ASSOCIATION OF THE MMP7 181A>G PROMOTER POLYMORPHISM WITH EARLY ONSET OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE
Tacheva T, Dimov D, Anastasov A, Zhelyazkova Y, Kurzawski M, Gulubova M, Drozdzik M, Vlaykova T
*Corresponding Author: Assistant Professor Tanya Tacheva, Department of Chemistry and Biochemistry, Medical Faculty, Trakia University, 11 Armeiska Str., Stara Zagora, Bulgaria. Tel: +359878334176. E-mail: tanya.ta4eva@abv.bg
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DISCUSSION

A common feature of COPD is the chronic in inflammation in the airways and the development of extensive tissue remodeling during the course of the disease process [25]. The matrix metalloproteinases are a family of zinccontaining enzymes with proteolytic activity against a wide range of extracellular proteins [10]. Under normal physiological conditions, the activities of MMPs are precisely regulated at the level of transcription, activation of the precursor zymogens and inhibition by endogenous inhibitors [26]. Due to their activity, MMPs participate in many physiological and pathological processes in the body such as development, involution, inflammation, tumor growth, and repair [27,28]. Matrix metalloproteinases play an important role in the turnover of almost all extracellular matrix molecules and thus, participate in the pathogenesis of COPD [22,29]. An A>G substitution in the promoter of the MMP7 gene has been shown to affect the promoter activity, as the G allele determines higher basal transcriptional activity in vitro in human monocyte/macrophage cell line U937 [15]. In this study, we did not find any significant difference in geno-type and allele distribution when we studied the entire COPD patient and control groups. However, the carries of the G allele (AG and GG genotypes) appeared to develop COPD significantly early compared to those with the AA genotype. Moreover, the G allele determines about a 3-fold higher risk for COPD before the age of 60 years. So far, only one study has been found in the literature exploring the role of MMP7 181A>G (rs11568818) in COPD. In the study of Mogulkoc et al. [23], the MMP-7 AA genotype has been found to be associated with an increased risk of COPD. On the contrary, in our study we found no association of the A allele with COPD, which might be explained by the difference in Bulgarian and Turkish populations (e.g., age, smoking, diagnosis, etc.). It has been shown that the same variant is not a risk factor for IPF, but influences the plasma level of MMP-7 in patients, as carriers of the AA genotype had higher concentrations than carriers of other genotypes [21]. MMP7 181A>G has shown no association with the risk for lung cancer [18]. However, an increased risk for devel-opment of bronchiolitis obliterans syndrome has been reported for carriers of the AA genotype in patients after lung transplantation [20]. In COPD patients, the serum levels of MMP-7, as well as of some other MMPs, MMP-1 and MMP-9, has been found to be significantly higher in exposed to biomass and tobacco smoke when compared with unexposed healthy controls. Moreover, the levels of those enzymes have been found in negative correlation with the lung function indexes (FEV1 %pr) [22]. Matrilysin 1 has also been reported to associate with moderate panlobular emphysema as well as with severe and moderate centrilobular emphysema [30]. Matrilysin 1 efficiently cleaves the basement membrane protein entac-tin, which bridges laminin and collagen type IV, and sug-gested a potentially important role for MMP-7 in the dis-ruption of basement membranes by inflammatory cells [31]. Matrilysin 1 is produced by the epithelium of several uninjured, uninflamed tissues, such as lung, liver and breast. Except in intact tissues, matrilysin is expressed in migrating epithelium in injured airways [5]. It has been shown that MMP-7 mediates shedding of E-cadherin from alveolar epithelium during progression of bleomycin-induced pulmonary fibrosis [7]. In specimens of emphysema, strong immunoreactive signal for matrilysin protein has been detected in epithelial cells lining damaged alveoli, especially in cells bordering denuded epithelium [6]. The higher promoter activity of the G allele may contribute to ongoing epithelial activation by mediating persistent shedding of the E-cadherin ectodomain, altering cell-cell interactions. By cleaving the Fas ligand, matrilysin can regulate apoptosis and it may promote local coagulation by cleaving tissue factor pathway inhibitor [31]. Altogether, these data suggest that the carriers of the G allele may lead to disruption of ECM and cell-cell interactions, impairment of the process of tissue repair or fibrosis, and thus, to early development of COPD. In conclusion, the results of our study suggest that MMP7 181A>G (rs11568818) promoter polymorphism might affect the risk for COPD, as the carriers of the G allele (AG and GG genotypes) could be considered as predisposing factors for early onset of COPD. This effect could be attributed to the increased production of the enzyme resulting in enhanced airway wall protein degra-dation and injury due to its direct ability for ECM degra-dation. In this respect, the latter suggestion is warranted to be proven by analyzing the possible association of geno-types with serum MMP-7 levels in patients with COPD.



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