Phenotypic determinants of uncontrolled asthma.

BACKGROUND: Although uncontrolled asthma remains frequent, determinants of asthma control are poorly studied. OBJECTIVES: The aim was to estimate the distribution and the phenotypic characteristics of asthma control in 2 groups of subjects defined by the use of inhaled corticosteroids (ICS) in the past 12 months, in the Epidemiological study on the Genetics and Environment of Asthma, bronchial hyperresponsiveness and atopy (EGEA). METHODS: Five hundred one adult current patients with asthma who participated in the follow-up of the EGEA study were included. Asthma control was assessed from survey questions reflecting asthma control, as defined in the 2006 Global Initiative for Asthma guidelines. The factors analyzed were age, sex, educational level, body mass index, active and passive smoking, sensitization to aeroallergens, total IgE, rhinitis, chronic cough/phlegm, and age at asthma onset. Analyses were stratified according to ICS use. RESULTS: Uncontrolled asthma was more frequent in ICS users (27.6%, 35.0%, and 37.4% with controlled, partly-controlled, and uncontrolled asthma respectively) compared with non-ICS users (60.0%, 23.9%, and 16.1%, respectively). In ICS users, chronic cough or phlegm and female sex were independently and significantly related to uncontrolled asthma. In non-ICS users, high total IgE and sensitization to molds were associated with uncontrolled asthma. Smoking and rhinitis were not associated with asthma control. CONCLUSION: Optimal asthma control remained unachieved in the majority of patients with asthma in this study. Factors associated with uncontrolled asthma were different in ICS users (chronic cough/phlegm, female sex) and non-ICS users (high total IgE and sensitization to molds).

CD14 and toll-like receptor gene polymorphisms, country living, and asthma in adults.

RATIONALE: It has been shown that country living protects against asthma, which may be explained by microbial exposures. OBJECTIVES: To study whether single nucleotide polymorphisms (SNPs) in CD14 and Toll-like receptor (TLR) 2, TLR4 and TLR9 genes are associated with asthma in adults, and whether these SNPs modify associations between country living and asthma. METHODS: Twenty-five SNPs in CD14, TLR2, TLR4, and TLR9 genes were genotyped in adult subjects from the French Epidemiological study on the Genetics and Environment of Asthma, Bronchial Hyperresponsiveness, and Atopy (EGEA). We conducted a case-control analysis on unrelated subjects (239 with asthma and 596 without asthma), and a family-based association test (FBAT) in 192 families ascertained through probands with asthma. MEASUREMENTS AND MAIN RESULTS: The TLR2/+596 C allele was associated with an increased risk for asthma in both case-control and family-based analyses (under a dominant model, odds ratio [OR] 1.91 and 95% confidence interval [CI] 1.34-2.72, P = 0.0003; Z statistics from FBAT = 2.48, P = 0.01). In skin prick test (SPT) positive subjects, the CD14/-260 C allele was negatively associated with asthma (additive model, OR 0.66; CI 0.48-0.91). Significant gene-environment interactions between variation in CD14 and TLR genes and country living during childhood were found for ten SNPs. In SPT positive subjects carrying CD14/-260 CC, country living protected against asthma (OR, 0.32; 95% CI, 0.12-0.85), whereas country living was not associated with asthma in subjects who were atopic and carrying CD14/-260 T (OR, 1.11; 95% CI, 0.65-1.90) (gene-environment interaction, P < 0.05). CONCLUSIONS: TLR2 and CD14 SNPs were associated with asthma and atopic asthma respectively. In addition, CD14, TLR2, TLR4, and TLR9 SNPs modified associations between country living and asthma.

Evidence for linkage of a new region (11p14) to eczema and allergic diseases.

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 the 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 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 the 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.

Evidence for a locus in 1p31 region specifically linked to the co-morbidity of asthma and allergic rhinitis in the EGEA study.

OBJECTIVE: A recent genome scan conducted in French EGEA families led to detect linkage of 1p31 to either asthma or allergic rhinitis (AR) and more significantly to asthma associated with AR. The goal of the present study was to assess formally whether 1p31 is a linkage region shared by two different diseases, asthma and AR, or whether it is specific to the co-morbidity asthma plus AR. METHODS: We used two different statistical approaches: the Triangle Test Statistic (TTS) and the Predivided Sample Test (PST), to search for heterogeneity of linkage to 1p31 according to the affection status being defined by either the presence of the two diseases (asthma plus AR) or the presence of only one disease ('asthma only' or 'AR only' or 'asthma only or AR only'). RESULTS: While no heterogeneity between the 'two diseases' phenotype and the 'one disease' phenotype was detected by the TTS, there was significant evidence for heterogeneity (p = 0.00007/0.002 after correction for multiple testing) using the PST. There was no indication of linkage in sib-pairs with 'one disease' only, while there was significant evidence for linkage in sib-pairs displaying asthma plus AR (p = 0.0002/0.0016 after correction). CONCLUSION: The present analysis shows that the co-morbidity, asthma plus AR, represents a phenotypic entity, distinct from asthma only or AR only, controlled by a genetic factor located on 1p31.

Interrelationships of quantitative asthma-related phenotypes in the Epidemiological Study on the Genetics and Environment of Asthma, Bronchial Hyperresponsiveness, and Atopy.

BACKGROUND: Delineating asthma subphenotypes is of interest to understand the cause of the disease. Few studies have addressed the interrelationships of quantitative asthma-related traits. OBJECTIVE: We sought to study the interrelationships of allergy markers and FEV(1) in relation to asthma and sex in children and adults. METHODS: Total IgE levels, skin prick test (SPT) positivity, eosinophil counts, and FEV(1) were assessed in 299 asthmatic cases (children and adults) recruited in chest clinics and 309 nonasthmatic population-based control subjects in the French Epidemiological Study on the Genetics and Environment of Asthma, Bronchial Hyperresponsiveness, and Atopy. RESULTS: Allergy parameters were significantly higher in asthmatic cases than in control subjects for children and adults and for both sexes. Sex and age modified the pattern of concordance of high IgE levels, SPT positivity, and eosinophilia among asthmatic cases, with the greatest overlap in male children (64%) and the lowest in male adults (18%). Patterns of change over the lifespan of IgE levels, eosinophil counts, and FEV(1)/height(2) varied, with the acceleration of FEV(1) decrease being particularly evident in asthmatic adults. In adult cases and control subjects, SPT positivity (particularly to indoor allergens) was significantly related to IgE levels but not to eosinophil counts. The association of eosinophil counts with IgE levels was evident only in children. Environmental factors (smoking, pets, and country living) did not alter the patterns observed. CONCLUSIONS: Each allergy-related phenotype showed a distinct relation with asthma, with the role for eosinophils being different than that for IgE levels and SPT responses. CLINICAL IMPLICATIONS: Taking age and sex into account is essential for understanding the interrelationships of the various allergy-related phenotypes to asthma status.

Does childhood immunization against infectious diseases protect from the development of atopic disease?

The argument of whether early immunization against infections promotes allergy or protects from it is presently under debate. The relationship between childhood immunization and the development of atopic diseases (asthma, allergic rhinitis and eczema) was examined in a population-based sample of 718 adolescents by taking individual data drawn from personal paediatric records on the schedule and the type of vaccination into account. Atopic diseases were determined using a standardized questionnaire. After adjustment for sex, age, father's socioeconomic status and active smoking, adolescents having been vaccinated (n = 694) had a significant lower risk to suffer from asthma or atopic diseases than non-vaccinated adolescents did (n = 24) [odds ratio (OR) = 0.30; 95% CI: 0.10, 0.92]. The relationship did not depend on the disease against which the vaccine was used as prophylaxis, the observance of the vaccination schedule or the number of inoculations. A higher protection was observed in the case of live attenuated vaccines (oral poliomyelitis and bacilli Camille-Guerin; OR = 0.26; 95% CI: 0.08, 0.83). These results, in agreement with previous ecological data, support the hypothesis that early vaccines could promote Th1 proliferation in response to the infectious agent contained in it, which inhibits the enhancement of atopic manifestations. Further studies are needed to confirm the phenomenon.

Clustering patterns of LOD scores for asthma-related phenotypes revealed by a genome-wide screen in 295 French EGEA families.

A genome-wide scan for asthma phenotypes was conducted in the whole sample of 295 EGEA families selected through at least one asthmatic subject. In addition to asthma, seven phenotypes involved in the main asthma physiopathological pathways were considered: SPT (positive skin prick test response to at least one of 11 allergens), SPTQ score being the number of positive skin test responses to 11 allergens, Phadiatop (positive specific IgE response to a mixture of allergens), total IgE levels, eosinophils, bronchial responsiveness (BR) to methacholine challenge and %predicted FEV(1). Four regions showed evidence for linkage (P

Influence of asthma on the validity of reported lifelong environmental tobacco smoke in the EGEA study.

The aim of this study was to assess the short-term reproducibility and the validity of reported ETS (environmental tobacco smoke) exposure, with a special emphasis on the potential misclassification related to personal or family history of asthma. Analyses were based on the data on the Epidemiological study on the Genetics and Environment of Asthma, bronchial hyperresponsiveness and atopy (EGEA), a case-control study of asthma that included first degree relatives of asthmatic cases. The study was comprised of 348 families of asthmatics recruited in six chest clinics throughout France and 416 population-based controls. For studying the validity of ETS reports, personal active smoking histories reported by family members were taken as reference. The reproducibility of ETS exposure report was good, and independent of asthma. The validity of the report of maternal and paternal smoking in childhood and spouse smoking during life was high (overall agreement > or = 84%). Mothers of asthmatic children significantly underreported their smoking habits when questioned on their children's passive tobacco exposure. Offspring of parents who had stopped smoking underestimated their ETS exposure in childhood. In conclusion, interviews with mothers on their personal active smoking habits may provide a more accurate estimate of their asthmatic child's passive exposure than asking mothers specifically about their children's passive exposure. There was no indication that asthma status (either of the parent/spouse or of the respondent) by itself influences the report of ETS exposure during childhood or adulthood.

Role of gender and hormone-related events on IgE, atopy, and eosinophils in the Epidemiological Study on the Genetics and Environment of Asthma, bronchial hyperresponsiveness and atopy.

BACKGROUND: The pattern of asthma over the lifespan is different in male and female patients, but etiologic differences according to gender are only partially understood. In women, information regarding factors explaining perimenstrual asthma and the role of hormone-related aspects on asthma-related phenotypes is scanty. OBJECTIVE: To assess the relationships of eosinophils, IgE, and atopy with (1) asthma according to gender and age of onset and (2) hormone-related events. METHODS: Using data from the Epidemiological study on the Genetics and Environment of Asthma, Bronchial Hyperresponsiveness and Atopy, adults and children with asthma recruited in chest clinics (n=313) and first-degree relatives of patients with asthma (n=214) were compared with nonasthmatic controls (n=334) and first-degree relatives without asthma (n=595). RESULTS: Among asthmatic women, eosinophilia was significantly associated with perimenstrual asthma independently from age, smoking, and asthma severity (eosinophils/mm(3) 330 vs 194; P=.01). In nonasthmatic women, IgE level was significantly decreased (by half) and atopy decreased with menopause, and IgE increased with oral contraceptive use, independently from age and smoking. Considering both genders, the increase of eosinophil counts with asthma was significantly greater in women with childhood-onset asthma than in women with adulthood-onset or in men in general. No interaction between gender and asthma was observed for eosinophils in children and for IgE level and atopy in children and adults. CONCLUSION: Results suggest a role of hormone-related events on asthma-related traits and support the hypothesis of the role of eosinophils in the persistence and severity of asthma.

Familial correlations and inter-relationships of four asthma-associated quantitative phenotypes in 320 French EGEA families ascertained through asthmatic probands.

Asthma is a complex disease, associated with biological and physiological phenotypes including immunoglobulin E (IgE) levels, sum of positive skin prick tests to allergens (SPTQ), eosinophil counts (EOS) and percent predicted forced expiratory volume in 1 s (%FEV1). We investigated the patterns of familial correlations and the inter-relationships of these four quantitative phenotypes, using the general class D regressive model, in 320 French EGEA nuclear families ascertained through 204 offspring (set A) and 116 parents (set B). Familial correlations of IgE and SPTQ were consistent with a model including no spouse correlation and equal parent-offspring and sib-sib correlations (rhoPO = rhoSS = 0.25 for IgE and 0.15 for SPTQ), this model being compatible with an additive polygenic model in the whole sample and the two family subsets A and B. Different patterns of familial correlations of EOS and %FEV1 were observed in these two sets. In set A, the best fitting model included no spouse correlation and equality of parent-offspring and sib-sib correlations (rhoPO = rhoSS = 0.14 for EOS and 0.23 for %FEV1). In set B, EOS had only a significant rhoSS of 0.28, while %FEV1 had significant rhoMO of 0.28 and rhoSS of 0.16. Analysis of shared familial determinants between these phenotypes indicated an overlap of at most 30% in rhoFO for IgE and SPTQ and in both rhoFO and rhoMO for IgE and EOS, while determinants of %FEV1 and atopy-related phenotypes appear distinct. These results may have implications for further linkage and association studies with genetic markers.

Methodologic aspects of the quantification of skin prick test responses: the EGEA study.

BACKGROUND: The expression of responses of allergy skin prick tests is not standardized. Usual definitions of atopy are not quantitative. OBJECTIVE: We sought to perform a biometric analysis of responses to various allergens to propose synthetic, quantitative indices independent of the heterogeneity of responses to various allergens. METHODS: Adults (N = 1286) from the Epidemiological Study on the Genetics and Environment of Asthma, Bronchial Hyperresponsiveness, and Atopy (EGEA) were included in the analysis. The first step, conducted for 678 subjects with at least 1 wheal >0, was to perform a standardization of wheal diameters to obtain comparable figures for 10 allergens through use of the means of the squares of wheal size as a scaling factor. The second step was a factor analysis of the standardized responses conducted not only for all subjects but also separately for asthmatic case and nonasthmatic control subjects. Finally, the strength of the link between various dichotomous and quantitative scores was assessed with multiRAST, total IgE, and asthma. Analyzed quantitative scores were based on the number of positive responses and on the nonstandardized and standardized sizes of the wheals. RESULTS: The standardization was efficient. Among asthmatic subjects but not other subjects, factor analysis evidenced a pattern with 3 factors, corresponding to outdoor, indoor, and mold allergens. The link study showed that all scores performed very similarly. CONCLUSION: The number of positive tests is a quantitative score with valid biometric properties. It should be used more widely in clinical settings and in epidemiology to assess the severity of atopy.