authors investigated the geographical variation and determinants of domestic endotoxin concentrations in mattress dust in Europe using data collected in the European Community Respiratory Health Survey follow-up (ECRHS II).
Abstract: Endotoxin exposures have manifold effects on human health. The geographical variation and determinants of domestic endotoxin levels in Europe have not yet been extensively described. To investigate the geographical variation and determinants of domestic endotoxin concentrations in mattress dust in Europe using data collected in the European Community Respiratory Health Survey follow-up (ECRHS II). Endotoxin levels were measured in mattress dust from 974 ECRHS II participants from 22 study centers using an immunoassay. Information on demographic, lifestyle, and housing characteristics of the participants was obtained in face-to-face interviews. The median endotoxin concentration in mattress dust ranged from 772 endotoxin units per gram (EU/g) dust in Reykjavik, Iceland, to 4806 EU/g in Turin, Italy. High average outdoor summer temperature of study center, cat or dog keeping, a high household crowding index, and visible damp patches in the bedroom were significantly associated with a higher endotoxin concentrations in mattress dust. There is a large variability in domestic endotoxin levels across Europe. Average outdoor summer temperature of study center, which explains only 10% of the variation in domestic endotoxin level by center, is the strongest meteorological determinant. The observed variation needs to be taken into account when evaluating the health effects of endotoxin exposures in international contexts. PRACTICAL IMPLICATIONS: The incoherent observations of the health effects of endotoxin may be partly owing to the geographical heterogeneity of endotoxin exposure. Therefore, the observed variation should be considered in further studies. Measurements of indoor endotoxin are recommended as an indicator for the level of exposures of individual domestic environments.