title: Genome-wide association meta-analysis identifies five modifier loci of lung disease severity in cystic fibrosis.
abstract: The identification of small molecules that target specific CFTR variants has ushered in a new era of treatment for cystic fibrosis (CF), yet optimal, individualized treatment of CF will require identification and targeting of disease modifiers. Here we use genome-wide association analysis to identify genetic modifiers of CF lung disease, the primary cause of mortality. Meta-analysis of 6,365 CF patients identifies five loci that display significant association with variation in lung disease. Regions on chr3q29 (MUC4/MUC20; P=3.3 × 10(-11)), chr5p15.3 (SLC9A3; P=6.8 × 10(-12)), chr6p21.3 (HLA Class II; P=1.2 × 10(-8)) and chrXq22-q23 (AGTR2/SLC6A14; P=1.8 × 10(-9)) contain genes of high biological relevance to CF pathophysiology. The fifth locus, on chr11p12-p13 (EHF/APIP; P=1.9 × 10(-10)), was previously shown to be associated with lung disease. These results provide new insights into potential targets for modulating lung disease severity in CF.
authors.affiliation: Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Trousseau, Pediatric Pulmonary Department; Institut National de la Santé et la Recherche Médicale (INSERM) U938, Paris 75012, France.|Sorbonne Universités, Université Pierre et Marie Curie (UPMC) Paris 06, Paris 75005, France.
authors.forename: Harriet
authors.initials: H
authors.lastname: Corvol
authors.affiliation: Division of Pediatric Endocrinology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Scott M
authors.identifier: http://orcid.org/0000-0002-4532-6421
authors.initials: SM
authors.lastname: Blackman
authors.affiliation: Sorbonne Universités, Université Pierre et Marie Curie (UPMC) Paris 06, Paris 75005, France.|AP-HP, Hôpital St Antoine, Biostatistics Department; Inserm U1136, Paris 75012, France.
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Boëlle
authors.affiliation: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Gallins
authors.affiliation: Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
authors.forename: Rhonda G
authors.initials: RG
authors.lastname: Pace
authors.affiliation: Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
authors.forename: Jaclyn R
authors.initials: JR
authors.lastname: Stonebraker
authors.affiliation: Department of Epidemiology, Colorado School of Public Health, University of Colorado Denver, Anschutz Medical Center, Aurora, Colorado 80045, USA.|Children's Hospital Colorado, Anschutz Medical Center, Aurora, Colorado 80045, USA.|Department of Pediatrics, School of Medicine, Anschutz Medical Center, Aurora, Colorado 80045, USA.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Accurso
authors.affiliation: Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Trousseau, Pediatric Pulmonary Department; Institut National de la Santé et la Recherche Médicale (INSERM) U938, Paris 75012, France.|Sorbonne Universités, Université Pierre et Marie Curie (UPMC) Paris 06, Paris 75005, France.
authors.forename: Annick
authors.initials: A
authors.lastname: Clement
authors.affiliation: Division of Pediatric Pulmonology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Collaco
authors.affiliation: Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Dang
authors.affiliation: Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Dang
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Arianna
authors.initials: A
authors.lastname: Franca
authors.affiliation: Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 0A4.
authors.forename: Jiafen
authors.initials: J
authors.lastname: Gong
authors.affiliation: Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Trousseau, Pediatric Pulmonary Department; Institut National de la Santé et la Recherche Médicale (INSERM) U938, Paris 75012, France.
authors.forename: Loic
authors.initials: L
authors.lastname: Guillot
authors.affiliation: Program in Physiology and Experimental Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 0A4.
authors.forename: Katherine
authors.initials: K
authors.lastname: Keenan
authors.affiliation: Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 0A4.
authors.forename: Weili
authors.initials: W
authors.lastname: Li
authors.affiliation: Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 0A4.
authors.forename: Fan
authors.initials: F
authors.lastname: Lin
authors.affiliation: Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
authors.forename: Michael V
authors.initials: MV
authors.lastname: Patrone
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Karen S
authors.initials: KS
authors.lastname: Raraigh
authors.affiliation: Department of Statistical Sciences, University of Toronto, Toronto, Ontario, Canada M5S 3G3.|Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada M5T 3M7.
authors.forename: Lei
authors.initials: L
authors.lastname: Sun
authors.affiliation: Bioinformatics Research Center and Department of Biological Sciences, North Carolina State University, Raleigh, North Carolina 27695, USA.
authors.forename: Yi-Hui
authors.initials: YH
authors.lastname: Zhou
authors.affiliation: Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
authors.forename: Wanda K
authors.initials: WK
authors.lastname: O'Neal
authors.affiliation: Department of Epidemiology, Colorado School of Public Health, University of Colorado Denver, Anschutz Medical Center, Aurora, Colorado 80045, USA.|Children's Hospital Colorado, Anschutz Medical Center, Aurora, Colorado 80045, USA.|Department of Pediatrics, School of Medicine, Anschutz Medical Center, Aurora, Colorado 80045, USA.
authors.forename: Marci K
authors.initials: MK
authors.lastname: Sontag
authors.affiliation: Division of Pulmonary Medicine, Department of Pediatrics, Stanley Manne Research Institute, Northwestern University Feinberg School of Medicine, Ann and Robert Lurie Children's Hospital of Chicago, Chicago, Illinois 60611, USA.
authors.forename: Hara
authors.initials: H
authors.lastname: Levy
authors.affiliation: Program in Physiology and Experimental Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 0A4.|Department of Pediatrics, University of Toronto, Toronto, Ontario M5G 1X8, Canada.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Durie
authors.affiliation: Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 0A4.|Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
authors.forename: Johanna M
authors.initials: JM
authors.lastname: Rommens
authors.affiliation: Department of Pediatrics, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106, USA.
authors.forename: Mitchell L
authors.initials: ML
authors.lastname: Drumm
authors.affiliation: Bioinformatics Research Center and Department of Statistics, North Carolina State University, Raleigh, North Carolina 27695, USA.|Department of Biological Sciences, North Carolina State University, Raleigh, North Carolina 27695, USA.
authors.forename: Fred A
authors.initials: FA
authors.lastname: Wright
authors.affiliation: Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 0A4.|Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada M5T 3M7.
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Strug
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.|Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Garry R
authors.initials: GR
authors.lastname: Cutting
authors.affiliation: Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Knowles
mesh_terms: D000293:Adolescent; D000328:Adult; D026905:Amino Acid Transport Systems; D026921:Amino Acid Transport Systems, Neutral / Q000235:genetics; D002648:Child; D003550:Cystic Fibrosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D055264:Mucin-4 / Q000235:genetics; D009077:Mucins / Q000235:genetics; D012720:Severity of Illness Index; D014157:Transcription Factors / Q000235:genetics; D055815:Young Adult
chemical_list: D026905:Amino Acid Transport Systems; D026921:Amino Acid Transport Systems, Neutral; C403306:EHF protein, human; C490965:MUC20 protein, human; C524658:MUC4 protein, human; D055264:Mucin-4; D009077:Mucins; C503995:SLC6A14 protein, human; D014157:Transcription Factors