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Interactive effect between ATPase-related genes and early-life tobacco smoke exposure on bronchial hyper-responsiveness detected in asthma-ascertained families
  1. Marie-Hélène Dizier1,2,
  2. Patricia Margaritte-Jeannin1,2,
  3. Lucile Pain3,
  4. Chloé Sarnowski1,2,
  5. Myriam Brossard1,2,
  6. Hamida Mohamdi1,2,
  7. Nolwenn Lavielle1,2,
  8. Marie-Claude C Babron1,2,
  9. Jocelyne Just4,
  10. Mark Lathrop5,
  11. Catherine Laprise3,
  12. Emmanuelle Bouzigon1,2,
  13. Florence Demenais1,2,
  14. Rachel Nadif6,7
  1. 1 INSERM, UMR-946, Genetic Variation and Human Diseases Unit, Paris, France
  2. 2 Sorbonne Paris Cité, Institut Universitaire d’Hématologie, Université Paris Diderot, Paris, France
  3. 3 Département des Sciences Fondamentales, Université du Québec, Chicoutimi, Quebec, Canada
  4. 4 Service d’Allergologie Pédiatrique, Centre de l’Asthme et des Allergies, Hôpital d’Enfants Armand-Trousseau (APHP), UPMC Paris 06, Paris, France
  5. 5 Department of Human Genetics, McGill University and Genome Quebec’s Innovation Centre, Montréal, Québec, Canada
  6. 6 Aging and Chronic Diseases–Epidemiological and Public Health Approaches (VIMA), Inserm, U1168, Villejuif, France
  7. 7 UMR-S 1168, Université de Versailles Saint-Quentin-en-Yvelines, Paris, France
  1. Correspondence to Marie-Hélène Dizier, UMR946, INSERM/Université Paris-Diderot, Paris F-75010, France; marie-helene.dizier{at}


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 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 and unexposed BHR siblings were conducted in 388 EGEA families. Twenty single-nucleotide polymorphisms (SNP) showing interaction signals (p5.10−3) 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.

  • BHR
  • FBAT
  • ETS
  • GxE interaction
  • ATP
  • asthma

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  • CL and EB contributed equally.

  • FD and RN contributed equally.

  • Contributors MHD and RN conducted the design. MHD and PMJ performed the data analysis. MHD and RN interpreted the findings and drafted the initial version of the manuscript. JJ, CL, ML, FD, EB and MHD contributed to the data acquisition. FD and EB revised the manuscript and all authors provided final approval of the version to be published.

  • Funding The French EGEA study was partly funded by grants from the French National Agency for Research (ANR 05-SEST-020-02/05-9-97, ANR 06-CEBS, ANR-11-BSV1-027-GWIS-AM). Genotyping of the asthma-ascertained samples was supported by grants from the European Commission (018996), the French Ministry of Higher Education and Research. We also acknowledge Region Ile de France (DIM-SEnT 2011) and Fondation pour la recherche Médicale (FRM 2013) for their support. The Canada Research Chair on Genetic Determinants of Asthma held by CL since 2005 allows the maintenance of the French Canadian study.

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval Ethical approval was obtained from the relevant institutional review board committees (Cochin Port-Royal Hospital and Necker-Enfants Malades Hospital, Paris). The SLSJ local ethics committee approved the study.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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