Background Atopic disease is a major health problem. Mutations in the filaggrin gene (FLG) confer major susceptibility to eczema and related asthma. Objective We sought to determine the natural ...history and burden of atopic disease conferred by the 2 most common FLG mutations in a large, population-based birth cohort study. Methods We analyzed the effect of the most common null alleles (R501X and 2282del4) on several atopic phenotypes in a cohort of approximately 7000 English children born in 1990-1991. Results FLG null alleles associated strongly with eczema; eczema associated with these mutations presents in early life and is more persistent (hazard ratio for eczema resolution for those with FLG mutations to FLG wild type, 0.67; 95% CI, 0.58-0.77; P = 5 × 10−8 ). FLG mutations conferred a population asthma risk of 1.80 (95% CI, 1.34-2.41; P = .00019); asthma risk was especially high in the context of eczema (odds ratio, 3.16; 95% CI, 2.25-4.43; P = 1.4 × 10−11 ). Strong associations were identified with sensitization to grass, house dust mite, and cat dander and sensitization to multiple allergens (odds ratio, 2.12; 95% CI, 1.03-4.37; P = 5.42 × 10−27 ). Conclusion FLG mutations are strong genetic determinants of eczema, early wheeze, asthma in the context of eczema, and atopic sensitization. They confer risk of a particular trajectory for eczema, with increased duration of disease and greater risk of asthma and multiple allergic sensitizations. FLG alleles help define the risk profile of children with eczema and help define the “eczema plus early wheeze” and “eczema plus asthma” phenotypes.
Background Animal data suggest that tobacco smoke exposure of a mother when she is in utero influences DNA methylation patterns in her offspring and that there is an effect on the respiratory system, ...particularly airway responsiveness. The only study, to our knowledge, in humans suggests that there is a similar effect on asthma. The present study tests whether an association with respiratory problems can be confirmed in a large population study and aims to determine whether in utero exposure of the father has similar effects on his offspring. Methods Information from the Avon Longitudinal Study of Parents and Children was used to compare the offspring of women and of men who had themselves been exposed to cigarette smoke in utero; separate analyses were performed for children of women smokers and nonsmokers. The outcome measures were trajectories of history of early wheezing, doctor-diagnosed asthma by age 7 years, and results of lung function and methacholine challenge tests at 8 years. A variety of social and environmental factors were taken into account; offspring sexes were examined separately. Results There was no association with any outcome in relation to maternal prenatal exposure. There was some evidence of an increase in asthma risk with paternal prenatal exposure when the study mother was a nonsmoker (adjusted OR, 1.17; 95% CI, 0.97-1.41). This was particularly strong for girls (adjusted OR, 1.39; 95% CI, 1.04-1.86). Conclusions We did not find that maternal prenatal exposure to her mother's smoking had any effect on her children's respiratory outcomes. There was suggestive evidence of paternal prenatal exposure being associated with asthma and persistent wheezing in the granddaughters.
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