title: Genome-wide association analysis of blood biomarkers in chronic obstructive pulmonary disease.
abstract: BACKGROUND
  A genome-wide association study (GWAS) for circulating chronic obstructive pulmonary disease (COPD) biomarkers could identify genetic determinants of biomarker levels and COPD susceptibility.
  
  
  OBJECTIVE
  To identify genetic variants of circulating protein biomarkers and novel genetic determinants of COPD.
  
  
  METHODS
  GWAS was performed for two pneumoproteins, Clara cell secretory protein (CC16) and surfactant protein D (SP-D), and five systemic inflammatory markers (C-reactive protein, fibrinogen, IL-6, IL-8, and tumor necrosis factor-α) in 1,951 subjects with COPD. For genome-wide significant single nucleotide polymorphisms (SNPs) (P < 1 × 10(-8)), association with COPD susceptibility was tested in 2,939 cases with COPD and 1,380 smoking control subjects. The association of candidate SNPs with mRNA expression in induced sputum was also elucidated.
  
  
  RESULTS
  Genome-wide significant susceptibility loci affecting biomarker levels were found only for the two pneumoproteins. Two discrete loci affecting CC16, one region near the CC16 coding gene (SCGB1A1) on chromosome 11 and another locus approximately 25 Mb away from SCGB1A1, were identified, whereas multiple SNPs on chromosomes 6 and 16, in addition to SNPs near SFTPD, had genome-wide significant associations with SP-D levels. Several SNPs affecting circulating CC16 levels were significantly associated with sputum mRNA expression of SCGB1A1 (P = 0.009-0.03). Several SNPs highly associated with CC16 or SP-D levels were nominally associated with COPD in a collaborative GWAS (P = 0.001-0.049), although these COPD associations were not replicated in two additional cohorts.
  
  
  CONCLUSIONS
  Distant genetic loci and biomarker-coding genes affect circulating levels of COPD-related pneumoproteins. A subset of these protein quantitative trait loci may influence their gene expression in the lung and/or COPD susceptibility. Clinical trial registered with www.clinicaltrials.gov (NCT 00292552).
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Deog Kyeom
authors.initials: DK
authors.lastname: Kim
authors.forename: Michael H
authors.initials: MH
authors.lastname: Cho
authors.forename: Craig P
authors.initials: CP
authors.lastname: Hersh
authors.forename: David A
authors.initials: DA
authors.lastname: Lomas
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Miller
authors.forename: Xiangyang
authors.initials: X
authors.lastname: Kong
authors.forename: Per
authors.initials: P
authors.lastname: Bakke
authors.forename: Amund
authors.initials: A
authors.lastname: Gulsvik
authors.forename: Alvar
authors.initials: A
authors.lastname: Agustí
authors.forename: Emiel
authors.initials: E
authors.lastname: Wouters
authors.forename: Bartolome
authors.initials: B
authors.lastname: Celli
authors.forename: Harvey
authors.initials: H
authors.lastname: Coxson
authors.forename: Jørgen
authors.initials: J
authors.lastname: Vestbo
authors.forename: William
authors.initials: W
authors.lastname: MacNee
authors.forename: Julie C
authors.initials: JC
authors.lastname: Yates
authors.forename: Stephen
authors.initials: S
authors.lastname: Rennard
authors.forename: Augusto
authors.initials: A
authors.lastname: Litonjua
authors.forename: Weiliang
authors.initials: W
authors.lastname: Qiu
authors.forename: Terri H
authors.initials: TH
authors.lastname: Beaty
authors.forename: James D
authors.initials: JD
authors.lastname: Crapo
authors.forename: John H
authors.initials: JH
authors.lastname: Riley
authors.forename: Ruth
authors.initials: R
authors.lastname: Tal-Singer
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Silverman
mesh_terms: D002097:C-Reactive Protein / Q000235:genetics; D005260:Female; D005340:Fibrinogen / Q000235:genetics; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D015850:Interleukin-6 / Q000097:blood / Q000235:genetics; D016209:Interleukin-8 / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D029424:Pulmonary Disease, Chronic Obstructive / Q000097:blood / Q000235:genetics*; D037663:Pulmonary Surfactant-Associated Protein D / Q000097:blood / Q000235:genetics*; D040641:Quantitative Trait Loci; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000235:genetics; D014598:Uteroglobin / Q000097:blood / Q000235:genetics*
chemical_list: D005819:Genetic Markers; D015850:Interleukin-6; D016209:Interleukin-8; D037663:Pulmonary Surfactant-Associated Protein D; D014409:Tumor Necrosis Factor-alpha; D005340:Fibrinogen; D002097:C-Reactive Protein; D014598:Uteroglobin