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1.  Genome-wide association study of body mass index in 23,000 individuals with and without asthma 
Background
Both asthma and obesity are complex disorders that are influenced by environmental and genetic factors. Shared genetic factors between asthma and obesity have been proposed to partly explain epidemiological findings of co-morbidity between these conditions.
Objective
To identify genetic variants that are associated with body mass index (BMI) in asthmatic children and adults, and to evaluate if there are differences between the genetics of BMI in asthmatics and healthy individuals.
Methods
In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23,000 individuals with predominantly European descent, of whom 8,165 are asthmatics.
Results
We report associations between several DENND1B variants (p=2.2×10−7 for rs4915551) on chromosome 1q31 and BMI from a meta-analysis of GWAS data using 2,691 asthmatic children (screening data). The top DENND1B SNPs were next evaluated in seven independent replication data sets comprising 2,014 asthmatics, and rs4915551 was nominally replicated (p<0.05) in two of the seven studies and of borderline significance in one (p=0.059). However, strong evidence of effect heterogeneity was observed and overall, the association between rs4915551 and BMI was not significant in the total replication data set, p=0.71. Using a random effects model, BMI was overall estimated to increase by 0.30 kg/m2 (p=0.01 for combined screening and replication data sets, N=4,705) per additional G allele of this DENND1B SNP. FTO was confirmed as an important gene for adult and childhood BMI regardless of asthma status.
Conclusions and Clinical Relevance
DENND1B was recently identified as an asthma susceptibility gene in a GWAS on children, and here we find evidence that DENND1B variants may also be associated with BMI in asthmatic children. However, the association was overall not replicated in the independent data sets and the heterogeneous effect of DENND1B points to complex associations with the studied diseases that deserve further study.
doi:10.1111/cea.12054
PMCID: PMC3608930  PMID: 23517042
Association; Asthma; BMI; Genetics; Genome-wide; Obesity
3.  Impact of Geocoding Methods on Associations between Long-term Exposure to Urban Air Pollution and Lung Function 
Environmental Health Perspectives  2013;121(9):1054-1060.
Background: Errors in address geocodes may affect estimates of the effects of air pollution on health.
Objective: We investigated the impact of four geocoding techniques on the association between urban air pollution estimated with a fine-scale (10 m × 10 m) dispersion model and lung function in adults.
Methods: We measured forced expiratory volume in 1 sec (FEV1) and forced vital capacity (FVC) in 354 adult residents of Grenoble, France, who were participants in two well-characterized studies, the Epidemiological Study on the Genetics and Environment on Asthma (EGEA) and the European Community Respiratory Health Survey (ECRHS). Home addresses were geocoded using individual building matching as the reference approach and three spatial interpolation approaches. We used a dispersion model to estimate mean PM10 and nitrogen dioxide concentrations at each participant’s address during the 12 months preceding their lung function measurements. Associations between exposures and lung function parameters were adjusted for individual confounders and same-day exposure to air pollutants. The geocoding techniques were compared with regard to geographical distances between coordinates, exposure estimates, and associations between the estimated exposures and health effects.
Results: Median distances between coordinates estimated using the building matching and the three interpolation techniques were 26.4, 27.9, and 35.6 m. Compared with exposure estimates based on building matching, PM10 concentrations based on the three interpolation techniques tended to be overestimated. When building matching was used to estimate exposures, a one-interquartile range increase in PM10 (3.0 μg/m3) was associated with a 3.72-point decrease in FVC% predicted (95% CI: –0.56, –6.88) and a 3.86-point decrease in FEV1% predicted (95% CI: –0.14, –3.24). The magnitude of associations decreased when other geocoding approaches were used [e.g., for FVC% predicted –2.81 (95% CI: –0.26, –5.35) using NavTEQ, or 2.08 (95% CI –4.63, 0.47, p = 0.11) using Google Maps].
Conclusions: Our findings suggest that the choice of geocoding technique may influence estimated health effects when air pollution exposures are estimated using a fine-scale exposure model.
Citation: Jacquemin B, Lepeule J, Boudier A, Arnould C, Benmerad M, Chappaz C, Ferran J, Kauffmann F, Morelli X, Pin I, Pison C, Rios I, Temam S, Künzli N, Slama R, Siroux V. 2013. Impact of geocoding methods on associations between long-term exposure to urban air pollution and lung function. Environ Health Perspect 121:1054–1060; http://dx.doi.org/10.1289/ehp.1206016
doi:10.1289/ehp.1206016
PMCID: PMC3764075  PMID: 23823697
4.  Air pollution and asthma control in the Epidemiological study on the Genetics and Environment of Asthma 
Background
The associations between exposure to air pollution and asthma control are not well known. The objective is to assess the association between long term exposure to NO2, O3 and PM10 and asthma control in the EGEA2 study (2003–2007).
Methods
Modeled outdoor NO2, O3 and PM10 estimates were linked to each residential address using the 4-km grid air pollutant surface developed by the French Institute of Environment for 2004. Asthma control was assessed in 481 subjects with current asthma using a multidimensional approach following the 2006–2009 GINA guidelines. Multinomial and ordinal logistic regressions were conducted adjusted on sex, age, BMI, education, smoking and use of inhaled corticosteroids. The association between air pollution and the three domains of asthma control (symptoms, exacerbations and lung function) was assessed. Odds Ratios (ORs) are reported per Inter Quartile Range (IQR).
Results
Median concentrations (μg.m−3) were 32(IQR 25–38) for NO2 (n=465), 46(41–52) for O3 and 21(18–21) for PM10 (n=481). In total, 44%, 29% and 27% had controlled, partly-controlled and uncontrolled asthma. The ordinal ORs for O3 and PM10 with asthma control were 1.69(95%CI 1.22–2.34) and 1.35(95%CI 1.13–1.64) respectively. When including both pollutants in the same model, both associations persisted. Associations were not modified by sex, smoking status, use of inhaled corticosteroids, atopy, season of examination or BMI. Both pollutants were associated with each of the three main domains of control.
Conclusions
The results suggest that long-term exposure to PM10 and O3 is associated with uncontrolled asthma in adults, defined by symptoms, exacerbations and lung function. Abstract Word count: 250 Key words: air pollution, asthma, asthma control
doi:10.1136/jech.2010.130229
PMCID: PMC3943770  PMID: 21690606
Adult; Air Pollutants; adverse effects; analysis; Asthma; epidemiology; etiology; genetics; Case-Control Studies; Cross-Sectional Studies; Environmental Exposure; adverse effects; analysis; Environmental Monitoring; Follow-Up Studies; France; epidemiology; Hospitalization; statistics & numerical data; Humans; Logistic Models; Lung; physiopathology; Nitrous Acid; adverse effects; analysis; Ozone; adverse effects; analysis; Residence Characteristics; Respiratory Tract Diseases; complications; epidemiology; genetics; Seasons; Severity of Illness Index; air pollution; asthma; asthma control
5.  Temporal Asthma Patterns Using Repeated Questionnaires over 13 Years in a Large French Cohort of Women 
PLoS ONE  2013;8(5):e65090.
Variable expression is one aspect of the heterogeneity of asthma. We aimed to define a variable pattern, which is relevant in general health epidemiological cohorts. Our objectives were to assess whether: 1) asthma patterns defined using simple asthma questions through repeated measurements could reflect disease variability 2) these patterns may further be classified according to asthma severity/control. Among 70,428 French women, we used seven questionnaires (1992–2005) and a comprehensive reimbursement database (2004–2009) to define three reliable asthma patterns based on repeated positive answers to the ever asthma attack question: “never asthma” (n = 64,061); “inconsistent” (“yes” followed by “no”, n = 3,514); “consistent” (fully consistent positive answers, n = 2,853). The “Inconsistent” pattern was related to both long-term (childhood-onset asthma with remission in adulthood) and short-term (reported asthma attack in the last 12 months, associated with asthma medication) asthma variability, showing that repeated questions are relevant markers of the variable expression of asthma. Furthermore, in this pattern, the number of positive responses (1992–2005) predicted asthma drug consumption in subsequent years, a marker of disease severity. The “Inconsistent” pattern is a phenotype that may capture the variable expression of asthma. Repeated answers, even to a simple question, are too often neglected.
doi:10.1371/journal.pone.0065090
PMCID: PMC3669014  PMID: 23741466
6.  Genome-wide association study of lung function decline in adults with and without asthma 
Background
Genome-wide association studies (GWAS) have identified determinants of chronic obstructive pulmonary disease, asthma and lung function level, however none addressed decline in lung function.
Aim
We conducted the first GWAS on age-related decline in forced expiratory volume in the first second (FEV1) and in its ratio to forced vital capacity (FVC) stratified a priori by asthma status.
Methods
Discovery cohorts included adults of European ancestry (1441 asthmatics, 2677 non-asthmatics; Epidemiological Study on the Genetics and Environment of Asthma (EGEA); Swiss Cohort Study on Air Pollution And Lung And Heart Disease In Adults (SAPALDIA); European Community Respiratory Health Survey (ECRHS)). The associations of FEV1 and FEV1/FVC decline with 2.5 million single nucleotide polymorphisms (SNPs) were estimated. Thirty loci were followed-up by in silico replication (1160 asthmatics, 10858 non-asthmatics: Atherosclerosis Risk in Communities (ARIC); Framingham Heart Study (FHS); British 1958 Birth Cohort (B58C); Dutch asthma study).
Results
Main signals identified differed between asthmatics and non-asthmatics. None of the SNPs reached genome-wide significance. The association between the height related gene DLEU7 and FEV1 decline suggested for non-asthmatics in the discovery phase was replicated (discovery P=4.8×10−6; replication P=0.03) and additional sensitivity analyses point to a relation to growth. The top ranking signal, TUSC3, associated with FEV1/FVC decline in asthmatics (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 may be extensive. Our results suggest that genetic determinants of longitudinal and cross-sectional lung function differ and vary by asthma status.
doi:10.1016/j.jaci.2012.01.074
PMCID: PMC3340499  PMID: 22424883
Asthma; cohort studies; genome-wide association; lung function decline; heterogeneity
7.  Quantifying the use of bioresources for promoting their sharing in scientific research 
GigaScience  2013;2:7.
An increasing portion of biomedical research relies on the use of biobanks and databases. Sharing of such resources is essential for optimizing knowledge production. A major obstacle for sharing bioresources is the lack of recognition for the efforts involved in establishing, maintaining and sharing them, due to, in particular, the absence of adequate tools. Increasing demands on biobanks and databases to improve access should be complemented with efforts of end-users to recognize and acknowledge these resources. An appropriate set of tools must be developed and implemented to measure this impact.
To address this issue we propose to measure the use in research of such bioresources as a value of their impact, leading to create an indicator: Bioresource Research Impact Factor (BRIF). Key elements to be assessed are: defining obstacles to sharing samples and data, choosing adequate identifier for bioresources, identifying and weighing parameters to be considered in the metrics, analyzing the role of journal guidelines and policies for resource citing and referencing, assessing policies for resource access and sharing and their influence on bioresource use. This work allows us to propose a framework and foundations for the operational development of BRIF that still requires input from stakeholders within the biomedical community.
doi:10.1186/2047-217X-2-7
PMCID: PMC3655103  PMID: 23634721
Data sharing; Bioresource; Biobank; Identifier; Metrics; Traceability; Impact factor; Biology; Science policy; Open data
8.  Association of lung function with physical, mental and cognitive function in early old age 
Age  2010;33(3):385-392.
Lung function predicts mortality; whether it is associated with functional status in the general population remains unclear. This study examined the association of lung function with multiple measures of functioning in early old age. Data are drawn from the Whitehall II study; data on lung function (forced expiratory volume in 1 s, height FEV1), walking speed (2.44 m), cognitive function (memory and reasoning) and self-reported physical and mental functioning (SF-36) were available on 4,443 individuals, aged 50–74 years. In models adjusted for age, 1 standard deviation (SD) higher height-adjusted FEV1 was associated with greater walking speed (beta = 0.16, 95% CI: 0.13, 0.19), memory (beta = 0.09, 95% CI: 0.06, 0.12), reasoning (beta = 0.16, 95% CI: 0.13, 0.19) and self-reported physical functioning (beta = 0.13, 95% CI: 0.10, 0.16). Socio-demographic measures, health behaviours (smoking, alcohol, physical activity, fruit/vegetable consumption), body mass index (BMI) and chronic conditions explained two-thirds of the association with walking speed and self-assessed physical functioning and over 80% of the association with cognitive function. Our results suggest that lung function is a good ‘summary’ measure of overall functioning in early old age.
doi:10.1007/s11357-010-9189-x
PMCID: PMC3168608  PMID: 20878489
Ageing; Lung function; Cognitive function; Physical function
9.  Association of lung function with physical, mental and cognitive function in early old age 
Age  2010;33(3):385-392.
Lung function predicts mortality, whether it is associated with functional status in the general population remains unclear. This study examined the association of lung function with multiple measures of functioning in early old age. Data are drawn from the Whitehall II study; data on lung function (forced expiratory volume in one second, height FEV1), walking speed (over 2.44 m), cognitive function (memory and reasoning), and self-reported physical and mental functioning (SF-36) were available on 4443 individuals, aged 50–74 years. In models adjusted for age, one standard deviation (SD) higher height-adjusted FEV1 was associated with greater walking speed (beta=0.16, 95% CI: 0.13, 0.19), memory (beta=0.09, 95% CI: 0.06, 0.12), reasoning (beta=0.16, 95% CI: 0.13, 0.19), and self-reported physical functioning (beta=0.13, 95% CI: 0.10, 0.16). Socio-demographic measures, health behaviours (smoking, alcohol, physical activity, fruit/vegetable consumption), BMI and chronic conditions explained two-thirds of the association with walking speed and self-assessed physical functioning and over 80% of the association with cognitive function. Our results suggest that lung function is a good “summary” measure of overall functioning in early old age.
doi:10.1007/s11357-010-9189-x
PMCID: PMC3168608  PMID: 20878489
Aged; Aging; physiology; psychology; Cognition; physiology; Female; Health Status; Humans; Lung; physiology; Male; Middle Aged; Spirometry; Walking; physiology; ageing; lung function; cognitive function; physical function
10.  Associations between Nitric Oxide Synthase Genes and Exhaled NO-Related Phenotypes according to Asthma Status 
PLoS ONE  2012;7(5):e36672.
Background
The nitric oxide (NO) pathway is involved in asthma, and eosinophils participate in the regulation of the NO pool in pulmonary tissues. We investigated associations between single nucleotide polymorphisms (SNPs) of NO synthase genes (NOS) and biological NO-related phenotypes measured in two compartments (exhaled breath condensate and plasma) and blood eosinophil counts.
Methodology
SNPs (N = 121) belonging to NOS1, NOS2 and NOS3 genes were genotyped in 1277 adults from the French Epidemiological study on the Genetics and Environment of Asthma (EGEA). Association analyses were conducted on four quantitative phenotypes: the exhaled fraction of NO (FeNO), plasma and exhaled breath condensate (EBC) nitrite-nitrate levels (NO2–NO3) and blood eosinophils in asthmatics and non-asthmatics separately. Genetic heterogeneity of these phenotypes between asthmatics and non-asthmatics was also investigated.
Principal Findings
In non-asthmatics, after correction for multiple comparisons, we found significant associations of FeNO levels with three SNPs in NOS3 and NOS2 (P≤0.002), and of EBC NO2–NO3 level with NOS2 (P = 0.002). In asthmatics, a single significant association was detected between FeNO levels and one SNP in NOS3 (P = 0.004). Moreover, there was significant heterogeneity of NOS3 SNP effect on FeNO between asthmatics and non-asthmatics (P = 0.0002 to 0.005). No significant association was found between any SNP and NO2–NO3 plasma levels or blood eosinophil counts.
Conclusions
Variants in NO synthase genes influence FeNO and EBC NO2–NO3 levels in adults. These genetic determinants differ according to asthma status. Significant associations were only detected for exhaled phenotypes, highlighting the critical relevance to have access to specific phenotypes measured in relevant biological fluid.
doi:10.1371/journal.pone.0036672
PMCID: PMC3348876  PMID: 22590587
11.  Transient receptor potential genes, smoking, occupational exposures and cough in adults 
Respiratory Research  2012;13(1):26.
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) 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).
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.
doi:10.1186/1465-9921-13-26
PMCID: PMC3342106  PMID: 22443337
Asthma; Gene-environment interaction; Irritant exposure; Smoking; TRP channel
12.  Why Does Lung Function Predict Mortality? Results From the Whitehall II Cohort Study 
American Journal of Epidemiology  2010;172(12):1415-1423.
The authors examined the extent to which socioeconomic position, behavior-related factors, cardiovascular risk factors, inflammatory markers, and chronic diseases explain the association between poor lung function and mortality in 4,817 participants (68.9% men) from the Whitehall II Study aged 60.8 years (standard deviation, 5.9), on average. Forced expiratory volume in 1 second (FEV1) was used to measure lung function in 2002–2004. A total of 139 participants died during a mean follow-up period of 6.4 years (standard deviation, 0.8). In a model adjusted for age and sex, being in the lowest tertile of FEV1/height2 was associated with a 1.92-fold (95% confidence interval: 1.35, 2.73) increased risk of mortality compared with being in the top 2 tertiles. Once age, sex, and smoking history were taken into account, the most important explanatory factors for this association were inflammatory markers (21.3% reduction in the FEV1/height2-mortality association), coronary heart disease, stroke, and diabetes (11.7% reduction), and alcohol consumption, diet, physical activity, and body mass index (9.8% reduction). The contribution of socioeconomic position and cardiovascular risk factors was small (≤3.5% reduction). Taken together, these factors explained 32.5% of the association. Multiple pathways link lung function to mortality; these results show inflammatory markers to be particularly important.
doi:10.1093/aje/kwq294
PMCID: PMC2998200  PMID: 20961971
forced expiratory volume; inflammation; middle aged; mortality; respiratory function tests
13.  Systems medicine and integrated care to combat chronic noncommunicable diseases 
Genome Medicine  2011;3(7):43.
We propose an innovative, integrated, cost-effective health system to combat major non-communicable diseases (NCDs), including cardiovascular, chronic respiratory, metabolic, rheumatologic and neurologic disorders and cancers, which together are the predominant health problem of the 21st century. This proposed holistic strategy involves comprehensive patient-centered integrated care and multi-scale, multi-modal and multi-level systems approaches to tackle NCDs as a common group of diseases. Rather than studying each disease individually, it will take into account their intertwined gene-environment, socio-economic interactions and co-morbidities that lead to individual-specific complex phenotypes. It will implement a road map for predictive, preventive, personalized and participatory (P4) medicine based on a robust and extensive knowledge management infrastructure that contains individual patient information. It will be supported by strategic partnerships involving all stakeholders, including general practitioners associated with patient-centered care. This systems medicine strategy, which will take a holistic approach to disease, is designed to allow the results to be used globally, taking into account the needs and specificities of local economies and health systems.
doi:10.1186/gm259
PMCID: PMC3221551  PMID: 21745417
14.  Meta-analysis of 20 genome-wide linkage studies evidenced new regions linked to asthma and atopy 
Asthma is caused by a heterogeneous combination of environmental and genetic factors. In the context of GA2LEN (Global Allergy and Asthma European Network), we carried out meta-analyses of almost all genome-wide linkage screens conducted to date in 20 independent populations from different ethnic origins (≥3024 families with ≥10 027 subjects) for asthma, atopic asthma, bronchial hyper-responsiveness and five atopy-related traits (total immunoglobulin E level, positive skin test response (SPT) to at least one allergen or to House Dust Mite, quantitative score of SPT (SPTQ) and eosinophils (EOS)). We used the genome scan meta-analysis method to assess evidence for linkage within bins of traditionally 30-cM width, and explored the manner in which these results were affected by bin definition. Meta-analyses were conducted in all studies and repeated in families of European ancestry. Genome-wide evidence for linkage was detected for asthma in two regions (2p21–p14 and 6p21) in European families ascertained through two asthmatic sibs. With regard to atopy phenotypes, four regions reached genome-wide significance: 3p25.3–q24 in all families for SPT and three other regions in European families (2q32–q34 for EOS, 5q23–q33 for SPTQ and 17q12–q24 for SPT). Tests of heterogeneity showed consistent evidence of linkage of SPTQ to 3p11–3q21, whereas between-study heterogeneity was detected for asthma in 2p22–p13 and 6p21, and for atopic asthma in 1q23–q25. This large-scale meta-analysis provides an important resource of information that can be used to prioritize further fine-mapping studies and also be integrated with genome-wide association studies to increase power and better interpret the outcomes of these studies.
doi:10.1038/ejhg.2009.224
PMCID: PMC2987334  PMID: 20068594
asthma; atopy; meta-analysis; linkage scan
15.  Postmenopausal hormone therapy and asthma onset in the E3N cohort 
Thorax  2010;65(4):292-297.
Background
Epidemiological studies have suggested that female hormones might play a role in asthma and that menopausal hormone therapy (MHT or HRT) might increase the risk of asthma in postmenopausal women. The only prospective study addressing this issue reports an increase in the risk of developing asthma which was similar for estrogen alone and estrogen/progestagen treatment.
Methods
The association between the use of different types of MHT and the risk of asthma onset in postmenopausal women was investigated prospectively from 1990 to 2002 by biennial questionnaire as part of the French E3N cohort study. Asthma onset was considered to be the time of medical diagnosis of asthma cases occurring during the follow up of women who were asthma free at baseline. Cox proportional hazards models were used, adjusting for potential confounding factors.
Results
Among 57,664 women free of asthma at menopause 569 incident cases of asthma were identified during 495,448 years of follow-up. MHT was related to an increased risk of asthma onset (HR= 1.20, 95% CI 0.98–1.46) among recent users. The increase in risk of asthma onset was only significant among women reporting the use of estrogen alone (HR= 1.54, 95% CI 1.13–2.09).particularly in never smokers (HR= 1.80 95% CI 1.15–2.80) and women reporting allergic disease prior to asthma onset (HR= 1.86 95% CI 1.18–2.93). A small increase in the risk of asthma onset associated with the use of estrogen/progestagen was also observed in these subgroups.
Conclusion
Postmenopausal use of estrogen alone was associated with an increased rate of newly diagnosed asthma in menopausal women.
doi:10.1136/thx.2009.116079
PMCID: PMC2962872  PMID: 20142267
Asthma; Epidemiology; Menopausal hormone therapy (MHT); Hormone replacement therapy (HRT); Asthma; chemically induced; epidemiology; Body Mass Index; Drug Combinations; Estrogen Replacement Therapy; adverse effects; utilization; Estrogens; adverse effects; Female; France; epidemiology; Humans; Middle Aged; Postmenopause; Progesterone; adverse effects; Prospective Studies; Risk Factors
16.  Cat sensitization according to cat window of exposure in adult asthmatics 
Clinical and Experimental Allergy  2009;39(10):1515-1521.
Background
In adults, there is limited information on tolerance to cat, which may be reflected by high IgG4 without IgE sensitization. Early exposure to cat may play a critical role.
Objective
The aim was to assess among adult the association of Fel d 1 IgG4, Fel d 1 IgE, skin prick test response to cat and pet-related symptoms in relation to exposure to cat considering the period of exposure.
Methods
Skin prick test response to cat, specific IgE and IgG4 to Fel d 1 were assessed in 167 asthmatics recruited in chest clinics (40 years of age in average) from the French Epidemiological study on the Genetics and Environment of Asthma (EGEA). Childhood and/or current exposure to cat were studied retrospectively.
Results
IgG4 was higher in relation to current cat exposure (0.53 vs. 0.09 ng/ml; p < 0.001) and higher in women than in men. The period of cat exposure was significantly related to Fel d 1 IgE, the IgE/IgG4 pattern and cat wheal size. The lowest values of Fel d 1 IgE, cat wheal size, pet-related nasal or respiratory symptoms were observed in those with both childhood and current exposure as well as the highest proportion of the IgE−/IgG4+ pattern observed in 1.4%, 4.0%, 38.1% and 12.5 % of those with −/−, +/−, +/+, −/+ childhood/current exposure respectively.
Conclusions
Adult asthmatics exposed to cats since childhood present an immunologic pattern with high IgG4 and low IgE. Continuous exposure may maintain a state of immunological tolerance to cat.
doi:10.1111/j.1365-2222.2009.03288.x
PMCID: PMC2878964  PMID: 19486030
Adult; Allergens; adverse effects; Animals; Asthma; blood; epidemiology; Case-Control Studies; Cats; Female; France; Glycoproteins; adverse effects; Humans; Immunoglobulin E; blood; Immunoglobulin G; blood; Male; Sex Factors; Adult; specific IgE positivity; cat; tolerance; asthma
17.  Candidate gene-environment interactions 
doi:10.1136/jech.2008.086199
PMCID: PMC2855723  PMID: 20203119
18.  Air pollution and asthma severity in adults 
Objectives
There is evidence that exposure to air pollution affects asthma, but the effect of air pollution on asthma severity has not been addressed. The aim was to assess the relation between asthma severity during the past 12 months and home outdoor concentrations of air pollution.
Methods
Asthma severity over the last 12 months was assessed in two complementary ways among 328 adult asthmatics from the French Epidemiological study on the Genetics and Environment of Asthma (EGEA) examined between 1991 and 1995. The 4-class severity score integrated clinical events and type of treatment. The 5-level asthma score is based only on the occurrence of symptoms. Nitrogen dioxide (NO2), sulphur dioxide (SO2) and ozone (O3) concentrations were assigned to each residence using two different methods. The first was based on the closest monitor data from 1991–1995. The second consisted in spatial models that used geostatistical interpolations and then assigned air pollutants to the geo-coded residences (1998).
Results
Higher asthma severity score was significantly related to the 8-hour average of ozone during April-September (O3-8hr) and the number of days (O3-days) with 8-hour ozone averages above 110 μg.m−3 (for a 36-day increase, equivalent to the inter quartile range, in O3-days, odds ratio (95% confidence interval) 2.22 (1.61–3.07) for one class difference in score). Adjustment for age, sex, smoking habits, occupational exposure, and educational level did not alter results. Asthma severity was unrelated to NO2. Both exposure assessment methods and severity scores resulted in very similar findings. SO2 correlated with severity but reached statistical significance only for the model based assignment of exposure.
Conclusions
The observed associations between asthma severity and air pollution, in particular O3, support the hypothesis that air pollution at levels far below current standards increases asthma severity.
doi:10.1136/oem.2007.038349
PMCID: PMC2663354  PMID: 19017701
air pollution; asthma severity; ozone
19.  Evidence for linkage of a new region (11p14) to eczema and allergic diseases 
Human Genetics  2007;122(6):605-614.
SUMMARY
Asthma, allergic rhinitis (AR) and atopic dermatitis also called eczema are allergic co-morbidites which are likely to depend on pleiotropic genetic effects as well as on specific genetic factors. After a previous genome-wide linkage screen conducted for asthma and AR in a sample of 295 French EGEA families ascertained through asthmatic subjects, the aim here was to search for genetic factors involved in eczema and more particularly those ones shared by the three allergic diseases using the same EGEA data. In this sake, eczema and phenotypes of ‘allergic disease’ accounting for the joint information on the presence/absence of the three diseases were examined by linkage analyses using the Maximum Likelihood Binomial (MLB) method. A fine mapping was carried out in regions detected for potential linkage, followed by association studies using the Family Based Association Test (FBAT). Evidence for linkage to 11p14 region was shown for ‘allergic disease’ and eczema. Linkage was also indicated between eczema and 5q13 and between ‘allergic disease’ and both 5p15 and 17q21 regions. Fine mapping supported the evidence of linkage to 11p14 and FBAT analyses showed association between ‘allergic disease’ and a marker located at the linkage peak on 11p14. Further investigations in this region will allow identifying genetic factor(s) which could have pleiotropic effect in the three allergic diseases.
doi:10.1007/s00439-007-0439-7
PMCID: PMC2575854  PMID: 17943316
Adolescent; Adult; Child; Chromosomes; Human; Pair 11; Eczema; genetics; Female; Genetic Markers; Genetic Screening; Humans; Hypersensitivity; genetics; Linkage (Genetics); Lod Score; Male; Nuclear Family; Questionnaires; atopic dermatitis; linkage analysis; genome screen; fine mapping; association study
20.  Occupational exposures and asthma in 14,000 adults from the general population 
American Journal of Epidemiology  2004;160(11):1108-1116.
The association of occupational exposures and asthma were studied in 14151 adults, aged 25–59 years, from the general population of the French PAARC (Pollution Atmospherique et Affections Respiratoires Chroniques, 1975) Survey. Associations of asthma to specific jobs such as personal care workers, waiters, stock clerks were observed, with age, sex, smoking adjusted odds ratios between 1.5 and 1.7. Exposures to 18 asthmagenic agents (low, high molecular weight and mixed environment) were estimated by an asthma-specific job exposure matrix. Risks associated with asthma increased when excluding subjects with imprecise estimates of exposure. Risks further increased when increasing specificity of the definition of asthma considering jobs or specific agents such as industrial cleaning agents, latex, flour, highly reactive chemicals, and textiles. For example, for industrial cleaning agents, odds ratios increased from 1.55 (95% CI: 1.08, 2.23) for ever asthma, to 2.51 (95% CI: 1.33, 4.75) for asthma with airflow limitation, to 2.17 (95% CI: 1.41, 3.34) for asthma onset after age 14, and to 2.35 (95% CI: 1.38, 4.00) for asthma onset after beginning of current job. Results underlined the importance of the specificity of exposure and asthma definitions and indicated a deleterious role of occupational exposure on asthma, especially for cleaning agents.
doi:10.1093/aje/kwh316
PMCID: PMC2519149  PMID: 15561990
Adult; Asthma; etiology; Epidemiologic Methods; Female; France; epidemiology; Humans; Male; Middle Aged; Occupational Exposure; adverse effects; Occupations; classification; Population Surveillance; methods; Questionnaires; Risk Factors; Smoking; adverse effects; asthma; occupational diseases; occupations; occupational exposures; job exposure matrix
21.  Polymorphisms in manganese superoxide dismutase and catalase genes: functional study in Hong Kong Chinese asthma patients 
Clinical and Experimental Allergy   2006;36(8):1104-1105.
doi:10.1111/j.1365-2222.2006.02545.x
PMCID: PMC2519150  PMID: 16911367
Asthma; enzymology; ethnology; Catalase; genetics; Erythrocytes; enzymology; Ethnic Groups; Humans; Oxidation-Reduction; Polymorphism, Genetic; Superoxide Dismutase; genetics
22.  Replication of Association between ADAM33 Polymorphisms and Psoriasis 
PLoS ONE  2008;3(6):e2448.
Polymorphisms in ADAM33, the first gene identified in asthma by positional cloning, have been recently associated with psoriasis. No replication study of this association has been published so far. Data available in the French EGEA study (Epidemiological study on Genetics and Environment of Asthma, bronchial hyperresponsivensess and Atopy) give the opportunity to attempt to replicate the association between ADAM33 and psoriasis in 2002 individuals. Psoriasis (n = 150) has been assessed by questionnaire administered by an interviewer and a sub-sample of subjects with early-onset psoriasis (n = 74) has been identified based on the age of the subjects at time of interview (<40 years). Nine SNPs in ADAM33 and 11 SNPs in PSORS1 were genotyped. Association analysis was conducted by using two methods, GEE regression-based method and a likelihood-based method (LAMP program). The rs512625 SNP in ADAM33 was found associated with psoriasis at p = 0.01, the usual threshold required for replication (OR [95% CI] for heterozygotes compared to the reference group of homozygotes for the most frequent allele = 0.61 [0.42;0.89]). The rs628977 SNP, which was not in linkage disequilibrium with rs512625, was significantly associated with early-onset psoriasis (p = 0.01, OR [95% CI] for homozygotes for the minor allele compared to the reference group = 2.52 [1.31;4.86]). Adjustment for age, sex, asthma and a PSORS1 SNP associated with psoriasis in the EGEA data did not change the significance of these associations. This suggests independent effects of ADAM33 and PSORS1 on psoriasis. This is the first study that replicates an association between genetic variants in ADAM33 and psoriasis. Interestingly, the 2 ADAM33 SNPs associated with psoriasis in the present analysis were part of the 3-SNPs haplotypes showing the strongest associations in the initial study. The identification of a pleiotropic effect of ADAM33 on asthma and psoriasis may contribute to the understanding of these common immune-mediated diseases.
doi:10.1371/journal.pone.0002448
PMCID: PMC2413006  PMID: 18560587
23.  Fruit and vegetable intakes and asthma in the E3N study 
Thorax  2006;61(3):209-215.
Background
A study was undertaken to investigate whether dietary intake predicted the prevalence of adult asthma among French women participating in the E3N study.
Methods
Of 68 535 women who completed a food frequency questionnaire in 1993 which included 238 food items, 2145 (3.1%) reported having asthma. The distribution of food intake was divided into quartiles (Q1–Q4) and the prevalence of asthma was compared between the different quartiles (lowest as reference) using logistic regression models on cross sectional data.
Results
After adjusting for age, body mass index, menopausal status, smoking status, total caloric intake, physical activity, and use of dietary supplements, women who had a greater intake of tomatoes (ORQ1–Q4 0.85 95% CI 0.75 to 0.96, test for trend p=0.02), carrots (ORQ1–Q4 0.81 95% CI 0.72 to 0.92, test for trend p=0.0003), and leafy vegetables (ORQ1–Q4 0.82 95% CI 0.73 to 0.93, test for trend p=0.0009) had a lower prevalence of asthma. Apples were marginally related to the prevalence of asthma. No other fruits or vegetables were significantly associated with asthma prevalence.
Conclusions
These results suggest that the intake of some vegetables may decrease the prevalence of adult asthma.
doi:10.1136/thx.2004.039123
PMCID: PMC1974844  PMID: 16396945
Adult; Aged; Asthma; epidemiology; Body Mass Index; Diet; Female; France; epidemiology; Fruit; Humans; Middle Aged; Odds Ratio; Prevalence; Questionnaires; Vegetables
24.  Polymorphisms in chemokine and chemokine receptor genes and the development of coal workers' pneumoconiosis 
Cytokine  2006;33(3):171-178.
Chemokines and their receptors are key regulators of inflammation and may participate in the lung fibrotic process. Associations of polymorphisms in CCL5 (G-403A) and its receptor CCR5 (Δ32), CCL2 (A-2578G) and CCR2 (V64I), and CX3CR1 V249I and T280M with Coal Worker’s Pneumoconiosis (CWP) were investigated in 209 miners examined in 1990, 1994 and 1999. Coal dust exposure was assessed by job history and ambient measures. The main health outcome was lung computed tomography (CT) score in 1990. Internal coherence was assessed by studying CT score in 1994, 4-year change in CT score, and CWP prevalence in 1999. CCR5 Δ32 carriers had significantly higher CT score in 1990 and 1994 (2.15 vs. 1.28, p=0.01; 3.04 vs. 1.80, p=0.04). The CX3CR1 1249 allele was significantly associated with lower 1990 CT score and lower progression in 4-year change in CT score in CCR5 Δ32 carriers only (p for interaction=0.03 and 0.02). CX3CR1 V249I was associated with lower 1999 CWP prevalence (16.7%, 13.2%, 0.0% for VV, VI and II); the effect was most evident in miners with high dust exposure (31.6%, 21.7%, 0.0%). Our findings indicate that chemokine receptors CCR5 and CX3CR1 may be involved in the development of pneumoconiosis.
doi:10.1016/j.cyto.2006.01.001
PMCID: PMC1913495  PMID: 16524739
Adult; Chemokine CCL2; genetics; Chemokines; genetics; Chemokines, CC; genetics; Coal Mining; Gene Frequency; Genotype; Humans; Membrane Proteins; genetics; Middle Aged; Phenotype; Pneumoconiosis; diagnosis; epidemiology; genetics; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Prevalence; Receptors, CCR5; genetics; Receptors, Chemokine; genetics; chemokines; interaction; occupational exposure; pneumoconiosis; polymorphism
25.  Effect of TNF and LTA polymorphisms on biological markers of response to oxidative stimuli in coal miners: a model of gene-environment interaction. Tumour necrosis factor and lymphotoxin alpha 
Journal of Medical Genetics  2003;40(2):96-103.
Introduction
Interaction between genetic background and oxidative environmental stimuli in the pathogenesis of human lung disease has been largely unexplored.
Methods
A prospective epidemiologic study was undertaken in 253 coal miners. Intermediate quantitative phenotypes of response to oxidant exposure, including erythrocyte glutathione peroxidase (GSH-Px) and catalase activities were studied. Oxidant exposures studied were smoking habits and cumulative dust exposure assessed by job history and ambient measures. Disease phenotypes included subclinical computed tomography score at the first survey and X-ray profusion grades twice, 5 years apart, to assess established coal workers’ pneumoconiosis (CWP). Miners were genotyped for common functional polymorphisms in the gene for tumor necrosis factor α (TNF) and lymphotoxin α (LTA), two proinflammatory cytokines that have been implicated in the pathogenesis of chronic lung diseases.
Results
Regarding gene-environment interaction on intermediate phenotypes, results showed interaction of a promoter polymorphism at the –308 position in TNF with occupational exposure on erythrocyte GSH-Px activity with a significant association in those with high exposure (p = 0.003) whereas no association was observed among those with low exposure (interaction p = 0.06). Regarding gene-intermediate phenotype interaction on clinical outcome, results showed an association of CWP prevalence with a NcoI polymorphism in LTA in those with low catalase activity (p = 0.05) whereas no association was observed in those with high activity (interaction p = 0.03). No other significant association was observed.
Conclusion
Results suggest that interactions of genetic background with environmental exposure and intermediate response phenotypes are important components in the pathogenesis of CWP.
PMCID: PMC1735359  PMID: 12566517
Catalase; metabolism; Coal Mining; Environmental Exposure; adverse effects; Erythrocytes; drug effects; enzymology; France; epidemiology; Genotype; Glutathione Peroxidase; metabolism; Humans; Longitudinal Studies; Lymphotoxin-alpha; genetics; Middle Aged; Occupational Exposure; adverse effects; Oxidants; adverse effects; Oxidative Stress; Phenotype; Pneumoconiosis; epidemiology; etiology; Polymorphism, Genetic; Prevalence; Prospective Studies; Tumor Necrosis Factor-alpha; genetics; TNF; LTA; oxidative stress; interaction; pneumoconiosis

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