title: Genome-Wide Association Study Identification of Novel Loci Associated with Airway Responsiveness in Chronic Obstructive Pulmonary Disease.
abstract: Increased airway responsiveness is linked to lung function decline and mortality in subjects with chronic obstructive pulmonary disease (COPD); however, the genetic contribution to airway responsiveness remains largely unknown. A genome-wide association study (GWAS) was performed using the Illumina (San Diego, CA) Human660W-Quad BeadChip on European Americans with COPD from the Lung Health Study. Linear regression models with correlated meta-analyses, including data from baseline (n = 2,814) and Year 5 (n = 2,657), were used to test for common genetic variants associated with airway responsiveness. Genotypic imputation was performed using reference 1000 Genomes Project data. Expression quantitative trait loci (eQTL) analyses in lung tissues were assessed for the top 10 markers identified, and immunohistochemistry assays assessed protein staining for SGCD and MYH15. Four genes were identified within the top 10 associations with airway responsiveness. Markers on chromosome 9p21.2 flanked by LINGO2 met a predetermined threshold of genome-wide significance (P < 9.57 × 10(-8)). Markers on chromosomes 3q13.1 (flanked by MYH15), 5q33 (SGCD), and 6q21 (PDSS2) yielded suggestive evidence of association (9.57 × 10(-8) < P ≤ 4.6 × 10(-6)). Gene expression studies in lung tissue showed single nucleotide polymorphisms on chromosomes 5 and 3 to act as eQTL for SGCD (P = 2.57 × 10(-9)) and MYH15 (P = 1.62 × 10(-6)), respectively. Immunohistochemistry confirmed localization of SGCD protein to airway smooth muscle and vessels and MYH15 to airway epithelium, vascular endothelium, and inflammatory cells. We identified novel loci associated with airway responsiveness in a GWAS among smokers with COPD. Risk alleles on chromosomes 5 and 3 acted as eQTLs for SGCD and MYH15 messenger RNA, and these proteins were expressed in lung cells relevant to the development of airway responsiveness.
authors.affiliation: 1 Department of Medicine, School of Medicine; and.|Departments of 2 Environmental Health Sciences.
authors.forename: Nadia N
authors.initials: NN
authors.lastname: Hansel
authors.affiliation: 3 Department of Pathology, Centre for Heart Lung Innovation, St. Paul's Hospital, Division of Respirology, University of British Columbia, Vancouver, British Columbia.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Paré
authors.affiliation: 1 Department of Medicine, School of Medicine; and.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Rafaels
authors.affiliation: 3 Department of Pathology, Centre for Heart Lung Innovation, St. Paul's Hospital, Division of Respirology, University of British Columbia, Vancouver, British Columbia.
authors.forename: Don D
authors.initials: DD
authors.lastname: Sin
authors.affiliation: 3 Department of Pathology, Centre for Heart Lung Innovation, St. Paul's Hospital, Division of Respirology, University of British Columbia, Vancouver, British Columbia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Sandford
authors.affiliation: 3 Department of Pathology, Centre for Heart Lung Innovation, St. Paul's Hospital, Division of Respirology, University of British Columbia, Vancouver, British Columbia.
authors.forename: Denise
authors.initials: D
authors.lastname: Daley
authors.affiliation: 1 Department of Medicine, School of Medicine; and.
authors.forename: Candelaria
authors.initials: C
authors.lastname: Vergara
authors.affiliation: 1 Department of Medicine, School of Medicine; and.
authors.forename: Lili
authors.initials: L
authors.lastname: Huang
authors.affiliation: 3 Department of Pathology, Centre for Heart Lung Innovation, St. Paul's Hospital, Division of Respirology, University of British Columbia, Vancouver, British Columbia.
authors.forename: W Mark
authors.initials: WM
authors.lastname: Elliott
authors.affiliation: 3 Department of Pathology, Centre for Heart Lung Innovation, St. Paul's Hospital, Division of Respirology, University of British Columbia, Vancouver, British Columbia.
authors.forename: Chris D
authors.initials: CD
authors.lastname: Pascoe
authors.affiliation: 3 Department of Pathology, Centre for Heart Lung Innovation, St. Paul's Hospital, Division of Respirology, University of British Columbia, Vancouver, British Columbia.
authors.forename: Bryna A
authors.initials: BA
authors.lastname: Arsenault
authors.affiliation: Departments of 4 Pulmonary Diseases and.|5 Groningen Research Institute for Asthma and COPD Research Institute, University Medical Center Groningen, Groningen; and.
authors.forename: Dirkje S
authors.initials: DS
authors.lastname: Postma
authors.affiliation: 6 Epidemiology, and.|5 Groningen Research Institute for Asthma and COPD Research Institute, University Medical Center Groningen, Groningen; and.
authors.forename: H Marike
authors.initials: HM
authors.lastname: Boezen
authors.affiliation: 7 Department of Molecular Medicine, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Laval University, Québec City, Québec, Canada.
authors.forename: Yohan
authors.initials: Y
authors.lastname: Bossé
authors.affiliation: Departments of 4 Pulmonary Diseases and.|5 Groningen Research Institute for Asthma and COPD Research Institute, University Medical Center Groningen, Groningen; and.
authors.forename: Maarten
authors.initials: M
authors.lastname: van den Berge
authors.affiliation: 8 Department of Pulmonology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Pieter S
authors.initials: PS
authors.lastname: Hiemstra
authors.affiliation: 9 Channing Division of Network Medicine, 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: 9 Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Augusto A
authors.initials: AA
authors.lastname: Litonjua
authors.affiliation: 10 VA Normative Aging Study and Boston University School of Medicine, Boston, Massachusetts.
authors.forename: David
authors.initials: D
authors.lastname: Sparrow
authors.affiliation: 11 Department of Human Genetics, University of Chicago, Chicago, Illinois.
authors.forename: Carole
authors.initials: C
authors.lastname: Ober
authors.affiliation: 1 Department of Medicine, School of Medicine; and.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Wise
authors.affiliation: 12 Division of Biostatistics, School of Public Health, University of Minnesota, St. Paul, Minnesota.
authors.forename: John
authors.initials: J
authors.lastname: Connett
authors.affiliation: 1 Department of Medicine, School of Medicine; and.
authors.forename: Enid R
authors.initials: ER
authors.lastname: Neptune
authors.affiliation: 13 Epidemiology, and.
authors.forename: Terri H
authors.initials: TH
authors.lastname: Beaty
authors.affiliation: 14 Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Ingo
authors.initials: I
authors.lastname: Ruczinski
authors.affiliation: 1 Department of Medicine, School of Medicine; and.
authors.forename: Rasika A
authors.initials: RA
authors.lastname: Mathias
authors.affiliation: 1 Department of Medicine, School of Medicine; and.|13 Epidemiology, and.
authors.forename: Kathleen C
authors.initials: KC
authors.lastname: Barnes
mesh_terms: D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D018995:Myosin Heavy Chains / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics* / Q000378:metabolism; D040641:Quantitative Trait Loci; D012306:Risk; D049031:Sarcoglycans / Q000235:genetics / Q000378:metabolism
chemical_list: C526570:SGCD protein, human; D049031:Sarcoglycans; D018995:Myosin Heavy Chains
keywords: COPD; airway reactivity; bronchial responsiveness; eQTL; δ-sarcoglycan