title: MMP12, lung function, and COPD in high-risk populations.
abstract: BACKGROUND
  Genetic variants influencing lung function in children and adults may ultimately lead to the development of chronic obstructive pulmonary disease (COPD), particularly in high-risk groups.
  
  
  METHODS
  We tested for an association between single-nucleotide polymorphisms (SNPs) in the gene encoding matrix metalloproteinase 12 (MMP12) and a measure of lung function (prebronchodilator forced expiratory volume in 1 second [FEV(1)]) in more than 8300 subjects in seven cohorts that included children and adults. Within the Normative Aging Study (NAS), a cohort of initially healthy adult men, we tested for an association between SNPs that were associated with FEV(1) and the time to the onset of COPD. We then examined the relationship between MMP12 SNPs and COPD in two cohorts of adults with COPD or at risk for COPD.
  
  
  RESULTS
  The minor allele (G) of a functional variant in the promoter region of MMP12 (rs2276109 [-82A-->G]) was positively associated with FEV(1) in a combined analysis of children with asthma and adult former and current smokers in all cohorts (P=2x10(-6)). This allele was also associated with a reduced risk of the onset of COPD in the NAS cohort (hazard ratio, 0.65; 95% confidence interval [CI], 0.46 to 0.92; P=0.02) and with a reduced risk of COPD in a cohort of smokers (odds ratio, 0.63; 95% CI, 0.45 to 0.88; P=0.005) and among participants in a family-based study of early-onset COPD (P=0.006).
  
  
  CONCLUSIONS
  The minor allele of a SNP in MMP12 (rs2276109) is associated with a positive effect on lung function in children with asthma and in adults who smoke. This allele is also associated with a reduced risk of COPD in adult smokers.
authors.affiliation: Channing Laboratory and Center for Genomic Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Gary M
authors.initials: GM
authors.lastname: Hunninghake
authors.forename: Michael H
authors.initials: MH
authors.lastname: Cho
authors.forename: Yohannes
authors.initials: Y
authors.lastname: Tesfaigzi
authors.forename: Manuel E
authors.initials: ME
authors.lastname: Soto-Quiros
authors.forename: Lydiana
authors.initials: L
authors.lastname: Avila
authors.forename: Jessica
authors.initials: J
authors.lastname: Lasky-Su
authors.forename: Chris
authors.initials: C
authors.lastname: Stidley
authors.forename: Erik
authors.initials: E
authors.lastname: Melén
authors.forename: Cilla
authors.initials: C
authors.lastname: Söderhäll
authors.forename: Jenny
authors.initials: J
authors.lastname: Hallberg
authors.forename: Inger
authors.initials: I
authors.lastname: Kull
authors.forename: Juha
authors.initials: J
authors.lastname: Kere
authors.forename: Magnus
authors.initials: M
authors.lastname: Svartengren
authors.forename: Göran
authors.initials: G
authors.lastname: Pershagen
authors.forename: Magnus
authors.initials: M
authors.lastname: Wickman
authors.forename: Christoph
authors.initials: C
authors.lastname: Lange
authors.forename: Dawn L
authors.initials: DL
authors.lastname: Demeo
authors.forename: Craig P
authors.initials: CP
authors.lastname: Hersh
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Klanderman
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Raby
authors.forename: David
authors.initials: D
authors.lastname: Sparrow
authors.forename: Steven D
authors.initials: SD
authors.lastname: Shapiro
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Silverman
authors.forename: Augusto A
authors.initials: AA
authors.lastname: Litonjua
authors.forename: Scott T
authors.initials: ST
authors.lastname: Weiss
authors.forename: Juan C
authors.initials: JC
authors.lastname: Celedón
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D001249:Asthma / Q000235:genetics* / Q000503:physiopathology; D002648:Child; D015331:Cohort Studies; D005260:Female; D005541:Forced Expiratory Volume / Q000235:genetics*; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D053508:Matrix Metalloproteinase 12 / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics* / Q000503:physiopathology; D012907:Smoking / Q000235:genetics / Q000503:physiopathology*
chemical_list: D005819:Genetic Markers; D053508:Matrix Metalloproteinase 12