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 [FEV1]) 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 FEV1 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 FEV1 in a combined analysis of children with asthma and adult former and current smokers in all cohorts (P=2×10−6). 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.

Distinct Macrophage Subpopulations Characterize Acute Infection and Chronic Inflammatory Lung Disease

“…Downstream MMP-12 upregulation is a common feature of all COPD animal models (7,17,41,42), implicating its role as a major COPD effector. Clinically, a minor SNP allele in MMP-12 that reduces its protease activity is protective against COPD onset in smokers (43). Because MMP-12 expression is also transiently upregulated in Mac-1 pos AMFs after LPS treatment, we postulate that deregulation of SHIP-1 signaling in a susceptible genetic background creates spontaneous AMF heterogeneity wherein chronic AMF Mac-1, and hence MMP-12, expression may be responsible for the lung disease pathogenesis.…”

NMR and Bioinformatics Discovery of Exosites That Tune Metalloelastase Specificity for Solubilized Elastin and Collagen Triple Helices

“…Progress curves for fEln-100, fEln-20, ␣1(V) 436 -447 fTHP, and DQ-collagen I and IV substrates were fitted through the plateau of the first kinetic phase, corresponding to 1-3 h of the progress curves, prior to the subsequent kinetic phase. 4 A lag of 10 -15 min was observed prior to fluorescence increase of the fEln-100 substrate. Example fits of progress curves are illustrated for fEln-100 and fEln-20 and the DQ-collagens in supplemental Figs.…”

“…Collagens are ubiquitous and comprise ϳ25% of the protein mass of the body. Damage to fibrils of the extracellular matrix by proteases such as MMP-12 contributes to the inflammation and chronic disease states of chronic obstructive pulmonary disease (2-4), atherosclerosis (5-6), abdominal aortic aneurysm (7), multiple sclerosis (8), ulcerative colitis (9), asthma (4), and rheumatoid arthritis (10). The progression of chronic obstructive pulmonary disease/emphysema and (abdominal aortic aneurysm) in smokers depends in large part on MMP-12 expression (11) and its degradation of elastin (7,12).…”

Transient early wheeze and lung function in early childhood associated with chronic obstructive pulmonary disease genes

“…[20][21][22][23][24][25][26][27][28][29][30] Genotyping methods and patterns of linkage disequilibrium (Table E1) within loci are described in the Methods section in this article's Online Repository. We have selected proxy-SNPs for unavailable SNPs in ALSPAC by using HapMap release 22 31 : rs975278 in SERPINE2 for rs729631 (r 2 5 1) and rs6734100 (r 2 5 0.82), rs17368659 in MMP12 for rs2276109 (r 2 5 1), and rs8109167 in TGFB1 for rs6957 (r 2 5 1).…”