Farming in childhood, diet in adulthood and asthma history.

The decrease in the number of children living on traditional farms in France during early childhood and changes in diet could both play a role in the increase in asthma prevalence over the last decades. This study aimed to assess 1) the association of farming lifestyle in childhood and asthma, and 2) whether diet in adulthood modifies the association between farming lifestyle in childhood and adult-onset asthma. In the French Etude Epidemiologique des Femmes de la Mutuelle Générale de l'Education Nationale (E3N) study (54,018 females; age 43-68 yrs), three indicators of farming lifestyle were defined: one using individual data (having farmer parents) and two using ecological data (born in a rural area and exposure to cattle). All farming lifestyle indicators were related to childhood- (<16 yrs) and adult-onset asthma (OR (95% CI) values for farmer parents were 0.54 (0.42-0.70) and 0.72 (0.62-0.84), respectively), and to diet in adulthood, in particular to high fruit and low wine intakes. The association between farmer parents and adult-onset asthma was not modified by diet in adulthood. Results extend previous observations in younger cohorts on the protective role of contact with livestock and farming lifestyle on asthma, in particular during childhood.

Cat sensitization according to cat window of exposure in adult asthmatics.

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.

Heterogeneity of asthma according to blood inflammatory patterns.

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.

Total serum IgE levels are associated with ambient ozone concentration in asthmatic adults.

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.

[Environmental factors for asthma severity and allergy: results from the EGEA study]. / Facteurs environnementaux de l'asthme sévère et de l'allergie: résultats de l'étude EGEA.

INTRODUCTION: EGEA (Epidemiological study on the genetics and environment of asthma, bronchial hyperresponsiveness and atopy), a case control and family study including 2048 individuals, was initiated to look for environmental and genetic risk factors for asthma. A synthesis of the results obtained since 2002 on phenotypic and environmental aspects of asthma severity and allergy are presented in this article. METHODS AND RESULTS: The results support a role for hormonal factors in asthma severity and in various allergic markers of asthma. A greater body mass index was related to a more severe asthma in women with early menarche. Associations between markers of allergy (eosinophils, IgE and atopy) and hormonal dependent events in women (premenstrual asthma, menopause and oral contraceptive use) have been found. In asthmatics, exposure to agents known to be associated with occupational asthma, active and passive smoking were associated with an increased clinical asthma severity score. The study underlines the protective role of country living and exposure to pets in early life on allergy markers in adulthood, supporting the hygiene hypothesis. CONCLUSIONS: New hypothesis will be tested in the near future from the second stage of this survey.

Genome screen in the French EGEA study: detection of linked regions shared or not shared by allergic rhinitis and asthma.

In the sample of 295 French EGEA families with at least one asthmatic subject, a genome screen was conducted to identify potential linkage regions specific either to allergic rhinitis (AR) or to asthma as well as those shared by the two diseases. Two binary rhinitis phenotypes based on (1) diagnosis (ARbin1) and (2) symptoms (ARbin2) and a categorical ordered trait (ARcat) were considered. Asthma phenotype was based on answers to a standardized questionnaire plus the presence of bronchial hyper-responsiveness. Linkage analyses were conducted using the maximum likelihood binomial (MLB) method. These analyses provided potential evidence for linkage to three regions in the whole sample: 1p31 for the phenotype defined by ARbin2 plus asthma (P=0.00016), 2q32 for ARbin2 (P=0.00016) and 3p24-p14 for ARcat (P=0.001). Two other regions were detected in the subset of 185 families with at most one asthmatic sib: 9p22 and 9q22-q34 for ARbin1 (P=0.001 and 0.0007, respectively). No region showed evidence for linkage to asthma without being also linked to AR. While 1p31 may contain a genetic determinant common to asthma and AR, 2q32, 3p24-p14, 9p22 and 9q22-q34 are more likely to harbor genetic factors specific to AR.

Increased prevalence of asthma and allied diseases among active adolescent tobacco smokers after controlling for passive smoking exposure. A cause for concern?

BACKGROUND: Whereas effects on allergic and respiratory health have been established for passive tobacco smoking, contradictory results still exist for active tobacco smoking. OBJECTIVE: Whether adolescents with asthma and allied diseases have higher rates of active smoking compared with adolescents without asthma was assessed after controlling for environmental tobacco smoking exposure. METHODS: A population-based sample of 14,578 adolescents was enrolled in an epidemiological survey on allergies in France. RESULTS: After controlling for age, sex, geographic region, familial allergy and passive smoking, current (in the past year) wheezing (12.4%), current asthma (5.6%), lifetime asthma (12.3%), current rhinoconjunctivitis (13.9%), lifetime hayfever (14.4%) and current eczema (9.3%) but not lifetime eczema (22.5%) were all significantly related to active smoking (>1 cigarette/day) (9.3%). A higher risk of current wheezing, current and lifetime asthma or current eczema was seen in smokers exposed to passive smoking compared with smokers not exposed to it using a polychotomous logistic regression model, in which the different modalities of exposure to active and passive smoking constituted the response variable. Passive smoking was significantly associated only with current diseases. Active smoking was also highly related to both severe asthma (OR=4.02; 95% confidence interval: 1.37, 11.79) and severe rhinoconjunctivitis (OR=2.95; 1.58, 5.49). The highest rate of adolescents suffering from the co-morbidity of lifetime asthma and hayfever (3.6%) was also seen in active smokers compared with passive and non-smokers (5.5% vs. 3.6% and 3.1%, respectively; P=0.001). CONCLUSIONS: Being asthmatic or allergic does not seem to act as a deterrent towards starting active smoking or continuing to smoke in adolescence. Results suggest the need for considering individual allergic status in programming health educational activities aimed at reducing smoking among adolescents.

Allergy markers in adults in relation to the timing of pet exposure: the EGEA study.

BACKGROUND: Studies suggest that early childhood exposure to pets may protect from the development of atopy, but limited information is available on adults. The association of allergy markers in adulthood with current and childhood exposure to pets was studied considering retrospectively the window of exposure. METHODS: Immunoglobulin E (IgE), skin prick tests (SPT), eosinophils were related to exposure to pets in 187 adult asthmatic cases and 243 controls from the Epidemiological Study on the Genetics and Environment of Asthma, bronchial hyperresponsiveness and atopy (EGEA) study. Analyses were redone after exclusion of subjects who removed pets or experienced symptoms to animals to take into account selection in that retrospective study. RESULTS: In asthmatic cases, current exposure to pets was unrelated to SPT positivity (+), whereas childhood exposure was significantly related to less SPT+ to any allergen, and to cat in particular, with an association restricted to those exposed before 2 years of age [OR = 0.30 (CI 0.12-0.76)]. Considering the relative timing of exposure in relation to asthma onset showed that the protective effect of exposure to pets occurs for pet exposure starting before asthma onset [OR for SPT+ = 0.19 (CI 0.08-0.48)]. CONCLUSION: Results support the hypothesis that exposure to pets in early life, and in particular before asthma onset, may protect against allergen sensitization in adulthood.

Relationships of allergic sensitization, total immunoglobulin E and blood eosinophils to asthma severity in children of the EGEA Study.

BACKGROUND: Although allergy is highly associated with childhood asthma, it is not well known if there is a relationship between the intensity of allergic sensitization and asthma severity. OBJECTIVE: The objectives of the study were to examine the relationships between several markers of allergy and asthma severity in asthmatic children included in the Epidemiological study on the Genetics and Environment of Asthma, bronchial hyper-responsiveness and atopy (EGEA). METHODS: The population comprised 216 asthmatic children below 16 years of age. Total IgE and blood eosinophil counts were measured and skin prick tests to 11 aeroallergens were performed. The intensity of the allergic sensitization was assessed by the number of positive skin prick tests and by skin weal sizes. Asthma severity was measured with four criteria: a clinical severity score, history of hospitalization for asthma, FEV1% predicted and inhaled steroid use in the last 12 months. RESULTS: Most of the children were sensitized to at least one aeroallergen (88.2%). Atopy was not related to the severity of asthma, except for a tendency for a more severe clinical score in non-atopic children. The type and intensity of the allergic sensitization were not associated with any criteria of asthma severity. Total IgE was significantly increased in children treated with inhaled corticosteroids and in children ever hospitalized for asthma (P-values 0.009 and 0.04, respectively). Eosinophil counts were not related to asthma severity. CONCLUSION: Our results suggest that severe childhood asthma may be related to a high level of total IgE but not to blood eosinophil counts. The lack of positive relationships between both atopy and the intensity of allergic sensitization with asthma severity supports the hypothesis of different risk factors being associated with asthma and with the severity of asthma.

The protective role of country living on skin prick tests, immunoglobulin E and asthma in adults from the Epidemiological study on the Genetics and Environment of Asthma, bronchial hyper-responsiveness and atopy.

BACKGROUND: Farming environment and traditional lifestyle seem to protect from childhood allergy. OBJECTIVE: The aim is to analyse the relationships of living in the country to asthma, positive skin prick tests and IgE among adults considering various windows of exposure over the life-span. METHODS: The study concerns 805 adults drawn from the Epidemiological study on the Genetics and Environment of Asthma, bronchial hyper-responsiveness and atopy (EGEA) (asthmatic cases, non-asthmatic controls, and parents of cases with and without asthma). Ever living in the country concerned 55% of the subjects. Early (beginning < 1 years), childhood (beginning < or = 16 years), prolonged (duration > or = 10 years) and current life in the country were studied. RESULTS: The results based on the case control and family components of the study show that IgE levels were significantly lower in those who ever lived in the country and in particular in those who lived for > or = 10 years. Positive skin prick tests (SPT) were significantly less prevalent in those who ever lived in the country and in particular in those with childhood (< or = 16 years) exposure. These associations remained independent of age, sex, smoking or asthma with IgE levels of 64 vs. 88 IU/mL; P = 0.004 for those ever living in the country vs. others and odds ratio for SPT positivity of 0.72 (95% CI [0.53-0.98]). In the more specific group with traditional mode of heating in childhood (use of wood) associations were stronger. The association with asthma, studied in parents of asthmatic probands showed that fathers, but not mothers, of asthmatics were significantly less often asthmatic themselves in relation to country living. CONCLUSION: Country life protects from asthma and adulthood allergy. The protective effect is not restricted to exposure in early childhood.

[Epidemiological study on the Genetics and Environment of Asthma, bronchial hyperresponsiveness and atopy (EGEA) - First results of a multi-disciplinary study]. / Etude Epidémiologique sur les facteurs Génétiques et Environnementaux de l'Asthme, l'hyperréactivité bronchique et l'atopie (EGEA). Premiers résultats d'une étude multidisciplinaire.

The French co-operative epidemiological study EGEA realised in 1991/95 combines a case control study and a study of the families of asthmatic cases. A synthesis of the results already obtained is presented. Smoking was related to IgE, even in asthmatics and was clearly related to the clinical severity of asthma, an aspect insufficiently taken into account. The relationships of occupational exposures to asthma have been assessed using a job exposure matrix. Segregation analyses on IgE have shown, after correction for the mode of ascertainment, the existence of a dominant major gene and familial residual correlation. A systematic genome screen realised in families with 2 asthmatic siblings showed linkage of various regions in the genome implicated to asthma or related phenotypes (1p, 11p, 11q, 12q, 13q, 17q, 19q), coherent with genome screens realised in other studies. Regarding candidate genes, no association was evidenced between asthma and the AF508 mutation of the cystic fibrosis gene. The analysis is still in progress by studies on the heterogeneity of asthma with refined genetic studies and by searching to integrate results regarding environmental and genetic factors and studying their interactions.

Allergy markers in respiratory epidemiology.

Assessing allergy by measurement of serum immunoglobulin (Ig) E antibodies is fast and safe to perform. Serum antibodies can preferably be assessed in patients with dermatitis and in those who regularly use antihistamines and other pharmacological agents that reduce skin sensitivity. Skin tests represent the easiest tool to obtain quick and reliable information for the diagnosis of respiratory allergic diseases. It is the technique more widely used, specific and reasonably sensitive for most applications as a marker of atopy. Measurement of serum IgE antibodies and skin-prick testing may give complimentary information and can be applied in clinical and epidemiological settings. Peripheral blood eosinophilia is less used, but is important in clinical practice to demonstrate the allergic aetiology of disease, to monitor its clinical course and to address the choice of therapy. In epidemiology, hypereosinophilia seems to reflect an inflammatory reaction in the airways, which may be linked to obstructive airflow limitation.

Cross sectional and longitudinal study on selenium, glutathione peroxidase, smoking, and occupational exposure in coal miners.

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.

Relationships of active and passive smoking to total IgE in adults of the Epidemiological Study of the Genetics and Environment of Asthma, Bronchial Hyperresponsiveness, and Atopy (EGEA).

The increase of total IgE in relation to active smoking has been shown in the general population, but little is known about subjects with a personal or family history of asthma. The objective of this report is to analyze the relationships of active and passive smoking to total IgE in the Epidemiological Study of the Genetics and Environment of Asthma, Bronchial Hyperresponsiveness, and Atopy (EGEA). The sample studied includes 122 asthmatic probands, 430 first-degree relatives, and 190 control subjects, age 25 to 54 yr. As expected, first-degree relatives had total IgE intermediate between cases and control subjects and men had higher values than women. Current smokers had significantly higher IgE than never smokers. The relationship was statistically significant restricting the analysis in asthmatic probands. In a model taking into account gender, personal and familial history of asthma, socio- occupational class, and the nonindependence of subjects from the same family, IgE were in current smokers, ex-smokers, and never smokers 128, 61, and 76 IU/ml and 77, 41, and 55 IU/ml in men (p = 0.01) and women (p = 0. 05), respectively. The relation was independent of skin test response. Some increase in IgE was observed in both men and women first-degree relatives in relation to passive smoking. That relation was statistically significant in women only (adjusted for asthma values: 103 IU/ml versus 48 IU/ ml, p = 0.02). Results show that an increase in total IgE in relation to active smoking may be evidenced even in asthmatics despite the healthy smoker effect. Susceptible subjects, such as women who are first-degree relatives of asthmatics, may increase total IgE in relation to passive smoking.

Relationships of active smoking to asthma and asthma severity in the EGEA study. Epidemiological study on the Genetics and Environment of Asthma.

The role of smoking as potential risk factor, selection factor ("healthy smoker" effect) and modifying factor (severity) of asthma was studied in the Epidemiological study on the Genetics and Environment of Asthma, bronchial hyperresponsiveness and atopy (EGEA). The analysis involved 200 adult asthmatic cases recruited in chest clinics, 265 nonasthmatic controls and 586 relatives of asthmatics (147 with asthma). Asthma in childhood was not associated with a reduced take-up of smoking (odds ratio (OR)=1.06 in males and 0.98 in females), but smoker asthmatic cases quit more often than controls (OR = 2.20 (95% confidence interval (95% CI) 1.11-4.34) in males and 2.76 (1.19-6.42) in females). Adult onset asthma was unrelated to ever smoking (OR 1.07 in males and 1.02 in females). In asthmatic cases, active smoking was associated with asthma severity. Current smokers, compared to never and exsmokers, had more asthma symptoms, more frequent (> or =1 attack x day(-1)) asthma attacks (OR 2.39 (95% CI 1.06-5.36)) and higher asthma severity scores. No clear pattern regarding the relationships of smoking habits with asthma was observed in first degree relatives. It is concluded that active smoking is not a risk factor for asthma in adulthood, but that smoking increases asthma severity.

Segregation analysis of IgE levels in 335 French families (EGEA) using different strategies to correct for the ascertainment through a correlated trait (asthma).

The main objective of this study was to search for a major gene controlling total serum immunoglobulin E (IgE) levels, an intermediate phenotype for asthma and allergy. We studied 335 French nuclear families of the EGEA study (Epidemiological study of the Genetics and Environment of Asthma), ascertained through asthmatic probands (123 are parents in the family, 212 children). Segregation analyses were performed by regressive models, which can take into account a major gene effect, various sources of familial covariation (genetic and/or environmental) as well as measured risk factors (i.e. , age, sex, smoking habits). Different strategies were considered to account for the mode of ascertainment of the families through a correlated trait (asthma): the ascertainment mode was either ignored (strategy A) or taken into account by adjusting IgE levels for the position in the family, i.e., probands, blood relatives, spouses (strategy B) or excluding the asthmatic children-probands and computing the likelihood of each family conditionally on parents' IgE levels (strategy C). Whereas a major gene effect could not be detected with strategy A, strategies B and C showed evidence for the transmission of a dominant major gene for high IgE levels, which was more significant with strategy B. This gene does not interact with any of the covariates and is responsible for approximately 15% of IgE variation (the allele frequency is 0.65).

Head circumference at birth and maternal factors related to cord blood total IgE.

BACKGROUND: A recent study reported an association between a large head circumference at birth and adult total IgE. However, no study has yet looked at the relation between head circumference and cord blood IgE. OBJECTIVES: To assess the relationship between child's cord blood total IgE and head circumference at birth taking parental allergy and smoking habits as well as placental calcifications into account. METHODS: Two samples of unselected newborns and their mothers with uncomplicated pregnancies were studied: 235 in study A with data on parental allergy and 99 in study B with data on placental calcifications. RESULTS: In both studies, cord blood IgE was significantly related to large head circumference at birth (0.07 vs 0.15 IU/mL for newborns < 37 cm vs >/= 37 cm, respectively, P = 0. 03 for study A and 0.09 vs 0.28 IU/mL, P = 0.04 for study B). Cord blood IgE was unrelated to parental smoking habits. Maternal IgE significantly increased in mothers exposed to both active and passive smoking during pregnancy compared with other pregnant women. High cord blood IgE were associated with high maternal IgE (r = 0. 38; P < 0.001). Multiple linear regression showed that large head circumference, maternal IgE and clinical manifestations of maternal, but not paternal, allergy were independently related to cord blood IgE (study A). Large head circumference and placental calcifications were independently related to a higher cord blood IgE level (study B). CONCLUSIONS: Besides the role of genetic factors, results on the preferential role of maternal vs paternal allergy and associations to large head circumference and placental calcifications support the hypothesis of the role of environmental factors during pregnancy on the level of cord blood IgE.

Epidemiological study of the genetics and environment of asthma, bronchial hyperresponsiveness, and atopy: phenotype issues.

The Epidemiological Study of the Genetics and Environment of Asthma (EGEA) combined a case-control study and a family study. The total sample of 1,854 consisted of 348 patients with asthma selected through chest clinics and 416 control subjects and nuclear families ascertained through the cases. The protocol included standardized questionnaires, bronchial responsiveness, allergen skin-prick tests according to international protocols, total serum immunoglobulin E (IgE) level measurements, and blood eosinophilia. Criteria used to select subjects with asthma and determine asthma status of relatives for affected sibling pair linkage analysis are described. Based on figures from the 348 asthma cases of the EGEA study, issues relative to the definition of severe asthma and intermediate phenotypes such as bronchial responsiveness and allergic markers are discussed. Given the phenotypic heterogeneity involved, relevant phenotypes that may lead to the detection of genetic factors will depend on the hypothesis tested. Standardization of primary data and subphenotypes is a prerequisite for pooling data, which will be needed in the future to better understand the genetics and environmental factors of asthma.

Relationship of upper airway disease to tobacco smoking and allergic markers: a cohort study of men followed up for 5 years.

Data derived from a cohort study of 191 men, seen 5 years apart, were used to investigate the involvement in allergic as well as in nonallergic upper airway disease (UAD) of two risk factors, immediate hypersensitivity and tobacco smoking, the roles of which have been well established in lower airway disease. At both surveys, UAD and smoking habits were assessed by an extended version of the BMRC/ECSC questionnaire. UAD consisted of usual or chronic rhinitis, seasonal allergic rhinitis and perceived nasal hyperresponsiveness (PNHR) to tobacco smoke, cold air or exercise. Immediate hypersensitivity was determined either in vivo (skin prick test, SPT, positivity) or in vitro (total IgE). UAD prevalence and smoking habits did not vary significantly over 5 years. On the contrary, SPT positivity increased significantly between the two surveys. At both surveys, SPT positivity for common aeroallergens (grass pollens overall) was significantly related to seasonal allergic rhinitis but not to usual or chronic rhinitis and to PNHR. Similarly, the total IgE level was increased in seasonal allergic rhinitis, but never significantly. Current smoking was always a habit significantly more frequent in men reporting chronic rhinitis (odds ratios of 5.3 and 4.9 in 1985 and 1990, respectively). The relationship was of the dose-response type: the more the subjects smoked, the more they reported chronic rhinitis. In contrast, seasonal allergic rhinitis was more associated with exsmoking, either in 1985 or in 1990. These results were confirmed longitudinally and after exclusion of asthmatics. Further investigations are needed to support the hypothesis raised by our data according to which immediate hypersensitivity, as assessed by SPT positivity for common aeroallergens, and tobacco smoking might intervene alternatively in UAD, probably because of the 'healthy smoker effect'.