title: Interaction between the DNAH9 gene and early smoke exposure in bronchial hyperresponsiveness.
abstract: A previous genome-wide linkage scan of bronchial hyperresponsiveness (BHR) in the French Epidemiological study on the Genetics and Environment of Asthma (EGEA) families, performed in the presence of a gene×early-life environmental tobacco smoke (ETS) exposure interaction, showed the strongest interaction in the 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 family-based association test (FBAT) association signals (p≤0.01) with BHR in unexposed siblings, and 2) a 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 not in 341 UK families, probably due in part to differences in phenotypic features between datasets.The SNP showing significant interaction with ETS belongs toDNAH9(dynein, axonemal, heavy chain 9), a promising candidate gene involved in respiratory cilia mobility and associated with primary ciliary dyskinesia, a disease associated with abnormalities of pulmonary function.
authors.affiliation: INSERM, UMR 946, Genetic Variation and Human Diseases Unit, Paris, France Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie, Paris, France Marie-Helene.Dizier@inserm.fr.
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Dizier
authors.affiliation: INSERM, U1168, Aging and Chronic Diseases, Epidemiological and Public Health Approaches (VIMA), Villejuif, France Université Versailles Saint-Quentin-en-Yvelines, UMR_S 1168, Paris, France These authors contributed equally to this work.
authors.forename: Rachel
authors.initials: R
authors.lastname: Nadif
authors.affiliation: INSERM, UMR 946, Genetic Variation and Human Diseases Unit, Paris, France Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie, Paris, France These authors contributed equally to this work.
authors.forename: Patricia
authors.initials: P
authors.lastname: Margaritte-Jeannin
authors.affiliation: MRC Lifecourse Epidemiology Unit, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: Sheila J
authors.initials: SJ
authors.lastname: Barton
authors.affiliation: INSERM, UMR 946, Genetic Variation and Human Diseases Unit, Paris, France Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie, Paris, France Université Paris-Sud, UMR_S 1018, Villejuif, France.
authors.forename: Chloé
authors.initials: C
authors.lastname: Sarnowski
authors.affiliation: Université du Québec, Chicoutimi, Canada.
authors.forename: Valérie
authors.initials: V
authors.lastname: Gagné-Ouellet
authors.affiliation: INSERM, UMR 946, Genetic Variation and Human Diseases Unit, Paris, France Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie, Paris, France Université Paris-Sud, UMR_S 1018, Villejuif, France.
authors.forename: Myriam
authors.initials: M
authors.lastname: Brossard
authors.affiliation: INSERM, UMR 946, Genetic Variation and Human Diseases Unit, Paris, France Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie, Paris, France Université Paris-Sud, UMR_S 1018, Villejuif, France.
authors.forename: Nolwenn
authors.initials: N
authors.lastname: Lavielle
authors.affiliation: Service d'Allergologie Pédiatrique, Centre de l'Asthme et des Allergies, Hôpital d'Enfants Armand-Trousseau (APHP) - Sorbonne Universités, UPMC Université Paris 06, UMR_S 1136, Institut Pierre Louis d'Epidémiologie et de Santé Publique, Equipe EPAR, Paris, France.
authors.forename: Jocelyne
authors.initials: J
authors.lastname: Just
authors.affiliation: McGill University and Genome Quebec's Innovation Centre, Montréal, Canada.
authors.forename: Mark
authors.initials: M
authors.lastname: Lathrop
authors.affiliation: Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: John W
authors.initials: JW
authors.lastname: Holloway
authors.affiliation: Université du Québec, Chicoutimi, Canada These authors contributed equally to this work.
authors.forename: Catherine
authors.initials: C
authors.lastname: Laprise
authors.affiliation: INSERM, UMR 946, Genetic Variation and Human Diseases Unit, Paris, France Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie, Paris, France These authors contributed equally to this work.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Bouzigon
authors.affiliation: INSERM, UMR 946, Genetic Variation and Human Diseases Unit, Paris, France Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie, Paris, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Demenais
mesh_terms: D000293:Adolescent; D001249:Asthma / Q000235:genetics*; D056444:Axonemal Dyneins / Q000235:genetics*; D016535:Bronchial Hyperreactivity / Q000209:etiology / Q000235:genetics*; D002648:Child; D002886:Chromosomes, Human, Pair 17; D005192:Family Health; D005260:Female; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011792:Quebec; D035781:Siblings; D012907:Smoking; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*; D006113:United Kingdom; D055815:Young Adult
chemical_list: D014028:Tobacco Smoke Pollution; D056444:Axonemal Dyneins; C430745:DNAH9 protein, human