Interactive effect between ATPase-related genes and early-life tobacco smoke exposure on bronchial hyper-responsiveness detected in asthma-ascertained families 1,2 1,2 3 1,2 1,2 1,2 MH Dizier , P Margaritte-Jeannin , L Pain , C Sarnowski , M Brossard , H Mohamdi , 1,2 4 5 1,2 3 1,2 6,7 N Lavielle , J Just , M Lathrop , E Bouzigon# , C Laprise# , F Demenais* , R Nadif* #: contributed equally *: contributed equally (1) INSERM, U946, Paris, France, (2) Université Paris Diderot, Paris, France, (3) Université du Québec à Chicoutimi, Québec, Canada, (4) Centre de l’Asthme et des Allergies – INSERM, UMR-S 1136, Equipe EPAR, France, (5) Mc Gill University, Montréal, Canada, (6) INSERM, UMR-S 1168, Villejuif, France, (7) Université Versailles Saint-Quentin en Yvelines, France In a previous positional cloning study of the 17p11 region, we identified genetic variants interacting with exposure to tobacco smoke (ETS) in early life for bronchial hyperresponsiveness (BHR) in the French Epidemiological study on the Genetics and Environment of Asthma (EGEA) (Dizier et al, 2007). These variants were located in DNAH9 (Dizier et al, 2016), a promising candidate gene, which has a key role in motile cilia function and is associated to primary ciliary dyskinesia, a disease associated with bronchiectasis and abnormalities of pulmonary function. The aim of the present study was to identify other genetic variants interacting with ETS for BHR by investigating genes involved in the "ATPase binding" and the "ATPase activity" pathways. These two pathways were selected because they both include DNAH9, are known to be target of cigarette smoke and are involved in the movement of respiratory cilia. Analyses were first conducted in a discovery sample of 388 asthmatic EGEA families, using family-based association test (FBAT). For all SNPs located within 277 genes belonging to the two pathways, we applied FBAT homogeneity test between exposed vs. unexposed siblings to detect SNP x ETS interactive effects on BHR. Replication was performed in Saguenay-LacSaint-Jean (SLSJ) asthma collection (Laprise 2014), another asthma-ascertained sample of 253 French-Canadian families. In EGEA families, 25 SNPs showed interaction signals (P≤5x10-3) with ETS among BHR siblings. One SNP on 4p13 region reached the threshold (P=2x10-5) for a significant interaction with ETS when correcting for multiple testing. This result did not quite reach the nominal level for replication in SLSJ families (P=0.13) but there was improvement of evidence for interaction in the meta-analysis of the two samples (P=10-5). Another SNP on 9q31 showed a stronger signal of interaction in the SLSJ study (P=0.003), and a suggestive interaction by meta-analysis (P=6.10-5). Further replication studies are now necessary to confirm these results. This study highlights that incorporating biological knowledge in the selection of genes may identify novel genes potentially interacting with ETS in BHR siblings.