ASSOCIATION OF THE MMP7 –181A>G PROMOTER
POLYMORPHISM WITH EARLY ONSET OF
CHRONIC OBSTRUCTIVE PULMONARY DISEASE
Tacheva T1,*, Dimov D2, Anastasov A1, Zhelyazkova Y2,
Kurzawski M3, Gulubova M4, Drozdzik M3, Vlaykova T1
*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
page: 59
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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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