RESUMEN
BACKGROUND: Children with multimorbid asthma and rhinitis show IgE polysensitization to several allergen sources. This association remains poorly studied in adolescents and adults using defined allergen molecules. We investigated IgE sensitization patterns towards a broad panel of aeroallergen components in adults and adolescents with a focus on individuals with asthma and rhinitis multimorbidity. METHODS: IgE reactivity to 64 micro-arrayed aeroallergen molecules was determined with the MeDALL-chip in samples from the French EGEA study (n = 840, age = 40.7 ± 17.1) and the Swedish population-based birth cohort BAMSE (n = 786, age = 16 ± 0.26). The age- and sex-adjusted associations between the number of IgE-reactive allergen molecules (≥0.3 ISU) and the asthma-rhinitis phenotypes were assessed using a negative binomial model. RESULTS: Groups representing 4 phenotypes were identified: no asthma-no rhinitis (A-R-; 30% in EGEA and 54% in BAMSE), asthma alone (A+R-; 11% and 8%), rhinitis alone (A-R+; 15% and 24%) and asthma-rhinitis (A+R+; 44% and 14%). The numbers of IgE-reactive aeroallergen molecules significantly differed between phenotypes (median in A-R-, A+R-, A-R+ and A+R+: 0, 1, 2 and 7 in EGEA and 0, 0, 3 and 5 in BAMSE). As compared to A-R- subjects, the adjusted ratio of the mean number of IgE-reactive molecules was higher in A+R+ than in A+R- or A-R+ (10.0, 5.4 and 5.0 in EGEA and 7.2, 0.7 and 4.8 in BAMSE). CONCLUSION: The A+R+ phenotype combined the sensitization pattern of both the A-R+ and A+R- phenotypes. This multimorbid polysensitized phenotype seems to be generalizable to various ages and allergenic environments and may be associated with specific mechanisms.
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Asma/epidemiología , Asma/inmunología , Inmunoglobulina E/inmunología , Rinitis/epidemiología , Rinitis/inmunología , Adolescente , Adulto , Alérgenos , Comorbilidad , Reacciones Cruzadas/inmunología , Femenino , Humanos , Inmunización , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Fenotipo , Vigilancia en Salud Pública , Suecia/epidemiología , Adulto JovenRESUMEN
BACKGROUND: Mono- and polysensitization are different IgE-mediated allergic phenotypes in children. Allergic sensitization is associated with both allergic asthma and allergic rhinitis, however, associations between the sensitization pattern and particularly polysensitization with asthma and rhinitis remains poorly studied in adults. AIM: The aim of this study was to assess how the allergic sensitization pattern associates with asthma, rhinitis and their multimorbidity. METHODS: 1199 adults from the EGEA study, with extensive phenotypic characterization and all data available on skin prick tests to 10 allergens, total IgE and blood eosinophils were included. Using questionnaires only, participants were classified into 6 groups: asymptomatic (no asthma, no rhinitis), non-allergic rhinitis alone, allergic rhinitis alone, asthma alone, asthma+non-allergic rhinitis and asthma+allergic rhinitis. Mono- and polysensitization were defined by a positive skin prick test to one or more than one allergen respectively. RESULTS: Asymptomatic participants and those with non-allergic rhinitis alone were mostly non-sensitized (around 72%) while around 12% were polysensitized. Between 32% and 43% of participants with allergic rhinitis alone, asthma alone and asthma+non-allergic rhinitis were non-sensitized and between 37% and 46% of them were polysensitized. 65% of the participants with asthma+allergic rhinitis were polysensitized. The level of total IgE followed a similar trend to that of allergic sensitization. Eosinophils were increased in asthma, especially when associated with rhinitis. Nasal symptoms were more severe and eczema more common in participants with both asthma and allergic rhinitis than in the other groups. CONCLUSIONS: Allergic sensitization and particularly polysensitization rates widely differ according to asthma and rhinitis status. This study emphasized the importance of taking into account multimorbidity between asthma and rhinitis and showed that allergic sensitization is not a dichotomic variable.
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Alérgenos/inmunología , Asma/epidemiología , Asma/inmunología , Rinitis/epidemiología , Rinitis/inmunología , Adulto , Asma/diagnóstico , Estudios de Casos y Controles , Comorbilidad , Eosinófilos , Femenino , Francia/epidemiología , Humanos , Inmunización , Inmunoglobulina E/sangre , Inmunoglobulina E/inmunología , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Fenotipo , Rinitis/diagnóstico , Factores de Riesgo , Índice de Severidad de la Enfermedad , Pruebas CutáneasRESUMEN
BACKGROUND: Exhaled nitric oxide (FeNO) is a biomarker for eosinophilic inflammation in the airways and for responsiveness to corticosteroids in asthmatics. OBJECTIVE: We sought to identify in adults the genetic determinants of fractional exhaled nitric oxide (FeNO) levels and to assess whether environmental and disease-related factors influence these associations. METHODS: We performed a genome-wide association study of FeNO through meta-analysis of two independent discovery samples of European ancestry: the outbred EGEA study (French Epidemiological study on the Genetics and Environment of Asthma, N = 610 adults) and the Hutterites (N = 601 adults), a founder population living on communal farms. Replication of main findings was assessed in adults from an isolated village in Sardinia (Talana study, N = 450). We then investigated the influence of asthma, atopy and tobacco smoke exposure on these genetic associations, and whether they were also associated with FeNO values in children of the EAGLE (EArly Genetics & Lifecourse Epidemiology, N = 8858) consortium. RESULTS: We detected a common variant in RAB27A (rs2444043) associated with FeNO that reached the genome-wide significant level (P = 1.6 × 10(-7) ) in the combined discovery and replication adult data sets. This SNP belongs to member of RAS oncogene family (RAB27A) and was associated with an expression quantitative trait locus for RAB27A in lymphoblastoid cell lines from asthmatics. A second suggestive locus (rs2194437, P = 8.9 × 10(-7) ) located nearby the sodium/calcium exchanger 1 (SLC8A1) was mainly detected in atopic subjects and influenced by inhaled corticosteroid use. These two loci were not associated with childhood FeNO values. CONCLUSIONS AND CLINICAL RELEVANCE: This study identified a common variant located in RAB27A gene influencing FeNO levels specifically in adults and with a biological relevance to the regulation of FeNO levels. This study provides new insight into the biological mechanisms underlying FeNO levels in adults.
Asunto(s)
Estudios de Asociación Genética , Variación Genética , Óxido Nítrico , Proteínas de Unión al GTP rab/genética , Adulto , Alelos , Asma/genética , Asma/inmunología , Asma/metabolismo , Biomarcadores , Mapeo Cromosómico , Espiración , Femenino , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Masculino , Metaanálisis como Asunto , Persona de Mediana Edad , Fenotipo , Polimorfismo de Nucleótido Simple , Sitios de Carácter Cuantitativo , Factores de Riesgo , Adulto Joven , Proteínas rab27 de Unión a GTPRESUMEN
Allergic diseases [asthma, rhinitis and atopic dermatitis (AD)] are complex. They are associated with allergen-specific IgE and nonallergic mechanisms that may coexist in the same patient. In addition, these diseases tend to cluster and patients present concomitant or consecutive diseases (multimorbidity). IgE sensitization should be considered as a quantitative trait. Important clinical and immunological differences exist between mono- and polysensitized subjects. Multimorbidities of allergic diseases share common causal mechanisms that are only partly IgE-mediated. Persistence of allergic diseases over time is associated with multimorbidity and/or IgE polysensitization. The importance of the family history of allergy may decrease with age. This review puts forward the hypothesis that allergic multimorbidities and IgE polysensitization are associated and related to the persistence or re-occurrence of foetal type 2 signalling. Asthma, rhinitis and AD are manifestations of a common systemic immune imbalance (mesodermal origin) with specific patterns of remodelling (ectodermal or endodermal origin). This study proposes a new classification of IgE-mediated allergic diseases that allows the definition of novel phenotypes to (i) better understand genetic and epigenetic mechanisms, (ii) better stratify allergic preschool children for prognosis and (iii) propose novel strategies of treatment and prevention.
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Alérgenos/inmunología , Hipersensibilidad/etiología , Hipersensibilidad/metabolismo , Inmunoglobulina E/inmunología , Transducción de Señal , Especificidad de Anticuerpos/inmunología , Comorbilidad , Femenino , Predisposición Genética a la Enfermedad , Humanos , Hipersensibilidad/epidemiología , Inmunización , Fenotipo , Embarazo , Efectos Tardíos de la Exposición PrenatalRESUMEN
BACKGROUND: The self-reporting of asthma frequently leads to patient misidentification in epidemiological studies. Strategies combining the triangulation of data sources may help to improve the identification of people with asthma. We aimed to combine information from the self-reporting of asthma, medication use and symptoms to identify asthma patterns in the users of an mHealth app. METHODS: We studied MASK-air® users who reported their daily asthma symptoms (assessed by a 0-100 visual analogue scale - "VAS Asthma") at least three times (either in three different months or in any period). K-means cluster analysis methods were applied to identify asthma patterns based on: (i) whether the user self-reported asthma; (ii) whether the user reported asthma medication use and (iii) VAS asthma. Clusters were compared by the number of medications used, VAS asthma levels and Control of Asthma and Allergic Rhinitis Test (CARAT) levels. FINDINGS: We assessed a total of 8,075 MASK-air® users. The main clustering approach resulted in the identification of seven groups. These groups were interpreted as probable: (i) severe/uncontrolled asthma despite treatment (11.9-16.1% of MASK-air® users); (ii) treated and partly-controlled asthma (6.3-9.7%); (iii) treated and controlled asthma (4.6-5.5%); (iv) untreated uncontrolled asthma (18.2-20.5%); (v) untreated partly-controlled asthma (10.1-10.7%); (vi) untreated controlled asthma (6.7-8.5%) and (vii) no evidence of asthma (33.0-40.2%). This classification was validated in a study of 192 patients enrolled by physicians. INTERPRETATION: We identified seven profiles based on the probability of having asthma and on its level of control. mHealth tools are hypothesis-generating and complement classical epidemiological approaches in identifying patients with asthma.
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Asma , Aplicaciones Móviles , Rinitis Alérgica , Humanos , Rinitis Alérgica/diagnóstico , Rinitis Alérgica/epidemiología , Asma/diagnóstico , Asma/epidemiología , Proyectos de InvestigaciónRESUMEN
INTRODUCTION: Adherence to controller medication is a major problem in asthma management, being difficult to assess and tackle. mHealth apps can be used to assess adherence. We aimed to assess the adherence to inhaled corticosteroids+long-acting ß2-agonists (ICS+LABA) in users of the MASK-air® app, comparing the adherence to ICS+formoterol (ICS+F) with that to ICS+other LABA. MATERIALS AND METHODS: We analysed complete weeks of MASK-air® data (2015-2022; 27 countries) from patients with self-reported asthma and ICS+LABA use. We compared patients reporting ICS+F versus ICS+other LABA on adherence levels, symptoms and symptom-medication scores. We built regression models to assess whether adherence to ICS+LABA was associated with asthma control or short-acting beta-agonist (SABA) use. Sensitivity analyses were performed considering the weeks with no more than one missing day. RESULTS: In 2598 ICS+LABA users, 621 (23.9%) reported 4824 complete weeks and 866 (33.3%) reported weeks with at most one missing day. Higher adherence (use of medication ≥80% of weekly days) was observed for ICS+other LABA (75.1%) when compared to ICS+F (59.3%), despite both groups displaying similar asthma control and work productivity. The ICS+other LABA group was associated with more days of SABA use than the ICS+F group (median=71.4% versus 57.1% days). Each additional weekly day of ICS+F use was associated with a 4.1% less risk in weekly SABA use (95%CI=-6.5;-1.6%;p=0.001). For ICS+other LABA, the percentage was 8.2 (95%CI=-11.6;-5.0%;p<0.001). CONCLUSIONS: In asthma patients adherent to the MASK-air app, adherence to ICS+LABA was high. ICS+F users reported lower adherence but also a lower SABA use and a similar level of control.
RESUMEN
Information on the healthy worker hire effect in relation to asthma is scant. We aimed to assess whether and how childhood asthma-related characteristics (before hire) relate to occupational exposures at first hire. Analyses were conducted in 298 children examined at the first survey of the Epidemiological Study on the Genetics and Environment of Asthma (1991-1995), who reported a training period or a job at follow-up in 2003-2007 (aged 17-29 yrs; 53% males). Exposure likelihood to dust, gases and/or fumes in their first occupation was estimated by the ALOHA job exposure matrix. Asthma before the first occupation and two asthma classifications for severity (Global Initiative for Asthma 2002 guidelines) and symptoms were defined by questionnaire. In their first job, 47% of subjects were exposed. After adjustment (age, sex and education), pre-hire onset asthmatics (59%) were nonsignificantly less likely to be exposed (OR 0.67, 95% CI 0.41-1.11). Associations were stronger when considering those with severe asthma or high symptom score in childhood (OR 0.27 (95% CI 0.11-0.63) and OR 0.49 (95% CI 0.25-0.99), respectively). The association was observed in those who completed a university degree (OR 0.55, 95% CI 0.29-1.04) but not in the others (OR 0.98, 95% CI 0.44-2.22), with consistent results for all asthma characteristics. Results suggest a healthy worker hire effect in subjects with more severe or more symptomatic asthma in childhood. Education may modulate self-selection.
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Asma/epidemiología , Exposición Profesional/estadística & datos numéricos , Adolescente , Adulto , Escolaridad , Femenino , Francia/epidemiología , Gases/toxicidad , Efecto del Trabajador Sano , Humanos , Estudios Longitudinales , Masculino , Material Particulado/toxicidad , Sesgo de Selección , Adulto JovenRESUMEN
INTRODUCTION: The objectives of our study were to estimate the prevalence of asthma in adults in France and to study the effects of gender on the associations of asthma with the corpulence and socio-economic characteristics of individuals. METHODS: We estimated the prevalence of current asthma (asthma attack in the past 12 months or current treatment for asthma) from data collected at inclusion in the Constances cohort study in 2013-2014. Analyses were performed separately in men and women, using robust Poisson regression for multivariate analysis. RESULTS: Using data from 34,100 participants in the cohort (men: 47.7 %; mean age: 44.6 years), the prevalence of current asthma was estimated to be 5.8 % (5.1 % in men, 6.4 % in women). The risk of asthma was increased in women with high body mass index (BMI) or waist circumference. In men, only a high waist circumference was associated with an increased risk of asthma. An association with low socioeconomic status was observed only among women. CONCLUSION: The associations of asthma with corpulence and socioeconomic status differed between men and women. Additional analyses should provide a better understanding of the mechanisms responsible for these differences.
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Asma , Adulto , Asma/epidemiología , Índice de Masa Corporal , Estudios de Cohortes , Estudios Transversales , Femenino , Francia/epidemiología , Humanos , Masculino , Prevalencia , Circunferencia de la CinturaRESUMEN
Single nucleotide polymorphisms (SNPs) at chromosome 17q21 confer an increased risk of early-onset asthma. The objective was to study whether 17q21 SNPs modify associations between early respiratory infections and asthma. Association analysis was conducted in 499 children (268 with asthma, median age 11 yrs) from the Epidemiological Study on the Genetics and Environment of Asthma (EGEA). The 12-yr follow-up data were used to assess persistent or remittent asthma in young adulthood. Respiratory infection before 2 yrs of age was assessed retrospectively. For the 12 17q21 SNPs studied, the odds ratios (OR) for association between infection and early-onset asthma (age at onset Asunto(s)
Asma/etiología
, Asma/genética
, Cromosomas Humanos Par 17/genética
, Infecciones del Sistema Respiratorio/complicaciones
, Infecciones del Sistema Respiratorio/genética
, Adolescente
, Edad de Inicio
, Niño
, Femenino
, Estudios de Seguimiento
, Estudios de Asociación Genética
, Predisposición Genética a la Enfermedad
, Humanos
, Masculino
, Proteínas de la Membrana/genética
, Proteínas de Neoplasias/genética
, Polimorfismo de Nucleótido Simple
, Estudios Retrospectivos
, Factores de Riesgo
, Factores Sexuales
, Contaminación por Humo de Tabaco/efectos adversos
RESUMEN
"General-purpose cohorts" in epidemiology and public health are designed to cover a broad scope of determinants and outcomes, in order to answer several research questions, including those not defined at study inception. In this context, the general objective of the CONSTANCES project is to set up a large population-based cohort that will contribute to the development of epidemiological research by hosting ancillary projects on a wide range of scientific domains, and to provide public health information. CONSTANCES was designed as a randomly selected sample of French adults aged 18-69 years at study inception; 202,045 subjects were included over an 8-year period. At inclusion, the selected participants are invited to attend one of the 24 participating Health Prevention Centers (HPCs) for a comprehensive health examination. The follow-up includes a yearly self-administered questionnaire, and a periodic visit to an HPC. Procedures have been developed to use the national healthcare databases to allow identification and validation of diseases over the follow-up. The biological collection (serum, lithium heparinized plasma, EDTA plasma, urine and buffy coat) began gradually in June 2018. At the end of the inclusions, specimens from 83,000 donors will have been collected. Specimens are collected according to a standardized protocol, identical in all recruitment centers. All operations relating to bio-banking have been entrusted by Inserm to the Integrated Biobank of Luxembourg (IBBL). A quality management system has been put in place. Particular attention has been paid to the traceability of all operations. The nature of the biological samples stored has been deliberately limited due to the economic and organizational constraints of the inclusion centers. Some research works may require specific collection conditions, and can be developed on request for a limited number of subjects and in specially trained centers. The biological specimens that are collected will allow for a large spectrum of biomarkers studies and genetic and epigenetic markers through candidate or agnostic approaches. By linking the extensive data on personal, lifestyle, environmental, occupational and social factors with the biomarker data, the CONSTANCES cohort offers the opportunity to study the interplays between these factors using an integrative approach and state-of-the-art methods.
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Bancos de Muestras Biológicas , Adolescente , Adulto , Anciano , Estudios de Cohortes , Bases de Datos Factuales , Humanos , Luxemburgo , Persona de Mediana Edad , Encuestas y Cuestionarios , Adulto JovenRESUMEN
RATIONALE: There is increasing interest regarding asthma heterogeneity in relation to inflammatory patterns. OBJECTIVES: To assess phenotypic characteristics, in particular clinical presentation of the disease, in 381 well-characterised adults with asthma from the French Epidemiological study on the Genetics and Environment of Asthma (EGEA) according to their blood inflammatory pattern. METHODS: Four blood inflammatory patterns were defined according to eosinophil (EOS) and neutrophil (NEU) count cut-off points. Samples with > or =250 EOS/mm(3) were classified as EOS(hi) and those with > or =5000 NEU/mm(3) as NEU(hi). Clinical characteristics include typical asthma and chronic obstructive pulmonary disease (COPD)-like symptoms, as well as composite quantitative scores addressing the activity of the disease. RESULTS: A substantial number of those with asthma (56.2%) had the EOS(lo) pattern (<250 EOS/mm(3)). Patients with asthma who had the EOS(hi) pattern had higher immunoglobulin E (IgE), a lower forced expiratory volume in 1 s (FEV(1)) and presented a more active asthma than those with the EOS(lo) pattern. Among those with the EOS(lo) pattern, neutrophil inflammation (NEU(hi)) was related to a less frequent positive skin prick test response (OR 0.44, 95% CI 0.20 to 0.96). Among those with the EOS(hi) pattern, neutrophil inflammation did not explain current asthma or asthma activity, and was significantly related to nocturnal symptoms (OR 5.21, 95% CI 1.44 to 18.8) independently of age, sex, smoking and inhaled corticosteroid treatment. In non-smokers with asthma, COPD-like symptoms, in particular chronic phlegm, were more frequent in those with neutrophil inflammation, independent of eosinophil inflammation (OR 2.35, 95% CI 1.08 to 5.10). CONCLUSIONS: Besides eosinophilia, neutrophil inflammation assessed in the blood is related to specific characteristics of asthma. Considering simultaneously neutrophilic and eosinophilic inflammation may contribute to help to disentangle this complex disease.
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Asma/etiología , Bronquitis/patología , Eosinófilos/patología , Neutrófilos/patología , Adulto , Factores de Edad , Asma/patología , Enfermedad Crónica , Tos/etiología , Tos/patología , Femenino , Humanos , Recuento de Leucocitos , Masculino , Fenotipo , Enfermedad Pulmonar Obstructiva Crónica/etiología , Enfermedad Pulmonar Obstructiva Crónica/patología , Eosinofilia Pulmonar/patología , Factores Sexuales , Adulto JovenRESUMEN
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 adults the association of Fel d 1 IgG4, Fel d 1 IgE, skin prick test (SPT) response to cat and pet-related symptoms in relation to exposure to cat considering the period of exposure. METHODS: SPT 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 weal size. The lowest values of Fel d 1 IgE, cat weal 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.
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Alérgenos/efectos adversos , Asma/sangre , Glicoproteínas/efectos adversos , Inmunoglobulina E/sangre , Inmunoglobulina G/sangre , Adulto , Animales , Asma/epidemiología , Estudios de Casos y Controles , Gatos , Femenino , Francia , Humanos , Masculino , Factores SexualesRESUMEN
BACKGROUND: Effects of air pollution exposure on IgE-mediated response in asthmatics are poorly investigated. The aim was to examine the relationship between air pollution concentrations and total IgE levels in adult asthmatics. METHODS: The present study relates to the 369 asthmatic adults from the French Epidemiological study on Genetics and Environment of Asthma (EGEA), with availability of data on both total serum IgE measurements and air pollution concentrations. Geo-statistical models were performed on 4 x 4 km grids to assess individual outdoor air pollution exposure. Annual outdoor concentrations of ozone (O(3)), nitrogen dioxide (NO(2)), sulphur dioxide (SO(2)), and particulate matter smaller than 10 microm size (PM(10)), and concentrations of summer ozone were assigned to subject's home address. RESULTS: The geometric mean of total IgE was 161 IU/ml and the average of O(3) exposure was 44.9 +/- 9.5 microg/m(3). Ozone concentrations were positively related to total IgE levels and an increase of 10 microg/m(3) of O(3) resulted in an increase of 20.4% (95% CI = 3.0-40.7) in total IgE levels. Adjustment for age, gender, smoking habits and previous life in the countryside did not change the results, and an increase of 19.1% (2.4-38.6) in total IgE was observed with O(3). Negative associations observed between NO(2) and total IgE levels disappeared after including O(3) in the models. Neither SO(2) nor PM(10) were correlated with total IgE levels. CONCLUSIONS: Results suggest that O(3) or related ambient pollutants may up-regulate total IgE levels among asthmatic adults.
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Asma/inmunología , Inmunoglobulina E/sangre , Ozono/efectos adversos , Adulto , Contaminación del Aire/efectos adversos , Asma/epidemiología , Asma/etiología , Salud de la Familia , Femenino , Humanos , Masculino , Persona de Mediana Edad , Oxidantes Fotoquímicos/efectos adversos , Adulto JovenRESUMEN
BACKGROUND: Genome-wide association studies have identified novel genetic associations for asthma, but without taking into account the role of active tobacco smoking. This study aimed to identify novel genes that interact with ever active tobacco smoking in adult onset asthma. METHODS: We performed a genome-wide interaction analysis in six studies participating in the GABRIEL consortium following two meta-analyses approaches based on 1) the overall interaction effect and 2) the genetic effect in subjects with and without smoking exposure. We performed a discovery meta-analysis including 4,057 subjects of European descent and replicated our findings in an independent cohort (LifeLines Cohort Study), including 12,475 subjects. RESULTS: First approach: 50 SNPs were selected based on an overall interaction effect at p<10-4. The most pronounced interaction effect was observed for rs9969775 on chromosome 9 (discovery meta-analysis: ORint = 0.50, p = 7.63*10-5, replication: ORint = 0.65, p = 0.02). Second approach: 35 SNPs were selected based on the overall genetic effect in exposed subjects (p <10-4). The most pronounced genetic effect was observed for rs5011804 on chromosome 12 (discovery meta-analysis ORint = 1.50, p = 1.21*10-4; replication: ORint = 1.40, p = 0.03). CONCLUSIONS: Using two genome-wide interaction approaches, we identified novel polymorphisms in non-annotated intergenic regions on chromosomes 9 and 12, that showed suggestive evidence for interaction with active tobacco smoking in the onset of adult asthma.
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Asma/inducido químicamente , Asma/genética , Interacción Gen-Ambiente , Estudio de Asociación del Genoma Completo , Fumar/efectos adversos , Adulto , Estudios de Cohortes , Predisposición Genética a la Enfermedad/genética , Humanos , Polimorfismo de Nucleótido SimpleRESUMEN
INTRODUCTION: Interaction between genetic background and oxidative environmental stimuli in the pathogenesis of human lung disease has been largely unexplored. METHODS: A prospective epidemiological 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, five years apart, to assess established coal workers' pneumoconiosis (CWP). Miners were genotyped for common functional polymorphisms in the gene for tumour necrosis factor alpha (TNF) and lymphotoxin alpha (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 an 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: The results suggest that interactions of genetic background with environmental exposure and intermediate response phenotypes are important components in the pathogenesis of CWP.
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Catalasa/metabolismo , Minas de Carbón , Glutatión Peroxidasa/metabolismo , Linfotoxina-alfa/genética , Factor de Necrosis Tumoral alfa/genética , Exposición a Riesgos Ambientales/efectos adversos , Eritrocitos/efectos de los fármacos , Eritrocitos/enzimología , Francia/epidemiología , Genotipo , Humanos , Estudios Longitudinales , Persona de Mediana Edad , Exposición Profesional/efectos adversos , Oxidantes/efectos adversos , Estrés Oxidativo , Fenotipo , Neumoconiosis/epidemiología , Neumoconiosis/etiología , Polimorfismo Genético , Prevalencia , Estudios ProspectivosRESUMEN
INTRODUCTION AND METHODS: The EGEA study (epidemiological study on the genetics and environment of asthma, bronchial hyperresponsiveness and atopy), which combines a case-control and a family-based study of asthma case (n=2120 subjects) with three surveys over 20 years, aims to identify environmental and genetic factors associated with asthma and asthma-related phenotypes. We summarize the results of the phenotypic characterization and the investigation of environmental and genetic factors of asthma and asthma-related phenotypes obtained since 2007 in the EGEA study (42 articles). RESULTS: Both epidemiological and genetic results confirm the heterogeneity of asthma. These results strengthen the role of the age of disease onset, the allergic status and the level of disease activity in the identification of the different phenotypes of asthma. The deleterious role of active smoking, exposure to air pollution, occupational asthmogenic agents and cleaning products on the prevalence and/or activity of asthma has been confirmed. Accounting for gene-environment interactions allowed the identification of new genetic factors underlying asthma and asthma-related traits and better understanding of their mode of action. CONCLUSION: The EGEA study is contributing to the advances in respiratory research at the international level. The new phenotypic, environmental and biological data available in EGEA study will help characterizing the long-term evolution of asthma and the factors associated to this evolution.
Asunto(s)
Asma/etiología , Hiperreactividad Bronquial/etiología , Interacción Gen-Ambiente , Hipersensibilidad Inmediata/etiología , Adolescente , Adulto , Anciano , Contaminación del Aire/efectos adversos , Asma/epidemiología , Asma/genética , Hiperreactividad Bronquial/epidemiología , Hiperreactividad Bronquial/genética , Estudios de Casos y Controles , Niño , Exposición a Riesgos Ambientales , Salud de la Familia , Francia , Estudios de Asociación Genética , Heterogeneidad Genética , Predisposición Genética a la Enfermedad , Encuestas Epidemiológicas , Humanos , Hipersensibilidad Inmediata/epidemiología , Hipersensibilidad Inmediata/genética , Masculino , Persona de Mediana Edad , Exposición Profesional , Fenotipo , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Fumar/efectos adversos , Contaminación por Humo de Tabaco/efectos adversosRESUMEN
It has been suggested that interleukin (IL)-18 plays a role in the development of inflammatory and fibrosing lung diseases. Associations of polymorphisms in the genes coding for IL-18 (IL18 /G-656T, C-607A, G-137C, T113G, C127T) and its receptor (IL18R1 /C-69T) with coal workers' pneumoconiosis (CWP) were studied in 200 miners who were examined in 1990, 1994 and 1999. Coal-dust exposure was assessed according to 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-yr change in CT score and CWP incidence and prevalence. CT score in 1990 was a good predictor of radiographic grade in 1999 and, therefore, an appropriate subclinical quantitative trait. The IL18 -137C allele was associated with lower CT score in 1990 and 1994 (1.24 versus 1.69 and 1.57 versus 2.46, respectively), slower progression of CT score between 1990 and 1994 and lower pneumoconiosis prevalence in 1999 relative to the G allele (0.33 versus 0.77 and 8.2 versus 19.6%, respectively). Smoking- or dust-adjustment, and stratification on IL18R1 genotype and adjustment for haplotype effects did not change the conclusions. In conclusion, the results of the present study suggest a role for IL18 in reducing the development of this fibrosing lung disease.
Asunto(s)
Minas de Carbón , Subunidad alfa del Receptor de Interleucina-18/genética , Interleucina-18/genética , Neumoconiosis/genética , Polimorfismo Genético , Tomografía Computarizada por Rayos X , Adulto , Frecuencia de los Genes , Genotipo , Humanos , Estudios Longitudinales , Persona de Mediana Edad , Fenotipo , Neumoconiosis/diagnóstico , Neumoconiosis/epidemiología , PrevalenciaRESUMEN
OBJECTIVES: To understand the variations of selenium (Se) concentration relative to changes in occupational exposure to coal dust, taking into account age and changes in smoking habits in miners surveyed twice, in 1990 and 1994. To better understand the relation of Se concentration with glutathione peroxidase activities (GSH-Px) in these miners. METHODS: In 1994, blood samples were obtained from active (n=131) and retired (n=40) miners without coal worker's pneumoconiosis, in whom Se concentration was available at both surveys and in whom International Labour Organisation (ILO) profusion grade had not been changed. Active miners were exposed to high dust concentrations (n=48) or low dust concentrations (n=83). Miners were classified into three subgroups according to their estimated cumulative exposure to dust, and into three subgroups according to their smoking habits. RESULTS: Selenium concentration and GSH-Px activities were significantly lower in active than in retired miners (Se adjusted means: 62.6 v 72.2 ng/ml p=0.01). Moreover, Se concentration was lower in miners exposed to high compared with those exposed to low dust concentrations (adjusted means: 59.4 v 65.8). In miners exposed to high dust concentrations, Se concentration was significantly lower whereas erythrocyte GSH-Px activity was significantly higher in the subgroup with estimated cumulative exposure >68 mg/m(3).y. In all miners, plasma GSH-Px activity was correlated with Se concentration (r=0.22, p<0.005). The 4 year Se changes were negatively related to exposure to high dust concentrations and positively related to change in exposure from high to retirement and to change from smoker to ex-smoker (p=0.01). CONCLUSION: The variations of Se concentration in relation to changes in occupational exposure to coal dust and in smoking habits, and the close correlation found between plasma Se concentration and GSH-Px activity suggest that both are required in antioxidant defence. These results agree well with the hypothesis that the decrease in Se concentration reflects its use against reactive oxygen species generated by exposure to coal mine dust and by smoking.
Asunto(s)
Minas de Carbón , Carbón Mineral , Polvo , Exposición Profesional , Selenio/sangre , Fumar/epidemiología , Adulto , Estudios Transversales , Eritrocitos/enzimología , Glutatión Peroxidasa/sangre , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Jubilación , Fumar/sangre , Cese del Hábito de FumarRESUMEN
OBJECTIVES: To better understand the relations between occupational exposure, blood antioxidant enzyme activities, total plasma antioxidant concentration, and the severity of coal workers' pneumoconiosis (CWP). METHODS: Blood samples were obtained from miners without CWP exposed to low dust concentrations for > or = 4 years at the time of the study (n = 105), or exposed to high dust concentrations for > or = 14 years at the time of the study (n = 58), and from retired miners with CWP (n = 19). Miners without CWP were classified into three subgroups according to their estimated cumulative exposure to dust. Chest x ray films were obtained for each miner. Miners were classified in five subgroups according to their International Labour Organisation (ILO) profusion grades. Univariate tests were completed by multiple linear regression analyses. RESULTS: The estimated cumulative exposure to dust was strongly positively related to erythrocyte catalase activity and strongly negatively related to Cu++/Zn++ SOD activity only in miners exposed to high dust concentrations for > or = 14 years at the time of the study (F tests p = 0.006 and p = 0.004 respectively). Moreover, catalase activity was strongly related to the severity of CWP expressed as five subgroups of ILO profusion grades (F test p = 0.003); the greatest difference in the mean values was found between the group of 1/1 to 1/2 ILO profusion grades and the group of 2/1 to 3/3 ILO profusion grades. CONCLUSION: These results are in good agreement with the hypothesis that production of reactive oxygen species may be an important event in the exposure to coal mine dusts and the severity of CWP. Erythrocyte catalase and Cu++/Zn++ SOD activities are more closely related to recent exposure to high dust concentrations than to cumulative exposure, and could be considered as biological markers of exposure rather than as markers of early adverse biological effect.
Asunto(s)
Catalasa/sangre , Minas de Carbón , Exposición Profesional/efectos adversos , Neumoconiosis/enzimología , Superóxido Dismutasa/sangre , Adulto , Antioxidantes/análisis , Biomarcadores/sangre , Eritrocitos/enzimología , Glutatión Peroxidasa/sangre , Humanos , Masculino , Persona de Mediana Edad , Neumoconiosis/sangre , Neumoconiosis/diagnóstico por imagen , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: We investigated if blood Cu++/Zn++ superoxide dismutase, glutathione peroxidase, and catalase activities are increased and total plasma antioxidant concentration is decreased in coke oven workers exposed to polycyclic aromatic hydrocarbons. METHODS: Ninety-six coke oven workers participated in the study. Nonexposed workers (n = 105) were randomly sampled among power plant workers in the same age range. The examination included a questionnaire on health status, occupational history, smoking, and dietary habits. Blood samples completed the examination. Coke oven workers were classified into low-, middle-, and high-exposure groups based on the benzo[a]pyrene (B[a]P) air concentrations and were further classified into the categories "topside" and "non-topside," according to their proximity to the ovens. RESULTS: Erythrocyte glutathione peroxidase activity increased with age (r = 0.18, P = 0.061) in power plant workers, whereas plasma glutathione peroxidase activity decreased with age (r = -0.18, P = 0.068) and erythrocyte glutathione peroxidase activity was inversely correlated with the number of cigarettes per day (r = -0.28, P = 0.08) in coke oven workers. Comparison of blood antioxidant enzyme activities and total plasma antioxidant concentration between coke oven and power plant workers showed that erythrocyte glutathione peroxidase activity was significantly lower in coke oven workers, even after adjustment for potential confounding factors. No differences were found either in other blood antioxidant enzyme activities or in total plasma antioxidant concentration between coke oven and power plant workers. Moreover, no trends toward decreased glutathione peroxidase activity among the three subgroups of B[a]P exposure were observed, and no differences either in blood antioxidant enzyme activities or in total plasma antioxidant concentration between the two groups of job categories were found. CONCLUSIONS: Production of reactive oxygen species seems not to be increased in coke oven workers.