title: Phenotypic and genetic heterogeneity among subjects with mild airflow obstruction in COPDGene.
abstract: BACKGROUND
  Chronic obstructive pulmonary disease (COPD) is characterized by marked phenotypic heterogeneity. Most previous studies have focused on COPD subjects with FEV1 < 80% predicted. We investigated the clinical and genetic heterogeneity in subjects with mild airflow limitation in spirometry grade 1 defined by the Global Initiative for chronic Obstructive Lung Disease (GOLD 1).
  
  
  METHODS
  Data from current and former smokers participating in the COPDGene Study (NCT00608764) were analyzed. K-means clustering was performed to explore subtypes within 794 GOLD 1 subjects. For all subjects with GOLD 1 and with each cluster, a genome-wide association study and candidate gene testing were performed using smokers with normal lung function as a control group. Combinations of COPD genome-wide significant single nucleotide polymorphisms (SNPs) were tested for association with FEV1 (% predicted) in GOLD 1 and in a combined group of GOLD 1 and smoking control subjects.
  
  
  RESULTS
  K-means clustering of GOLD 1 subjects identified putative "near-normal", "airway-predominant", "emphysema-predominant" and "lowest FEV1% predicted" subtypes. In non-Hispanic whites, the only SNP nominally associated with GOLD 1 status relative to smoking controls was rs7671167 (FAM13A) in logistic regression models with adjustment for age, sex, pack-years of smoking, and genetic ancestry. The emphysema-predominant GOLD 1 cluster was nominally associated with rs7671167 (FAM13A) and rs161976 (BICD1). The lowest FEV1% predicted cluster was nominally associated with rs1980057 (HHIP) and rs1051730 (CHRNA3). Combinations of COPD genome-wide significant SNPs were associated with FEV1 (% predicted) in a combined group of GOLD 1 and smoking control subjects.
  
  
  CONCLUSIONS
  Our results indicate that GOLD 1 subjects show substantial clinical heterogeneity, which is at least partially related to genetic heterogeneity.
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA; Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, School of Medicine, Ewha Womans University, Seoul, Republic of Korea. Electronic address: jinhwalee@ewha.ac.kr.
authors.forename: Jin Hwa
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Cho
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Merry-Lynn N
authors.initials: ML
authors.lastname: McDonald
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Craig P
authors.initials: CP
authors.lastname: Hersh
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Castaldi
authors.affiliation: National Jewish Health and University of Colorado Denver, Denver, CO, USA.
authors.forename: James D
authors.initials: JD
authors.lastname: Crapo
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Emily S
authors.initials: ES
authors.lastname: Wan
authors.affiliation: Department of Electrical and Computer Engineering, Northeastern University, Boston, MA, USA.
authors.forename: Jennifer G
authors.initials: JG
authors.lastname: Dy
authors.affiliation: Department of Electrical and Computer Engineering, Northeastern University, Boston, MA, USA.
authors.forename: Yale
authors.initials: Y
authors.lastname: Chang
authors.affiliation: National Jewish Health and University of Colorado Denver, Denver, CO, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Regan
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Megan
authors.initials: M
authors.lastname: Hardin
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Dawn L
authors.initials: DL
authors.lastname: DeMeo
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA. Electronic address: ed.silverman@channing.harvard.edu.
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Silverman
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D005541:Forced Expiratory Volume / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D029424:Pulmonary Disease, Chronic Obstructive / Q000150:complications / Q000235:genetics*; D012307:Risk Factors; D012907:Smoking / Q000453:epidemiology*; D013147:Spirometry
keywords: Chronic obstructive; Cluster analysis; Genetic association; Population characteristics; Pulmonary disease