title: 6q12 and 11p14 variants are associated with postnatal exhaled nitric oxide levels and respiratory symptoms.
abstract: BACKGROUND
  Exhaled nitric oxide (eNO) is a biomarker of airway inflammation and seems to precede respiratory symptoms, such as asthma, in childhood. Identifying genetic determinants of postnatal eNO levels might aid in unraveling the role of eNO in epithelial function or airway inflammation and disease.
  
  
  OBJECTIVE
  We sought to identify genetic determinants of early postnatal eNO levels and subsequent respiratory symptoms during the first year of life.
  
  
  METHODS
  Within a population-based birth cohort, eNO levels were measured in healthy term infants aged 5 weeks during quiet tidal breathing in unsedated sleep. We assessed associations of single nucleotide polymorphisms with eNO levels in a genome-wide association study and subsequent symptoms of lower respiratory tract infections during the first year of life and asked whether this was modified by prenatal and early-life environmental factors.
  
  
  RESULTS
  We identified thus far unknown determinants of infant eNO levels: rs208515 (P = 3.3 × 10-8), which is located at 6q12, probably acting in "trans" and explaining 10.3% of eNO level variance, and rs1441519 (P = 1.6 × 10-6), which is located at 11p14, potentially affecting nitric oxide synthase 3 (NOS3) expression, as shown by means of in vitro functional analyses. Moreover, the 6q12 locus was inversely associated with subsequent respiratory symptoms (P < .05) and time to recovery after first respiratory symptoms during the first year of life (P < .05).
  
  
  CONCLUSIONS
  The identification of novel genetic determinants of infant eNO levels might implicate that postnatal eNO metabolism in healthy infants before first viral infections and sensitization is related to mechanisms other than those associated with asthma, atopy, or increased risk thereof later in life.
authors.affiliation: University Children's Hospital (UKBB), University of Basel, Basel, Switzerland; Dr von Hauner Children's Hospital, Ludwig-Maximilians-Universität, Munch, and the Comprehensive Pneumology Center Munich (CPC-M; Member of the German Center for Lung Research [DZL]), Munich, Germany; Division of Respiratory Medicine, Department of Pediatrics, Inselspital, University of Bern, Bern, Switzerland.
authors.forename: Oliver
authors.initials: O
authors.lastname: Fuchs
authors.affiliation: University Children's Hospital (UKBB), University of Basel, Basel, Switzerland.
authors.forename: Olga
authors.initials: O
authors.lastname: Gorlanova
authors.affiliation: University Children's Hospital (UKBB), University of Basel, Basel, Switzerland; Division of Respiratory Medicine, Department of Pediatrics, Inselspital, University of Bern, Bern, Switzerland.
authors.forename: Philipp
authors.initials: P
authors.lastname: Latzin
authors.affiliation: University Children's Hospital (UKBB), University of Basel, Basel, Switzerland.
authors.forename: Anne
authors.initials: A
authors.lastname: Schmidt
authors.affiliation: Department of Pediatric Pneumology and Allergy, University Children's Hospital Regensburg (KUNO), Regensburg, Germany; Institute of Human Genetics, Hannover Medical School, Hannover, Germany.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Schieck
authors.affiliation: Department of Pediatric Pneumology and Allergy, University Children's Hospital Regensburg (KUNO), Regensburg, Germany.
authors.forename: Antoaneta A
authors.initials: AA
authors.lastname: Toncheva
authors.affiliation: Department of Pediatric Pneumology and Allergy, University Children's Hospital Regensburg (KUNO), Regensburg, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Michel
authors.affiliation: Department of Pediatric Pneumology and Allergy, University Children's Hospital Regensburg (KUNO), Regensburg, Germany.
authors.forename: Vincent D
authors.initials: VD
authors.lastname: Gaertner
authors.affiliation: Department of Pediatric Pneumology and Allergy, University Children's Hospital Regensburg (KUNO), Regensburg, Germany; Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany, and Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Germany (member of the German Center for Lung Research [DZL]), Hannover, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Kabesch
authors.affiliation: University Children's Hospital (UKBB), University of Basel, Basel, Switzerland. Electronic address: urs.frey@ukbb.ch.
authors.forename: Urs
authors.initials: U
authors.lastname: Frey
mesh_terms: D000075368:Anoctamins; D001944:Breath Tests; D002460:Cell Line; D018118:Chloride Channels / Q000235:genetics; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D015331:Cohort Studies; D045853:Exhalation; D005136:Eye Proteins / Q000235:genetics; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D011014:Pneumonia / Q000276:immunology*; D020641:Polymorphism, Single Nucleotide; D020545:Respiratory Mucosa / Q000502:physiology*
chemical_list: C577591:ANO3 protein, human; D000075368:Anoctamins; D018118:Chloride Channels; C533105:EYS protein, human; D005136:Eye Proteins; D009569:Nitric Oxide
keywords: Infants; airway inflammation; asthma; exhaled nitric oxide; genetics; genome-wide association study; wheeze