Interactive effect between atpase-related genes and early-life tobacco smoke exposure on bronchial hyper-responsiveness detected in asthma-ascertained families

Abstract

Background A positional cloning study of bronchial hyper-responsiveness (BHR) at the 17p11 locus in the French Epidemiological study on the Genetics and Environment of Asthma (EGEA) families showed significant interaction between early-life environmental tobacco smoke (ETS) exposure and genetic variants located in DNAH9.This gene encodes the heavy chain subunit of axonemal dynein, which is involved with AT P in the motile cilia function.Our goal was to identify genetic variants at other genes interacting with ETS in BHR by investigating all genes belonging to the 'ATP-binding' and 'ATPase activity' pathways which include DNAH9, are targets of cigarette smoke and play a crucial role in the airway inflammation.Methods Family-based interaction tests between ETSexposed and unexposed BHR siblings were conducted in 388 EGEA families.Twenty single-nucleotide polymorphisms (SNP) showing interaction signals (p=5.10-3) were tested in the 253 Saguenay-Lac-Saint- Jean (SLSJ) families.Results One of these SNPs was significantly replicated for interaction with ETS in SLSJ families (p=0.003).Another SNP reached the significance threshold after correction for multiple testing in the combined analysis of the two samples (p=10-5).Results were confirmed using both a robust log-linear test and a gene-based interaction test.Conclusion T he SNPs showing interaction with ETS belong to the ATP8A1 and ABCA1 genes, which play a role in the maintenance of asymmetry and homeostasis of lung membrane lipids.