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: Gary M Hunninghake, Michael H Cho, Yohannes Tesfaigzi, Manuel E Soto-Quiros, Lydiana Avila, Jessica Lasky-Su, Chris Stidley, Erik Melén, Cilla Söderhäll, Jenny Hallberg, Inger Kull, Juha Kere, Magnus Svartengren, Göran Pershagen, Magnus Wickman, Christoph Lange, Dawn L Demeo, Craig P Hersh, Barbara J Klanderman, Benjamin A Raby, David Sparrow, Steven D Shapiro, Edwin K Silverman, Augusto A Litonjua, Scott T Weiss, Juan C Celedón
• Journal: The New England journal of medicine (N Engl J Med) Vol. 361 Issue 27 Pg. 2599-608 (Dec 31 2009) ISSN: 1533-4406 [Electronic] United States
• PMID: 20018959 (Publication Type: Clinical Trial, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)
• Copyright: 2009 Massachusetts Medical Society

Chemical References

• Genetic Markers
• Matrix Metalloproteinase 12

Topics

• Adult
• Aged
• Alleles
• Asthma (genetics, physiopathology)
• Child
• Cohort Studies
• Female
• Forced Expiratory Volume (genetics)
• Genetic Markers
• Genetic Predisposition to Disease
• Humans
• Male
• Matrix Metalloproteinase 12 (genetics)
• Middle Aged
• Polymorphism, Single Nucleotide
• Promoter Regions, Genetic
• Pulmonary Disease, Chronic Obstructive (genetics, physiopathology)
• Smoking (genetics, physiopathology)