Asthma exacerbations are among the most frequent causes of hospitalization during childhood, but the underlying mechanisms are poorly understood. We performed a genome-wide association study of a specific asthma phenotype characterized by recurrent, severe exacerbations occurring between 2 and 6 years of age in a total of 1,173 cases and 2,522 controls. Cases were identified from national health registries of hospitalization, and DNA was obtained from the Danish Neonatal Screening Biobank. We identified five loci with genome-wide significant association. Four of these, GSDMB, IL33, RAD50 and IL1RL1, were previously reported as asthma susceptibility loci, but the effect sizes for these loci in our cohort were considerably larger than in the previous genome-wide association studies of asthma. We also obtained strong evidence for a new susceptibility gene, CDHR3 (encoding cadherin-related family member 3), which is highly expressed in airway epithelium. These results demonstrate the strength of applying specific phenotyping in the search for asthma susceptibility genes.

Using data from two population-based birth cohorts, Danielle Belgrave and colleagues examine the evidence for atopic march in developmental profiles for allergic disorders. Please see later in the article for the Editors' Summary

BackgroundFilaggrin (FLG) loss-of-function mutations lead to an impaired skin barrier associated with peanut allergy. Household peanut consumption is associated with peanut allergy, and peanut allergen in household dust correlates with household peanut consumption.ObjectiveWe sought to determine whether environmental peanut exposure increases the odds of peanut allergy and whether FLG mutations modulate these odds.MethodsExposure to peanut antigen in dust within the first year of life was measured in a population-based birth cohort. Peanut sensitization and peanut allergy (defined by using oral food challenges or component-resolved diagnostics [CRD]) were assessed at 8 and 11 years. Genotyping was performed for 6 FLG mutations.ResultsAfter adjustment for infantile atopic dermatitis and preceding egg skin prick test (SPT) sensitization, we found a strong and significant interaction between natural log (ln [loge]) peanut dust levels and FLG mutations on peanut sensitization and peanut allergy. Among children with FLG mutations, for each ln unit increase in the house dust peanut protein level, there was a more than 6-fold increased odds of peanut SPT sensitization, CRD sensitization, or both in children at ages 8 years, 11 years, or both and a greater than 3-fold increased odds of peanut allergy compared with odds seen in children with wild-type FLG. There was no significant effect of exposure in children without FLG mutations. In children carrying an FLG mutation, the threshold level for peanut SPT sensitization was 0.92 μg of peanut protein per gram (95% CI, 0.70-1.22 μg/g), that for CRD sensitization was 1.03 μg/g (95% CI, 0.90-1.82 μg/g), and that for peanut allergy was 1.17 μg/g (95% CI, 0.01-163.83 μg/g).ConclusionEarly-life environmental peanut exposure is associated with an increased risk of peanut sensitization and allergy in children who carry an FLG mutation. These data support the hypothesis that peanut allergy develops through transcutaneous sensitization in children with an impaired skin barrier.

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By adopting a machine learning approach to longitudinal data on allergic sensitization from two independent unselected birth cohorts, we identified latent classes with strikingly similar patterns of atopic response and association with clinical outcomes, suggesting the existence of multiple atopy phenotypes.

Rationale: Developmental patterns of lung function during childhood may have major implications for our understanding of the pathogenesis of respiratory disease throughout life.Objectives: To explore longitudinal trajectories of lung function during childhood and factors associated with lung function decline.Methods: In a population-based birth cohort, specific airway resistance (sRaw) was assessed at age 3 (n = 560), 5 (n = 829), 8 (n = 786), and 11 years (n = 644). Based on prospective data (questionnaires, skin tests, IgE), children were assigned to wheeze phenotypes (no wheezing, transient, late-onset, and persistent) and atopy phenotypes (no atopy, dust mite, non-dust mite, multiple early, and multiple late). We used longitudinal linear mixed models to determine predictors of change in sRaw over time.Measurements and Main Results: Contrary to the assumption that sRaw is independent of age and sex, boys had higher sRaw than girls (mean difference, 0.080; 95% confidence interval [CI], 0.049-0.111; P , 0.001) and a higher rate of increase over time. For girls, sRaw increased by 0.017 kPa $ s 21 per year (95% CI, 0.011-0.023). In boys this increase was significantly greater (P = 0.012; mean betweensex difference, 0.011 kPa $ s 21; 95% CI, 0.003-0.019). Children with persistent wheeze (but not other wheeze phenotypes) had a significantly greater rate of deterioration in sRaw over time compared with never wheezers (P = 0.009). Similarly, children with multiple early, but not other atopy phenotypes had significantly poorer lung function than those without atopy (mean difference, 0.116 kPa $ s 21 ; 95% CI, 0.065-0.168; P , 0.001). sRaw increased progressively with the increasing number of asthma exacerbations.Conclusions: Children with persistent wheeze, frequent asthma exacerbations, and multiple early atopy have diminished lung function throughout childhood, and are at risk of a progressive loss of lung function from age 3 to 11 years. These effects are more marked in boys.

The nature of developmental longitudinal trajectories of IgE responses differed between grass and mite allergen components, with temporal differences (early vs late onset) dominant in grass and diverging patterns of IgE responses (group 1 allergens, group 2 allergens, or both) in mite. Different longitudinal patterns bear different associations with clinical outcomes, which varied by allergen.