title: Genetics and Genomics of Longitudinal Lung Function Patterns in Individuals with Asthma.
abstract: Patterns of longitudinal lung function growth and decline in childhood asthma have been shown to be important in determining risk for future respiratory ailments including chronic airway obstruction and chronic obstructive pulmonary disease.
  
  
  
  To determine the genetic underpinnings of lung function patterns in subjects with childhood asthma.
  
  
  
  We performed a genome-wide association study of 581 non-Hispanic white individuals with asthma that were previously classified by patterns of lung function growth and decline (normal growth, normal growth with early decline, reduced growth, and reduced growth with early decline). The strongest association was also measured in two additional cohorts: a small asthma cohort and a large chronic obstructive pulmonary disease metaanalysis cohort. Interaction between the genomic region encompassing the most strongly associated single-nucleotide polymorphism and nearby genes was assessed by two chromosome conformation capture assays.
  
  
  
  An intergenic single-nucleotide polymorphism (rs4445257) on chromosome 8 was strongly associated with the normal growth with early decline pattern compared with all other pattern groups (P = 6.7 × 10-9; odds ratio, 2.8; 95% confidence interval, 2.0-4.0); replication analysis suggested this variant had opposite effects in normal growth with early decline and reduced growth with early decline pattern groups. Chromosome conformation capture experiments indicated a chromatin interaction between rs4445257 and the promoter of the distal CSMD3 gene.
  
  
  
  Early decline in lung function after normal growth is associated with a genetic polymorphism that may also protect against early decline in reduced growth groups. Clinical trial registered with www.clinicaltrials.gov (NCT00000575).
authors.affiliation: 1 Channing Division of Network Medicine and.|2 Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: McGeachie
authors.affiliation: 3 Bloomberg School of Public Health and.
authors.forename: Katherine P
authors.initials: KP
authors.lastname: Yates
authors.affiliation: 1 Channing Division of Network Medicine and.|2 Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Zhou
authors.affiliation: 1 Channing Division of Network Medicine and.|2 Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Feng
authors.initials: F
authors.lastname: Guo
authors.affiliation: 3 Bloomberg School of Public Health and.
authors.forename: Alice L
authors.initials: AL
authors.lastname: Sternberg
authors.affiliation: 3 Bloomberg School of Public Health and.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Van Natta
authors.affiliation: 4 School of Medicine, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Wise
authors.affiliation: 5 National Jewish Health and Research Center, Denver, Colorado.|6 Children's Hospital Colorado and.
authors.forename: Stanley J
authors.initials: SJ
authors.lastname: Szefler
authors.affiliation: 7 Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado, Denver, Colorado.
authors.forename: Sunita
authors.initials: S
authors.lastname: Sharma
authors.affiliation: 1 Channing Division of Network Medicine and.|2 Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.|8 Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Alvin T
authors.initials: AT
authors.lastname: Kho
authors.affiliation: 1 Channing Division of Network Medicine and.|2 Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Cho
authors.affiliation: 1 Channing Division of Network Medicine and.|2 Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Damien C
authors.initials: DC
authors.lastname: Croteau-Chonka
authors.affiliation: 1 Channing Division of Network Medicine and.|2 Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Castaldi
authors.affiliation: 9 Program in Systems Biology, Department of Biochemistry and Molecular Pharmacology, and.
authors.forename: Gaurav
authors.initials: G
authors.lastname: Jain
authors.affiliation: 9 Program in Systems Biology, Department of Biochemistry and Molecular Pharmacology, and.|10 School of Biological Sciences, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.
authors.forename: Amartya
authors.initials: A
authors.lastname: Sanyal
authors.affiliation: 9 Program in Systems Biology, Department of Biochemistry and Molecular Pharmacology, and.
authors.forename: Ye
authors.initials: Y
authors.lastname: Zhan
authors.affiliation: 9 Program in Systems Biology, Department of Biochemistry and Molecular Pharmacology, and.
authors.forename: Bryan R
authors.initials: BR
authors.lastname: Lajoie
authors.affiliation: 11 Howard Hughes Medical Institute, Program in Systems Biology, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts.
authors.forename: Job
authors.initials: J
authors.lastname: Dekker
authors.affiliation: 12 Genome Sciences, School of Medicine, University of Washington, Seattle, Washington.
authors.forename: John
authors.initials: J
authors.lastname: Stamatoyannopoulos
authors.affiliation: 5 National Jewish Health and Research Center, Denver, Colorado.|6 Children's Hospital Colorado and.|13 University of Colorado, Denver, Colorado.
authors.forename: Ronina A
authors.initials: RA
authors.lastname: Covar
authors.affiliation: 14 Department of Pediatrics, University of California at San Diego, La Jolla, California.|15 Kaiser Permanente Southern California Region, San Diego, California.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Zeiger
authors.affiliation: 4 School of Medicine, Johns Hopkins University, Baltimore, Maryland.
authors.forename: N Franklin
authors.initials: NF
authors.lastname: Adkinson
authors.affiliation: 16 ASTHMA, Inc., Clinical Research Center and Northwest Asthma & Allergy Center, Seattle, Washington.
authors.forename: Paul V
authors.initials: PV
authors.lastname: Williams
authors.affiliation: 17 University of New Mexico Health Sciences Center, Albuquerque, New Mexico.
authors.forename: H William
authors.initials: HW
authors.lastname: Kelly
authors.affiliation: 18 Division of Respiratory Medicine, Department of Pediatrics, The Hospital for Sick Children and University of Toronto, Toronto, Canada.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Grasemann
authors.affiliation: 19 Department of Epidemiology.
authors.forename: Judith M
authors.initials: JM
authors.lastname: Vonk
authors.affiliation: 20 Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital, and.
authors.forename: Gerard H
authors.initials: GH
authors.lastname: Koppelman
authors.affiliation: 21 Department of Pulmonology, University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, Groningen, the Netherlands.
authors.forename: Dirkje S
authors.initials: DS
authors.lastname: Postma
authors.affiliation: 1 Channing Division of Network Medicine and.|2 Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Raby
authors.affiliation: 1 Channing Division of Network Medicine and.|2 Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Isaac
authors.initials: I
authors.lastname: Houston
authors.affiliation: 22 Program in Molecular and Integrative Physiological Sciences, Departments of Environmental Health and Genetics & Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts; and.
authors.forename: Quan
authors.initials: Q
authors.lastname: Lu
authors.affiliation: 1 Channing Division of Network Medicine and.|23 Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, Massachusetts.|2 Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Anne L
authors.initials: AL
authors.lastname: Fuhlbrigge
authors.affiliation: 1 Channing Division of Network Medicine and.|2 Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Kelan G
authors.initials: KG
authors.lastname: Tantisira
authors.affiliation: 1 Channing Division of Network Medicine and.|2 Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Silverman
authors.affiliation: 3 Bloomberg School of Public Health and.
authors.forename: James
authors.initials: J
authors.lastname: Tonascia
authors.affiliation: 24 Division of Allergy, Immunology, and Pulmonary Medicine, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Strunk
authors.affiliation: 1 Channing Division of Network Medicine and.|2 Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Scott T
authors.initials: ST
authors.lastname: Weiss
mesh_terms: D001249:Asthma / Q000235:genetics* / Q000503:physiopathology*; D002648:Child; D002675:Child, Preschool; D005260:Female; D005541:Forced Expiratory Volume; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D023281:Genomics / Q000379:methods*; D006801:Humans; D008137:Longitudinal Studies; D008168:Lung / Q000503:physiopathology*; D008297:Male; D009426:Netherlands; D020641:Polymorphism, Single Nucleotide / Q000235:genetics / Q000502:physiology
keywords: CSMD3; asthma; chronic obstructive pulmonary disease; genome-wide association studies; longitudinal lung function patterns