F Gormand

Effect of 17q21 Variants and Smoking Exposure in Early-Onset Asthma

BACKGROUND A genomewide association study has shown an association between variants at chromosome 17q21 and an increased risk of asthma. To elucidate the relationship between this locus and disease, we examined a large, family-based data set that included extensive phenotypic and environmental data from the Epidemiological Study on the Genetics and Environment of Asthma. METHODS We tested 36 single-nucleotide polymorphisms (SNPs) in the 17q21 region in 1511 subjects from 372 families for an association with asthma. We also tested for genetic heterogeneity according to the age at the onset of asthma and exposure to environmental tobacco smoke in early life. RESULTS Eleven SNPs were significantly associated with asthma (P<0.01), of which three (rs8069176, rs2305480, and rs4795400) were strongly associated (P<0.001). Ordered-subset regression analysis led us to select an onset at 4 years of age or younger to classify patients as having early-onset asthma. Association with early-onset asthma was highly significant (P<10(-5) for four SNPs), whereas no association was found with late-onset asthma. With respect to exposure to environmental tobacco smoke in early life, we observed a significant association with early-onset asthma only in exposed subjects (P<5x10(-5) for six SNPs). Under the best-fitting recessive model, homozygous status (GG) at the most strongly associated SNP (rs8069176) conferred an increase in risk by a factor of 2.9, as compared with other genotypes (AG and AA) in the group exposed to environmental tobacco smoke (P=2.8x10(-6); P=0.006 for the test for heterogeneity of the SNP effect on early-onset asthma between groups with tobacco exposure and those without such exposure). CONCLUSIONS This study shows that the increased risk of asthma conferred by 17q21 genetic variants is restricted to early-onset asthma and that the risk is further increased by early-life exposure to environmental tobacco smoke. These findings provide a greater understanding of the functional role of the 17q21 variants in the pathophysiology of asthma.

17q21 variants modify the association between early respiratory infections and asthma

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 ≤4 yrs) were higher in carriers of risk genotypes (OR 3.42–6.36) than in noncarriers (OR 1.84–2.44; p-value for interaction 0.02–0.04 for five SNPs). Risk genotypes also increased the association between infection and childhood asthma that remits in adulthood (OR 4.84–7.16 in carriers and 1.74–2.25 in noncarriers; p-value for interaction 0.008–0.05 for 10 SNPs). In children with 17q21 risk genotypes and early-life environmental tobacco smoke (ETS) exposure, associations between infection and asthma were further enhanced. 17q21 genetic variants and early ETS exposure enhance the association between early respiratory infections and early-onset asthma and childhood asthma that remits in adulthood.

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.

Sex-specific effect of IL9 polymorphisms on lung function and polysensitization.

Sex differences in asthma-associated phenotypes are well known but the genetic factors that may account for these differences have received little attention. This study aimed to characterize sex-specific and pleiotropic genetic factors underlying four quantitative phenotypes involved in the main asthma physiopathological pathways: immunoglobulin E levels, a measure of polysensitization (SPTQ), eosinophil counts and a measure of lung function FEV1/H2 (forced expiratory volume in one second divided by height square). Sex-stratified univariate and bivariate linkage analyses were conducted in 295 families from the Epidemiological study on the Genetics and Environment of Asthma study. We found genome-wide significant evidence for a male-specific pleiotropic QTL (quantitative trait loci) on 5q31 (P=7 × 10−9) influencing both FEV1/H2 and SPTQ and for a female-specific pleiotropic QTL on 11q23 underlying SPTQ and immunoglobulin E (P=2 × 10−5). Three other sex-specific regions of linkage were detected for eosinophil: 4q24 and 22q13 in females, and 3p25 in males. Further, bivariate association analysis of FEV1/H2 and SPTQ with 5q31 candidate genes in males showed a significant association with two single-nucleotide polymorphisms within IL9 gene, rs2069885 and rs2069882 (P=0.02 and P=0.002, respectively, after Bonferronis correction). This study underlies the importance of taking into account complex mechanisms, such as heterogeneity according to sex and pleiotropy to unravel the genes involved in asthma phenotypes.

Facteurs environnementaux de l’asthme sévère et de l’allergie : résultats de l’étude EGEA

Resume Introduction L’etude EGEA (Etude epidemiologique des facteurs Genetiques et Environnementaux de l’Asthme, l’atopie et l’hyperreactivite bronchique), une etude cas-temoins et familiale regroupant 2 048 individus, a ete initiee afin de rechercher les facteurs environnementaux et genetiques de l’asthme. Nous presentons les resultats portant sur les aspects phenotypiques et environnementaux de l’asthme severe et de l’allergie obtenus depuis 2002 dans l’etude EGEA. Methodes et Resultats Les resultats etayent le role de facteurs hormonaux dans la severite de l’asthme et certains marqueurs allergiques associes a l’asthme. Un indice de masse corporelle eleve etait associe a la severite de l’asthme chez les femmes ayant eu des regles precoces. Des associations sont apparues entre des marqueurs d’allergie (eosinophiles, IgE, atopie) et des evenements hormono-dependants chez les femmes (asthme premenstruel, menopause et contraceptifs oraux). Chez les asthmatiques, l’exposition professionnelle aux nuisances asthmogenes, le tabagisme actif et passif etaient associes a un score clinique de severite plus eleve. L’etude a mis en evidence le role protecteur de la vie a la campagne et de l’exposition aux animaux domestiques dans la petite enfance vis-a-vis de l’allergie chez l’adulte, etayant ainsi l’hypothese hygieniste. Conclusions De nouvelles hypotheses seront prochainement testees grâce a la seconde phase de l’etude actuellement en cours.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.