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

International audienceBackground: 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 adenosine triphosphate (ATP) 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 ETS exposed versus unexposed BHR siblings were conducted in 388 EGEA families. Twenty SNPs 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: The 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

A Common variant in <i>RAB27A</i> gene is associated with fractional exhaled nitric oxide levels in adults

Background: Exhaled nitric oxide (FeNO) is a biomarker for eosinophilic inflammation in the airways and for responsiveness to corticosteroids in asthmatics. Objective: We sought to identify in adults the genetic determinants of fractional exhaled nitric oxide (FeNO) levels and to assess whether environmental and disease-related factors influence these associations. Methods: We performed a genome-wide association study of FeNO through meta-analysis of two independent discovery samples of European ancestry: the outbred EGEA study (French Epidemiological study on the Genetics and Environment of Asthma, N = 610 adults) and the Hutterites (N = 601 adults), a founder population living on communal farms. Replication of main findings was assessed in adults from an isolated village in Sardinia (Talana study, N = 450). We then investigated the influence of asthma, atopy and tobacco smoke exposure on these genetic associations, and whether they were also associated with FeNO values in children of the EAGLE (EArly Genetics &#38; Lifecourse Epidemiology, N = 8858) consortium. Results: We detected a common variant in RAB27A (rs2444043) associated with FeNO that reached the genome-wide significant level (P = 1.6 × 10−7) in the combined discovery and replication adult data sets. This SNP belongs to member of RAS oncogene family (RAB27A) and was associated with an expression quantitative trait locus for RAB27A in lymphoblastoid cell lines from asthmatics. A second suggestive locus (rs2194437, P = 8.9 × 10−7) located nearby the sodium/calcium exchanger 1 (SLC8A1) was mainly detected in atopic subjects and influenced by inhaled corticosteroid use. These two loci were not associated with childhood FeNO values. Conclusions and Clinical Relevance: This study identified a common variant located in RAB27A gene influencing FeNO levels specifically in adults and with a biological relevance to the regulation of FeNO levels. This study provides new insight into the biological mechanisms underlying FeNO levels in adults