Rationale: Several genes identified by positional cloning have been associated with asthma and atopy but few findings have been replicated. Age at onset of asthma has been associated with different phenotypic characteristics, and with variants at chromosome 17q21 identified through genome-wide association. We examined associations and age-specific effects on asthma, atopy and bronchial hyperresponsiveness of five candidate genes previously identified by positional cloning (ADAM33, PHF11, NPSR1, DPP10, SPINK5).
Methods: We studied 51 polymorphisms from 2474 participants from 13 countries who took part in the European Community Respiratory Health Survey (1990–2000). Asthma and age at onset of asthma were assessed by questionnaire data, bronchial hyperresponsiveness by methacholine challenge and atopy by specific immunoglobulin E to four common allergens.
Results: Significant associations with asthma, atopy and particularly for asthma with atopy were observed for a large region of 47 kilobases in the NPSR1 gene, even after Bonferroni correction for multiple comparisons (p-value<0.001). The associations with NPSR1 were stronger among those reporting a first attack of asthma before age of 15, with statistically significant interactions with age of onset found for three SNPs. Weaker evidences were observed for ADAM33 and bronchial hyperresponsiveness and for an age-specific effect of two SNPs in DPP10 and asthma.
Conclusion: This study provides further evidence for an effect of NPSR1 on asthma, atopy and atopic asthma. In addition this analysis suggests a role of NPSR1 on early onset asthma driven by the strong effect of this gene on atopic asthma.