title: A common variant in RAB27A gene is associated with fractional exhaled nitric oxide levels in adults.
abstract: 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 & 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
  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.
authors.affiliation: Inserm, UMR-946, Paris, France; Univ Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie, Paris, France.
authors.forename: E
authors.initials: E
authors.lastname: Bouzigon
authors.forename: R
authors.initials: R
authors.lastname: Nadif
authors.forename: E E
authors.initials: EE
authors.lastname: Thompson
authors.forename: M P
authors.initials: MP
authors.lastname: Concas
authors.forename: S
authors.initials: S
authors.lastname: Kuldanek
authors.forename: G
authors.initials: G
authors.lastname: Du
authors.forename: M
authors.initials: M
authors.lastname: Brossard
authors.forename: N
authors.initials: N
authors.lastname: Lavielle
authors.forename: C
authors.initials: C
authors.lastname: Sarnowski
authors.forename: A
authors.initials: A
authors.lastname: Vaysse
authors.forename: P
authors.initials: P
authors.lastname: Dessen
authors.forename: R J P
authors.initials: RJ
authors.lastname: van der Valk
authors.forename: L
authors.initials: L
authors.lastname: Duijts
authors.forename: A J
authors.initials: AJ
authors.lastname: Henderson
authors.forename: V W V
authors.initials: VW
authors.lastname: Jaddoe
authors.forename: J C
authors.initials: JC
authors.lastname: de Jongste
authors.forename: S
authors.initials: S
authors.lastname: Casula
authors.forename: G
authors.initials: G
authors.lastname: Biino
authors.forename: M-H
authors.initials: MH
authors.lastname: Dizier
authors.forename: I
authors.initials: I
authors.lastname: Pin
authors.forename: R
authors.initials: R
authors.lastname: Matran
authors.forename: M
authors.initials: M
authors.lastname: Lathrop
authors.forename: M
authors.initials: M
authors.lastname: Pirastu
authors.forename: F
authors.initials: F
authors.lastname: Demenais
authors.forename: C
authors.initials: C
authors.lastname: Ober
mesh_terms: D000328:Adult; D000483:Alleles; D001249:Asthma / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015415:Biomarkers; D002874:Chromosome Mapping; D045853:Exhalation; D005260:Female; D056726:Genetic Association Studies; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D015201:Meta-Analysis as Topic; D008875:Middle Aged; D009569:Nitric Oxide; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D012307:Risk Factors; D055815:Young Adult; D020691:rab GTP-Binding Proteins / Q000235:genetics*; D000075745:rab27 GTP-Binding Proteins
chemical_list: D015415:Biomarkers; D000075745:rab27 GTP-Binding Proteins; D009569:Nitric Oxide; C066694:RAB27A protein, human; D020691:rab GTP-Binding Proteins
keywords: airway inflammation; asthma; atopy; exhaled nitric oxide; genetics; genome-wide association study