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.

OBJECTIVES: Immune diseases such as asthma, allergy, inflammatory bowel disease, and type 1 diabetes have shown a parallel increase in prevalence during recent decades in westernized countries. The rate of cesarean delivery has also increased in this period and has been associated with the development of some of these diseases.METHODS: Mature children born by cesarean delivery were analyzed for risk of hospital contact for chronic immune diseases recorded in the Danish national registries in the 35-year period 1977-2012. Two million term children participated in the primary analysis. We studied childhood diseases with a suspected relation to a deviant immune-maturation and a debut at young age. The effect of cesarean delivery on childhood disease incidences were estimated by means of confounderadjusted incidence rate ratios with 95% confidence intervals obtained in Poisson regression analyses.