title: Exome Array Analysis Identifies a Common Variant in IL27 Associated with Chronic Obstructive Pulmonary Disease.
abstract: Chronic obstructive pulmonary disease (COPD) susceptibility is in part related to genetic variants. Most genetic studies have been focused on genome-wide common variants without a specific focus on coding variants, but common and rare coding variants may also affect COPD susceptibility.
  
  
  
  To identify coding variants associated with COPD.
  
  
  
  We tested nonsynonymous, splice, and stop variants derived from the Illumina HumanExome array for association with COPD in five study populations enriched for COPD. We evaluated single variants with a minor allele frequency greater than 0.5% using logistic regression. Results were combined using a fixed effects meta-analysis. We replicated novel single-variant associations in three additional COPD cohorts.
  
  
  
  We included 6,004 control subjects and 6,161 COPD cases across five cohorts for analysis. Our top result was rs16969968 (P = 1.7 × 10(-14)) in CHRNA5, a locus previously associated with COPD susceptibility and nicotine dependence. Additional top results were found in AGER, MMP3, and SERPINA1. A nonsynonymous variant, rs181206, in IL27 (P = 4.7 × 10(-6)) was just below the level of exome-wide significance but attained exome-wide significance (P = 5.7 × 10(-8)) when combined with results from other cohorts. Gene expression datasets revealed an association of rs181206 and the surrounding locus with expression of multiple genes; several were differentially expressed in COPD lung tissue, including TUFM.
  
  
  
  In an exome array analysis of COPD, we identified nonsynonymous variants at previously described loci and a novel exome-wide significant variant in IL27. This variant is at a locus previously described in genome-wide associations with diabetes, inflammatory bowel disease, and obesity and appears to affect genes potentially related to COPD pathogenesis.
authors.affiliation: 1 Channing Division of Network Medicine.|2 Division of Pulmonary and Critical Care Medicine.
authors.forename: Brian D
authors.identifier: 0000-0001-9564-0745
authors.initials: BD
authors.lastname: Hobbs
authors.affiliation: 1 Channing Division of Network Medicine.
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Parker
authors.affiliation: 3 Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, Massachusetts.
authors.forename: Han
authors.initials: H
authors.lastname: Chen
authors.affiliation: 1 Channing Division of Network Medicine.
authors.forename: Taotao
authors.initials: T
authors.lastname: Lao
authors.affiliation: 1 Channing Division of Network Medicine.|2 Division of Pulmonary and Critical Care Medicine.
authors.forename: Megan
authors.initials: M
authors.lastname: Hardin
authors.affiliation: 1 Channing Division of Network Medicine.
authors.forename: Dandi
authors.initials: D
authors.lastname: Qiao
authors.affiliation: 4 National Tuberculosis and Lung Disease Research Institute, Warsaw, Poland.
authors.forename: Iwona
authors.initials: I
authors.lastname: Hawrylkiewicz
authors.affiliation: 4 National Tuberculosis and Lung Disease Research Institute, Warsaw, Poland.
authors.forename: Pawel
authors.initials: P
authors.lastname: Sliwinski
authors.affiliation: 5 Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Jae-Joon
authors.initials: JJ
authors.lastname: Yim
authors.affiliation: 6 Kangwon National University, Chuncheon, South Korea.
authors.forename: Woo Jin
authors.initials: WJ
authors.lastname: Kim
authors.affiliation: 7 Seoul National University Boramae Medical Center, Seoul, South Korea.
authors.forename: Deog Kyeom
authors.initials: DK
authors.lastname: Kim
authors.affiliation: 1 Channing Division of Network Medicine.|8 Division of General Medicine and Primary Care, and.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Castaldi
authors.affiliation: 1 Channing Division of Network Medicine.|2 Division of Pulmonary and Critical Care Medicine.
authors.forename: Craig P
authors.initials: CP
authors.lastname: Hersh
authors.affiliation: 1 Channing Division of Network Medicine.
authors.forename: Jarrett
authors.initials: J
authors.lastname: Morrow
authors.affiliation: 2 Division of Pulmonary and Critical Care Medicine.
authors.forename: Bartolome R
authors.initials: BR
authors.lastname: Celli
authors.affiliation: 9 Department of Critical Care Medicine and Pulmonary Disease, Baystate Medical Center, Springfield, Massachusetts.
authors.forename: Victor M
authors.initials: VM
authors.lastname: Pinto-Plata
authors.affiliation: 10 Division of Pulmonary and Critical Care Medicine and.
authors.forename: Gerald J
authors.initials: GJ
authors.lastname: Criner
authors.affiliation: 11 Department of Thoracic Medicine and Surgery, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Marchetti
authors.affiliation: 12 Division of Thoracic Surgery, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Raphael
authors.initials: R
authors.lastname: Bueno
authors.affiliation: 13 Thorax Institute, Hospital Clinic, IDIBAPS, University of Barcelona, CIBERES, Barcelona, Spain.
authors.forename: Alvar
authors.initials: A
authors.lastname: Agustí
authors.affiliation: 14 National Jewish Health, Denver, Colorado.
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Make
authors.affiliation: 14 National Jewish Health, Denver, Colorado.
authors.forename: James D
authors.initials: JD
authors.lastname: Crapo
authors.affiliation: 15 University of Liverpool, Liverpool, United Kingdom.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Calverley
authors.affiliation: 16 Mondo Medico di I.F.I.M. srl, Multidisciplinary and Rehabilitation Outpatient Clinic, Borgomanero (NO), Italy.
authors.forename: Claudio F
authors.initials: CF
authors.lastname: Donner
authors.affiliation: 17 University College London, London, United Kingdom.
authors.forename: David A
authors.initials: DA
authors.lastname: Lomas
authors.affiliation: 18 University Hospital Maastricht, Maastricht, the Netherlands.
authors.forename: Emiel F M
authors.initials: EF
authors.lastname: Wouters
authors.affiliation: 19 University of Manchester, Manchester, United Kingdom.
authors.forename: Jorgen
authors.initials: J
authors.lastname: Vestbo
authors.affiliation: 20 University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Paré
authors.affiliation: 20 University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Levy
authors.affiliation: 21 Pulmonary and Critical Care Medicine, University of Nebraska Medical Center, Omaha, Nebraska.|22 Clinical Discovery Unit, AstraZeneca, Cambridge, United Kingdom; and.
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Rennard
authors.affiliation: 1 Channing Division of Network Medicine.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Zhou
authors.affiliation: 5 Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Nan M
authors.initials: NM
authors.lastname: Laird
authors.affiliation: 3 Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, Massachusetts.
authors.forename: Xihong
authors.initials: X
authors.lastname: Lin
authors.affiliation: 23 Department of Epidemiology, Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, Maryland.
authors.forename: Terri H
authors.initials: TH
authors.lastname: Beaty
authors.affiliation: 1 Channing Division of Network Medicine.|2 Division of Pulmonary and Critical Care Medicine.
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Silverman
authors.affiliation: 1 Channing Division of Network Medicine.|2 Division of Pulmonary and Critical Care Medicine.
authors.forename: Michael H
authors.identifier: 0000-0002-4907-1657
authors.initials: MH
authors.lastname: Cho
mesh_terms: D000328:Adult; D000368:Aged; D059472:Exome / Q000235:genetics*; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D064094:Interleukin-27 / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics*
chemical_list: D064094:Interleukin-27
keywords: IL-27; chronic obstructive pulmonary disease; exome; genetics