The role of matrix metalloproteinase polymorphisms in the rate of decline in lung function

Abstract

The matrix metalloproteinases (MMPs) comprise a family of at least 20 proteolytic enzymes that play an essential role in tissue remodeling. MMP1 (interstitial collagenase), MMP9 (gelatinase B) and MMP12 (macrophage elastase) are thought to be important in the development of emphysema. A number of naturally occurring polymorphisms of human MMP gene promoters have been identified and found to alter transcriptional activity. Additionally, we detected a novel polymorphism in the MMP12 coding region (Asn357Ser). The aim of this study was to investigate the role of MMP polymorphisms in the development of chronic obstructive lung disease. We determined the prevalence of these polymorphisms in 590 continuing smokers chosen from the National Heart Lung and Blood Institute, Lung Health Study for having the fastest (n = 284) and slowest (n = 306) 5 year rate of decline of lung function. Of the five polymorphisms, only G-1607GG was associated with a rate of decline in lung function. The -1607GG allele was associated with a fast rate of decline (P = 0.02) [corrected]. However, haplotypes consisting of alleles from the MMP1 G-1607GG and MMP12 Asn357Ser polymorphisms were associated with rate of decline of lung function (P = 0.0007). These data suggest that polymorphisms in the MMP1 and MMP12 genes, but not MMP9, are either causative factors in smoking-related lung injury or are in linkage disequilibrium with causative polymorphisms.

Polymorphisms in Matrix Metalloproteinase-1, -9 and -12 Genes and the Risk of Chronic Obstructive Pulmonary Disease in a Korean Population

“…Among the polymorphisms in the MMP-1, - 9 and - 12 genes, we focused on the MMP-1 –1607G→GG, MMP-9 –1562C→T and MMP-12 N357S polymorphisms because it has been suggested that they influence gene expression or function, and because it has been reported that they are associated with COPD [15,16,17,18,19,20]. The insertion of a G allele at position –1607 (–1607GG allele) in the promoter of the MMP-1 gene has been shown to create a binding site for the ETS-1 transcription factor, which results in enhanced gene expression [24].…”

“…Due to the important role that MMP play in the pathogenesis of COPD, several studies have investigated the association of polymorphisms in the MMP-1, -9 and -12 genes with COPD-related phenotypes; however, the results of these studies have been inconsistent [15,16,17,18,19,20]. Therefore, we investigated the association of polymorphisms in the MMP-1, -9 and - 12 genes with the risk of COPD in a Korean population.…”

“…Therefore, we investigated the association of polymorphisms in the MMP-1, -9 and - 12 genes with the risk of COPD in a Korean population. Specifically, in this study, we evaluated the MMP-1 –1607G→GG (rs1799750), MMP-9 –1562C→T (rs3918242) and MMP-12 N357S (rs652438A→G) polymorphisms, which had been found to be associated with COPD-related phenotypes in the previous studies [15,16,17,18,19,20]. …”

Glutathione S-transferase and Microsomal Epoxide Hydrolase Gene Polymorphisms and Risk of Chronic Obstructive Pulmonary Disease in Slovak Population

“…In addition, many studies were performed to search for potential associations between a given gene polymorphism and susceptibility to COPD (7,(30)(31)(32). Up to now, more than 25 different candidate genes have been investigated for their potential role in lung function impairment in smokers (7,(30)(31)(32).…”

“…The development and progression of COPD involves multiple genes, gene-gene, and gene-environment interactions (4). In general, although association studies have successfully identified various significant genetic associations to the reduction in lung function in smokers (7,9,(12)(13)(14)(15)21,22,31), the inconsistency and lack of replication has been a major flaw in these studies. In addition, in some studies the distribution of genotypes deviated from Hardy-Weinberg equilibrium (9,14,17).…”