MMP12, lung function, and COPD in high-risk populations.
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.
Hunninghake
Gary M
GM
Channing Laboratory and Center for Genomic Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
Cho
Michael H
MH
Tesfaigzi
Yohannes
Y
Soto-Quiros
Manuel E
ME
Avila
Lydiana
L
Lasky-Su
Jessica
J
Stidley
Chris
C
Melén
Erik
E
Söderhäll
Cilla
C
Hallberg
Jenny
J
Kull
Inger
I
Kere
Juha
J
Svartengren
Magnus
M
Pershagen
Göran
G
Wickman
Magnus
M
Lange
Christoph
C
Demeo
Dawn L
DL
Hersh
Craig P
CP
Klanderman
Barbara J
BJ
Raby
Benjamin A
BA
Sparrow
David
D
Shapiro
Steven D
SD
Silverman
Edwin K
EK
Litonjua
Augusto A
AA
Weiss
Scott T
ST
Celedón
Juan C
JC
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*
D005819:Genetic Markers; D053508:Matrix Metalloproteinase 12