title: SOX5 is a candidate gene for chronic obstructive pulmonary disease susceptibility and is necessary for lung development.
abstract: BACKGROUND
  Chromosome 12p has been linked to chronic obstructive pulmonary disease (COPD) in the Boston Early-Onset COPD Study (BEOCOPD), but a susceptibility gene in that region has not been identified.
  
  
  OBJECTIVE
  We used high-density single-nucleotide polymorphism (SNP) mapping to implicate a COPD susceptibility gene and an animal model to determine the potential role of SOX5 in lung development and COPD.
  
  
  METHODS
  On chromosome 12p, we genotyped 1,387 SNPs in 386 COPD cases from the National Emphysema Treatment Trial and 424 control smokers from the Normative Aging Study. SNPs with significant associations were then tested in the BEOCOPD study and the International COPD Genetics Network. Based on the human results, we assessed histology and gene expression in the lungs of Sox5(-/-) mice.
  
  
  RESULTS
  In the case-control analysis, 27 SNPs were significant at P ≤ 0.01. The most significant SNP in the BEOCOPD replication was rs11046966 (National Emphysema Treatment Trial-Normative Aging Study P = 6.0 × 10(-4), BEOCOPD P = 1.5 × 10(-5), combined P = 1.7 × 10(-7)), located 3' to the gene SOX5. Association with rs11046966 was not replicated in the International COPD Genetics Network. Sox5(-/-) mice showed abnormal lung development, with a delay in maturation before the saccular stage, as early as E16.5. Lung pathology in Sox5(-/-) lungs was associated with a decrease in fibronectin expression, an extracellular matrix component critical for branching morphogenesis.
  
  
  CONCLUSIONS
  Genetic variation in the transcription factor SOX5 is associated with COPD susceptibility. A mouse model suggests that the effect may be due, in part, to its effects on lung development and/or repair processes.
authors.affiliation: Channing Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA. craig.hersh@channing.harvard.edu
authors.forename: Craig P
authors.initials: CP
authors.lastname: Hersh
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Silverman
authors.forename: Jody
authors.initials: J
authors.lastname: Gascon
authors.forename: Soumyaroop
authors.initials: S
authors.lastname: Bhattacharya
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Klanderman
authors.forename: Augusto A
authors.initials: AA
authors.lastname: Litonjua
authors.forename: Véronique
authors.initials: V
authors.lastname: Lefebvre
authors.forename: David
authors.initials: D
authors.lastname: Sparrow
authors.forename: John J
authors.initials: JJ
authors.lastname: Reilly
authors.forename: Wayne H
authors.initials: WH
authors.lastname: Anderson
authors.forename: David A
authors.initials: DA
authors.lastname: Lomas
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Mariani
mesh_terms: D000368:Aged; D000818:Animals; D016022:Case-Control Studies; D004195:Disease Models, Animal; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics*; D055755:SOXD Transcription Factors / Q000235:genetics*
chemical_list: C490301:SOX5 protein, human; D055755:SOXD Transcription Factors; C089186:Sox5 protein, mouse