title: Fraction of exhaled nitric oxide values in childhood are associated with 17q11.2-q12 and 17q12-q21 variants.
abstract: BACKGROUND
  The fraction of exhaled nitric oxide (Feno) value is a biomarker of eosinophilic airway inflammation and is associated with childhood asthma. Identification of common genetic variants associated with childhood Feno values might help to define biological mechanisms related to specific asthma phenotypes.
  
  
  OBJECTIVE
  We sought to identify the genetic variants associated with childhood Feno values and their relation with asthma.
  
  
  METHODS
  Feno values were measured in children age 5 to 15 years. In 14 genome-wide association studies (N = 8,858), we examined the associations of approximately 2.5 million single nucleotide polymorphisms (SNPs) with Feno values. Subsequently, we assessed whether significant SNPs were expression quantitative trait loci in genome-wide expression data sets of lymphoblastoid cell lines (n = 1,830) and were related to asthma in a previously published genome-wide association data set (cases, n = 10,365; control subjects: n = 16,110).
  
  
  RESULTS
  We identified 3 SNPs associated with Feno values: rs3751972 in LYR motif containing 9 (LYRM9; P = 1.97 × 10(-10)) and rs944722 in inducible nitric oxide synthase 2 (NOS2; P = 1.28 × 10(-9)), both of which are located at 17q11.2-q12, and rs8069176 near gasdermin B (GSDMB; P = 1.88 × 10(-8)) at 17q12-q21. We found a cis expression quantitative trait locus for the transcript soluble galactoside-binding lectin 9 (LGALS9) that is in linkage disequilibrium with rs944722. rs8069176 was associated with GSDMB and ORM1-like 3 (ORMDL3) expression. rs8069176 at 17q12-q21, but not rs3751972 and rs944722 at 17q11.2-q12, were associated with physician-diagnosed asthma.
  
  
  CONCLUSIONS
  This study identified 3 variants associated with Feno values, explaining 0.95% of the variance. Identification of functional SNPs and haplotypes in these regions might provide novel insight into the regulation of Feno values. This study highlights that both shared and distinct genetic factors affect Feno values and childhood asthma.
authors: The Generation R Study Group, Erasmus Medical Center, Rotterdam, The Netherlands.|Department of Pediatrics, Erasmus Medical Center, Rotterdam, The Netherlands.|Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: Ralf Jp
authors: RJ
authors: van der Valk
authors: Department of Pediatrics, Erasmus Medical Center, Rotterdam, The Netherlands.|Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.|School of Social and Community Medicine, University of Bristol, Uk.
authors: Liesbeth
authors: L
authors: Duijts
authors: School of Social and Community Medicine, University of Bristol, Uk.|MRC Centre for Causal Analyses in Translational Epidemiology, University of Bristol, UK.
authors: Nicolas J
authors: NJ
authors: Timpson
authors: Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, USA.
authors: Muhammad T
authors: MT
authors: Salam
authors: Institute of Epidemiology I, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
authors: Marie
authors: M
authors: Standl
authors: University of Manchester, Manchester Academic Health Science Centre, University Hospital of South Manchester NHS Foundation Trust, Manchester, United Kingdom.
authors: John A
authors: JA
authors: Curtin
authors: Institute of Epidemiology and Medical Biometry, Ulm University, Ulm, Germany.
authors: Jon
authors: J
authors: Genuneit
authors: University Medical Center Groningen, University of Groningen, Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital.
authors: Marjan
authors: M
authors: Kerhof
authors: COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, The Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.|The Danish Pediatric Asthma Center, Copenhagen University Hospital, Gentofte, Copenhagen, Denmark.
authors: Eskil
authors: E
authors: Kreiner-Møller
authors: Center for Research in Environmental Epidemiology (CREAL), Barcelona, Catalonia, Spain.|Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona, Catalonia, Spain.|Spanish consortium for Research on Epidemiology and Public Health (CIBERESP), Spain.
authors: Alejandro
authors: A
authors: Cáceres
authors: Institute of Environmental Medicine and Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden.
authors: Anna
authors: A
authors: Gref
authors: Department of Epidemiology, Harvard School of Public Health, Boston, USA.|Department of Biostatistics, Harvard School of Public Health, Boston, USA.
authors: Liming L
authors: LL
authors: Liang
authors: The Generation R Study Group, Erasmus Medical Center, Rotterdam, The Netherlands.|Department of Pediatrics, Erasmus Medical Center, Rotterdam, The Netherlands.|Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: H Rob
authors: HR
authors: Taal
authors: Inserm, UMR 946, Genetic Variation and Human Diseases Unit, F-75010, Paris, France.|Univ Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie, F- 75007, Paris, France.
authors: Emmanuelle
authors: E
authors: Bouzigon
authors: Inserm, UMR 946, Genetic Variation and Human Diseases Unit, F-75010, Paris, France.|Univ Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie, F- 75007, Paris, France.
authors: Florence
authors: F
authors: Demenais
authors: Inserm, Centre for research in Epidemiology and Population Health (CEPH), U1018, Respiratory and Environmental Epidemiology Team, F-94807, Villejuif, France.|Univ Paris-Sud, UMRS 1018, F-94807, Villejuif, France.
authors: Rachel
authors: R
authors: Nadif
authors: Department of Human Genetics, University of Chicago, Chicago, IL 60637.
authors: Carole
authors: C
authors: Ober
authors: Department of Human Genetics, University of Chicago, Chicago, IL 60637.
authors: Emma E
authors: EE
authors: Thompson
authors: Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.|Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: Karol
authors: K
authors: Estrada
authors: Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: Albert
authors: A
authors: Hofman
authors: The Generation R Study Group, Erasmus Medical Center, Rotterdam, The Netherlands.|Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.|Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: André G
authors: AG
authors: Uitterlinden
authors: Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: Cornélia
authors: C
authors: van Duijn
authors: Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: Fernando
authors: F
authors: Rivadeneira
authors: Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, USA.
authors: Xia
authors: X
authors: Li
authors: Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, USA.
authors: Sandrah P
authors: SP
authors: Eckel
authors: Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, USA.
authors: Kiros
authors: K
authors: Berhane
authors: Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, USA.
authors: W James
authors: WJ
authors: Gauderman
authors: School of Social and Community Medicine, University of Bristol, Uk.
authors: Raquel
authors: R
authors: Granell
authors: School of Social and Community Medicine, University of Bristol, Uk.|MRC Centre for Causal Analyses in Translational Epidemiology, University of Bristol, UK.
authors: David M
authors: DM
authors: Evans
authors: School of Social and Community Medicine, University of Bristol, Uk.
authors: Beate
authors: B
authors: St Pourcain
authors: School of Social and Community Medicine, University of Bristol, Uk.
authors: Wendy
authors: W
authors: McArdle
authors: School of Social and Community Medicine, University of Bristol, Uk.|MRC Centre for Causal Analyses in Translational Epidemiology, University of Bristol, UK.
authors: John P
authors: JP
authors: Kemp
authors: School of Social and Community Medicine, University of Bristol, Uk.|MRC Centre for Causal Analyses in Translational Epidemiology, University of Bristol, UK.
authors: George Davey
authors: GD
authors: Smith
authors: Institute of Epidemiology I, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
authors: Carla Mt
authors: CM
authors: Tiesler
authors: Institute of Epidemiology I, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
authors: Claudia
authors: C
authors: Flexeder
authors: University of Manchester, Manchester Academic Health Science Centre, University Hospital of South Manchester NHS Foundation Trust, Manchester, United Kingdom.
authors: Angela
authors: A
authors: Simpson
authors: University of Manchester, Manchester Academic Health Science Centre, University Hospital of South Manchester NHS Foundation Trust, Manchester, United Kingdom.
authors: Clare S
authors: CS
authors: Murray
authors: Inselspital, Universitätsspital, Bern, Universitätklinik für Kinderheilkunde, Bern, Switzerland.|Dr. von Hauner Children's Hospital, Ludwig Maximilian University, Munich, Germany.
authors: Oliver
authors: O
authors: Fuchs
authors: University of Groningen, University Medical Center Groningen, Department of Pulmonology, Groningen, The Netherlands.|Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors: Dirkje S
authors: DS
authors: Postma
authors: COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, The Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.|The Danish Pediatric Asthma Center, Copenhagen University Hospital, Gentofte, Copenhagen, Denmark.
authors: Klaus
authors: K
authors: Bønnelykke
authors: Spanish consortium for Research on Epidemiology and Public Health (CIBERESP), Spain.|ib-salut, Area de Salut de Menorca, Balearic Islands, Spain.
authors: Maties
authors: M
authors: Torrent
authors: Department of Public Health Sciences, Karolinska Institutet, Stockholm, Sweden.|Department of Physiology, South Central Hospital, Stockholm, Sweden.
authors: Martin
authors: M
authors: Andersson
authors: Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors: Patrick
authors: P
authors: Sleiman
authors: Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors: Hakon
authors: H
authors: Hakonarson
authors: National Heart and Lung Institute, Imperial College London, London SW3 6LY.
authors: William O
authors: WO
authors: Cookson
authors: National Heart and Lung Institute, Imperial College London, London SW3 6LY.
authors: Miriam F
authors: MF
authors: Moffatt
authors: School of Social and Community Medicine, University of Bristol, Uk.|MRC Centre for Causal Analyses in Translational Epidemiology, University of Bristol, UK.
authors: Lavinia
authors: L
authors: Paternoster
authors: Institute of Environmental Medicine and Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden.|Sach's Children's Hospital, Stockholm, Sweden.
authors: Erik
authors: E
authors: Melén
authors: Center for Research in Environmental Epidemiology (CREAL), Barcelona, Catalonia, Spain.|Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona, Catalonia, Spain.|Spanish consortium for Research on Epidemiology and Public Health (CIBERESP), Spain.|Pompeu Fabra University (UPF), Barcelona, Catalonia, Spain.
authors: Jordi
authors: J
authors: Sunyer
authors: COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, The Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.|The Danish Pediatric Asthma Center, Copenhagen University Hospital, Gentofte, Copenhagen, Denmark.
authors: Hans
authors: H
authors: Bisgaard
authors: University Medical Center Groningen, University of Groningen, Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital.|University of Groningen, University Medical Center Groningen, Department of Pulmonology, Groningen, The Netherlands.|Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors: Gerard H
authors: GH
authors: Koppelman
authors: Dr. von Hauner Children's Hospital, Ludwig Maximilian University, Munich, Germany.
authors: Markus
authors: M
authors: Ege
authors: University of Manchester, Manchester Academic Health Science Centre, University Hospital of South Manchester NHS Foundation Trust, Manchester, United Kingdom.
authors: Adnan
authors: A
authors: Custovic
authors: Institute of Epidemiology I, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
authors: Joachim
authors: J
authors: Heinrich
authors: Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, USA.
authors: Frank D
authors: FD
authors: Gilliland
authors: School of Social and Community Medicine, University of Bristol, Uk.
authors: Alexander J
authors: AJ
authors: Henderson
authors: The Generation R Study Group, Erasmus Medical Center, Rotterdam, The Netherlands.|Department of Pediatrics, Erasmus Medical Center, Rotterdam, The Netherlands.|Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: Vincent Wv
authors: VW
authors: Jaddoe
authors: Department of Pediatrics, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: Johan C
authors: JC
authors: de Jongste
mesh_terms: D000293:Adolescent; D001249:Asthma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D001944:Breath Tests; D002648:Child; D002675:Child, Preschool; D002886:Chromosomes, Human, Pair 17; D045853:Exhalation; D005260:Female; D055106:Genome-Wide Association Study; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D018832:Molecular Chaperones / Q000235:genetics* / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D012306:Risk; D000094524:Gasdermins
chemical_list: D015415:Biomarkers; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C485887:GSDMA protein, human; D000094524:Gasdermins; C496319:NOS2 protein, human
keywords: Airway inflammation; asthma phenotypes; biomarker; genetics; genome-wide association study