Interaction between the DNAH9 gene and early smoke exposure in bronchial hyper-responsiveness

A previous genome-wide linkage scan of bronchial hyper-responsiveness (BHR) in EGEA families, performed in presence of G x ETS (early life environmental tobacco smoke) exposure interaction, showed the strongest interaction in 17p11 region where linkage was detected only among unexposed siblings. Our goal was to conduct fine-scale mapping of 17p11 to identify single nucleotide polymorphisms (SNPs) interacting with ETS that influence BHR. Analyses were performed in 388 French EGEA asthmatic families, using a two-step strategy: 1) selection of SNPs displaying FBAT (family-based association test) association signals (P?0.01) with BHR in unexposed siblings; 2) FBAT homogeneity test between exposed and unexposed siblings plus a robust log-linear interaction test. A single SNP reached the threshold (P? 3.10-3) for significant interaction with ETS using both interaction tests, after accounting for multiple testing. Results were replicated in 253 French-Canadian families but were not in 341 UK families, probably due in part to differences in phenotypic features between datasets.The SNP showing significant interaction with ETS belongs to DNAH9, a promising candidate gene involved in respiratory cilia mobility and associated with Primary Ciliary Dyskinesia, a disease associated with abnormalities of pulmonary function