Is MMP-7 Gene Polymorphism a Possible Risk Factor for Chronic Obstructive Pulmonary Disease in Turkish Patients

Abstract

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease that leads to fixed narrowing of small airways and alveolar wall destruction (emphysema). This study was performed to test the association between MMP-7 (rs155668818) and MMP-12 (rs56184183) polymorphisms in the MMP-7 gene and COPD risk and its severity in the Turkish population. MMP-7 and MMP-12 polymorphisms were genotyped in 85 patients with COPD and 73 healthy control subjects using real-time polymerase chain reaction analysis. There were significant differences in the distribution of MMP-7 genotypes but not in the frequencies of these alleles between COPD patients and controls (p=0.009, p=0.102, respectively). The MMP-7 AA genotype was found to be associated with an increased risk of COPD (p=0.004; odds ratio: 2.576; confidence interval: 1.297-5.119). The lowest values of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), FEV1/FVC in patients with GG homozygosity were determined and these values were statistically significant compared to the control subjects (p<0.001, p<0.001, p<0.001). When the present study groups were analyzed for MMP-12 polymorphism, it was found that all the subjects had wild-type genotype for this polymorphism. These findings have suggested that MMP-7 polymorphism might be associated with the risk and progression of COPD in the Turkish population.

Introduction

Chronıc obstructıve pulmonary dısease (COPD) is a major cause of morbidity and mortality worldwide (Haq et al., 2010). It is known that this disease is characterized by airflow limitation and irreparable damage in lung tissue. The airflow limitation is usually an abnormal inflammatory response of the lungs against harmful particles or gases (Shapiro, 1998). The prevention of chronic airflow, especially the small airways, and enzymatic degradation by proteases in lung parenchyma leads to loss of lung elasticity. The protease - antiprotease imbalance is thought to play a key role in COPD (Belvisi and Bottomley, 2003). There are many studies that are focused on the cathepsin family and the role of serine proteases, neutrophil elastases, and proteinases. According to the widely accepted hypothesis, the imbalance of proteolytic enzymes and their inhibitor's (alpha1-antitrypsin) deficiency at an early age renders smokers susceptible to emphysema (Shapiro, 1998; Belvisi and Bottomley, 2003). COPD can also be considered as a model of pulmonary inflammation. It involves multiple processes including abnormal inflammation, and an imbalance between the oxidant and antioxidant systems, impaired cellular and molecular alveolar maintenance programs, abnormal cell repair, and extracellular matrix (ECM) destruction (Yoshida and Tuder, 2007). The mechanism of the destruction of ECM, which involves the interaction of several enzymes and cross-linking fibrils, and matrix metalloproteinases (MMPs), play an important role in the cross-linking of elastin and collagen fibrils in the ECM. The MMPs are a family of zinc dependent proteolytic enzymes that have multiple physiological roles including remodeling and repair of the ECM, facilitation of cell migration, cleavage of cytokines, and activating defensins (Segura-Valdez et al., 2000; Babusyte et al., 2007). However, excess MMP activity may lead to tissue destruction. There is evidence that implicates excess MMP activity in causing matrix breakdown in COPD (Shapiro et al., 1991; Elkington and Friedland, 2006). The MMPs can be defined according to the substrate specificity of collagenases (MMP-1, -8, and -13), gelatinases (MMP-2 and -9), stromelysins (MMP-3, -10, -11), elastases (MMP-7 and -12), and membrane type MMPs (MT-MMPs, MMP-14, -15, -16, and -17) (Elkington and Friedland, 2006). MMP-7, which is produced by the alveolar macrophage, breaks down elastin and has a crucial role in the maintenance of innate immunity, proteolytically activating antibacterial peptides in the lung (Yu et al., 2004). Its role in COPD is still unclear (Demedts et al., 2005; Elkington and Friedland, 2006). It is known that there are several polymorphisms in the promoters of a number of MMP genes. They may affect the respective MMP protein expression and production (Ye, 2000; Yu et al., 2004).These functional polymorphisms may affect interindividual differences and susceptibility to COPD (Ye, 2000; Egeblad and Werb, 2002). It is known that there are several functional polymorphisms in the promoter region of the MMP-7 gene. Two of them are A-181G and C-153T. Several investigators reported the association betweenA-181G polymorphism and the risk of some cancer types such as colorectal and ovarian cancer (Sternlicht and Werb, 2001; Elander et al., 2006; Li et al., 2006). In this study, the MMP-7 and MMP-12 gene polymorphisms were investigated using the real-time polymerase chain reaction (RT-PCR) technique in the study groups. Using data obtained from our COPD patients, the aim of the present study was to analyze the relationships between MMP-7 and MMP-12 gene polymorphisms and disease susceptibility, clinic and respiratory implications in 85 Turkish COPD patients.

Materials and Methods

Study population

This study was conducted at Yedikule Chest Diseases and Thoracic Surgery Training and Research Hospital between June 2010 and July 2011 in our center. Thirty-five patients were admitted with a diagnosis of COPD, with an inclusion-eligible age of 40, and a history of cigarette smoking. A control group contained 73 healthy people with no COPD symptoms or physical findings. After selecting patients according to the appropriate selection criteria, patients were informed about the study and gave consent, then the required tests were performed and the resulting data were analyzed. Local Ethical Committee approval was obtained for this study from the Istanbul Medical Faculty.

Measurement and evaluation

All patients gave detailed histories and physical examinations were performed. The age, gender, smoking, height (m), and weight (kg) were recorded. Cigarette use was evaluated, by packets/year; pulmonary function tests and a diffusion capacity of carbon monoxide test were performed to choose the patients. For the degree of obstruction the Modified Medical Research Council dyspnea scale was used. Blood samples were taken after fasting for 12 hours. Blood samples were assessed for cell blood count (CBC), C-reactive protein (CRP), and lactate dehydrogenase (LDH) tests. A 10 cc blood sample was taken using an ethylenediaminetetraacetic acid tube from patients who signed the consent form and were brought to Istanbul University, Department of Molecular Medicine. In this study, we used RT-PCR to detect MMP-7 and MMP-12 gene polymorphisms in the Turkish COPD patients and controls. Genomic DNA isolation was performed on blood samples according to the kit protocol (Roche kit; Roche) with a spin column. The LightCycler 1.5 system was used to perform single nucleotide polymorphism (SNP) genotyping using hybridization probes consisting of 3′- fluorescein and a 5′-LightCycler Red labeled pairs of oligonucleotide probes (Kosaka et al., 2011).

Statistical analysis

All statistical analyses were carried out using SPSS version 13.0 for Windows (SPSS, Inc.). Numeric values were analyzed by Student's t-test. Differences in characteristics between COPD cases and controls were assessed with the chi-square test, and disparities in genotype and allele frequencies. Odds ratios (ORs) and 95% confidence intervals (95% CI) were calculated to estimate the risk for COPD. A p-value less than 0.05 was considered statistically significant.

Results

Table 1 shows the characteristics and laboratory parameters of our patients and controls. Blood samples were taken from patients and controls to determine the CBC, CRP, and LDH ranges. Statistically significant differences in CRP, WBC, and LDH ranges were found but none were found in the hemoglobin or hematocrit (%) values between patients and controls. Genotypes and allele frequencies for MMP-7 in COPD patients and controls are listed in Table 2. We found statistical differences in MMP-7 genotype frequencies between COPD patients and controls (p=0.009) but not in the allele frequencies (p=0.102). The frequency of the AA genotype was found higher in COPD patients than controls (p=0.004; OR: 2.576; 95% CI: 1.297-5.119). On the contrary, the patients who carry the AG genotype were lower than the controls (p=0.009; OR: 0.707; 95% CI: 0.544-0.920). Distrubutions of MMP-7 genotypes according to clinical features and respiratory parameters of COPD patients are summarized in Table 3. There was no association between MMP-7 genotypes or allele frequencies and the severity of the disease (p>0.05). The difference between the patients with the AG genotype who had higher LDH levels (186.93±7.59) from those with the same genotype in controls (163.04±3.86) was statistically significant (p=0.007). Among COPD patients, there was a statistically significant association between all the MMP-7 genotypes and some respiratory parameters such as forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), FEV1/FVC. The AA genotype frequency was higher in male patients (33.3%) than male controls (14.3%) (p=0.013; OR: 2.33; 95% CI: 1.139-4.779). The lowest values of FEV1, FVC, FEV1/FVC were observed in the GG homozygote patients and these values were statistically significant compared with controls (p<0.001, p<0.001, p<0.001). When the frequencies of the MMP-7 GG, AG, and AA genotypes of COPD patients were analyzed according to the stage distributions, there were no statistical differences between stages and MMP-7 genotypes.

Table 1.

Characterıstıcs and Laboratory Parameters of the Chronıc Obstructıve Pulmonary Dısease Patıents and the Controls

Characteristic	COPD patients (n=85)	Controls (n=73)	p-Value^a
Age (years, mean±SD)	60.38±0.94	57.9±1.11	>0.05
Male n (%)	75 (88.2)	56 (76.7)	>0.05
Female n (%)	10 (11.8)	17 (23.3)
CRP (mg/dL)	1.56±0.19	0.96±0.21	0.040
WBC (/10⁶ μL)	7623±221	6995±214	0.045
Hemoglobin (g/L)	14.18±0.12	14.08±0.16	>0.05
Hematocrite(%)	43.1±0.36	42.4±0.48	>0.05
LDH (U/L)	183.4±5.11	163.6±3.22	0.020
Smoking history (pack/years)	53.58±2.87	45.67±3.05	>0.05
FEV1	48.66±1.99	98.13±1.83	<0.001
FVC	70.84±2.42	96.7±1.74	<0.001
FEV1/FVC	55.99±1.23	93.35±2.8	<0.001

Data are reported as number (percentage in parentheses) or as mean±SD.

p-Values obtained by student t-test.

COPD, chronic obstructive pulmonary disease; CRP, C-reactive protein; WBC, white blood cell; LDH, lactate dehydrogenase; SD, standard deviation.

Table 2.

Genotypes and Allele Frequencıes for MMP-7 ın the Chronıc Obstructıve Pulmonary Dısease Patıents and the Controls

Genotype/alleles	COPD patients n(%)	Controls n(%)	p-Value^a
GG	16 (18.8)	13 (17.8)	0.009
AG	42 (49.4)	51 (69.9)
AA	27 (31.8)	9 (12.3)
G allele	74 (81.3)	77 (52.7)	0.102
A allele	17 (18.7)	69 (47.3)

p-Values obtained by chi-square test.

Table 3.

Dıstrıbutıon of MMP-7 Genotypes wıth Clınıcal Features and Respıratory Parameters ın the Chronıc Obstructıve Pulmonary Dısease Patıents

	Genotypes and p-Value
	GG	p-Value	AG	p-Value	AA	p-Value
Age
COPD patients	57.8±7.89	0.149	60.3±1.40	0.692	60.48±1.76	0.071
Controls	31.6±4.41		59.5±1.5		53.87±2.62
Men
COPD patients (%)	14 (18.7)	0.211	36 (48)	0.002	25 (33.3)	0.013
Controls (%)	6 (10.7)		42 (75)		8 (14.3)
Women
COPD patients n (%)	2 (20)	0.406	6 (60)	0.722	2 (20)	0.535
Controls n (%)	7 (41.2)		9 (52.9)		1 (5.9)
Smoking history (pack/years)
COPD patients	57.80±7.89	0.169	53.44±3.34	0.502	51.44±5.97	0.387
Controls	31.67±4.41		49.63±3.81		39.00±4.00
FEV1 (% predicted)
COPD patients	42.37±4.45	<0.001	49.97±2.82	<0.001	50.13±3.63	<0.001
Controls	92.67±6.49		98.14±1.93		100.83±5.8
FVC
COPD patients	64.71±5.36	<0.001	72.25±3.34	<0.001	72.04±4.6	0.007
Controls	96.67±1.76		95.45±1.79		101.5±6.21
FEV1/FVC (%)
COPD patients	52.52±2.62	<0.001	56.6±1.84	<0.001	56.95±2.055	0.000
Controls	85.67±11.68		94.86±3.33		91.67±6.13
Stage
1-2	11 (23.9)	0.212	19 (41.3)	0.130	16 (34.8)	0.569
3-4	5 (13.2)		22 (57.9)		11 (28.9)

Data are reported as number (percentage in parentheses) or as mean±standard error of the mean dependent on its distribution.

FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity.

Discussion

COPD is defined as a chronic inflammatory disease and many studies have focused on the nature of this inflammatory response. When the cell profile of alveoli and small airways are analyzed in COPD patients, it may be seen that all of the cell types including macrophages, T-lymphocytes, B-lymphocytes, and neutrophils are increased in number (Retamales et al., 2001). Many clinical studies have reported the presence of MMPs in the lung, with elevated levels in subjects with COPD (Finlay et al., 1997; Ohnishi et al., 1998). MMPs have a crucial role in the degradation of ECM and they are defined as biomarkers of tissue damage in several smoking related lung diseases (Barnes, 2004; Burke, 2005; Elkington and Friedland, 2006). Over 30 MMPs have been characterized until now and some of them are activated by smoking and/or oxidative stress (Lohi et al., 2001; Kinnula, 2005). Due to the important role that MMP plays in the pathogenesis of COPD, several studies have focused on the association of polymorphisms in the MMP-1, -7, -9, and -12 genes with COPD-related phenotypes. However, the data obtained from these studies have been inconsistent (Minematsu et al., 2001; Joos et al., 2002; Zhou et al., 2004; Hersh et al., 2005; Ito et al., 2005; Saitoh et al., 2006). Although these COPD phenotypes share some similar pathophysiology and likely share some similar genetic determinants, there may also be divergent underlying pathways involved in their development. It is possible that the effects of the MMP-9 SNP on the risk of COPD will differ according to the phenotype of COPD (Lee et al., 2010). It is known that MMP-7, is induced by hypoxia (Burke et al., 2003) and produced by alveolar macrophages, breaks down elastin, and has an important role in the maintenance of innate immunity proteolytically activating antibacterial peptides in the lung (Burke, 2005). The MMP-7, is expressed by macrophages and its expression is upregulated and also epithelial cells in lung tissue in the presence of chronic infection, which might support the hypothesis that MMP-7 contributes to pulmonary immunity (Dunsmore et al., 1998). It has been reported that MMP-12 expression in alveolar macrophages was higher compared with the healthy control group (Haq et al., 2010). In studies of each gene there is a weak correlation between one SNP polymorphism and risk of COPD, but multiple polymorphisms are deemed to be important in the pathogenesis of COPD as in other complex diseases (Barnes, 2004). However, most studies focused on polymorphisms in the promoter region of the MMP gene. These are MMP1-1607-/G (rs1799750), MMP-9-1562 C/T (rs3918242), and MMP-12-82A/G (rs2276109) (Burke, 2005). This is the first study to investigate a possible association between MMP-7 and MMP-12 gene polymorphisms and functional parameters and some biochemical markers, disease occurrence and severity of COPD disease. RT-PCR technique was used to analyze MMP-7; rs155668818 position -181 A/G, and MMP-12; rs56184183 position +11898 A/C in the study groups. Some previous studies have reported that polymorphisms in MMP-1 and MMP-12 genes, but not those encoding MMP-9, are related with the rate in decline of lung function in smokers (Joos et al., 2002). Recent studies have examined the relationship between COPD and MMP-12, MMP-1, MMP-3, MMP-9, and MMP-14. In Japanese populations, Minematsu et al. studied MMP-9 (1562C/T) polymorphism in Japanese populations and found that the frequency of the-1562T allele was higher in smokers with emphysema compared with those without emphysema. At the end of their study, they suggested that MMP-9 polymorphism acts as a genetic factor for the development of smoking-induced pulmonary emphysema. In addition, they did not find significant differences when COPD was characterized by FEV1. In this study, the lowest values of FEV1, FVC, FEV1/FVC were observed in patients who were GG homozygous and these values were statistically significant compared with controls. These differences may be due to the association being specific for a specific ethnic group. Joos et al. (2002) reported that haplotypes consisting of alleles from the MMP-1 G-1607 GG and MMP-12 Asn 357 Ser polymorphisms were associated with a rate of decline of lung function. Ito et al. (2005) investigated MMP-9 (C-1562T) polymorphism in 84 COPD patients and 85 controls. They reported that there was no difference in polymorphism of MMP-9 (C-1562T) between patients with COPD and the controls. The T allele was related with the development of upper lung dominant emphysema in patients with COPD. Cheng et al. (2009) conducted a study on cigarette smokers in Taiwan. Their aim was to investigate the relationship between the CYP and MMP genotypes and susceptibility to and severity of COPD. They found that the coexistence of genes, including homozygous *2A alleles of CYP1A1 and homozygotes with T alleles in MMP-9 (having increased proteolytic activity), is a significant risk factor in susceptibility to COPD in the Taiwanese population. Joos et al., investigated the role of MMP polymorphism in the development of COPD. They suggest that MMP-1 and MMP-12 polymorphisms, but not MMP-9 are causative factors in smoking-related lung injury. Jormsjö et al. (2000) investigated the -82 A/G polymorphism in the MMP-12 promoter and suggested that this polymorphism may have an effect on MMP-12 expression. In their study, they reported that the frequency of the carriers of the A allele have higher MMP-12 transcriptional activity than carriers with G allele. Schirmer et al., designed a study for MMP 3, 9, and 12 gene polymorphisms to investigate COPD risk assessment in a Brazilian population. They found no evidence for MMP 3, 9, and 12 gene polymorphisms in COPD patients (Lee et al., 2010). Reasons for the different results between studies are unknown; the inconsistent results of different ethnic groups might be real differences in the genetic determinants of phenotypic heterogeneity and population stratification. In this study with 73 control subjects, we found that the frequencies of the MMP-7-181 G allele and GG genotype were 52.7% and 17.8%, compared with around 0.40% and 0.13%, respectively, among Caucasians from Italy (Haq et al., 2010). Our data was similar to Ghilardi's findings (Ghilardi et al., 2003), but not similar to the Chinese population (Li et al., 2006). It must be emphasized that ethnic variation in the MMP genotype distribution warrants additional comparative studies in other populations of different ancestry, such as Caucasians and Chinese or African-Americans, to confirm our results. Silverman et al. (2000) suggested that women appear to be more sensitive to smoking than men for the development of airway obstruction. Although there were no differences in the frequencies of MMP-7 genotypes between patients and controls for women, we found that the frequency of male patients with AA genotype (33.3%) was higher than male controls with the same genotype. Further investigations will be necessary to clarify the contribution of the MMP-7 gene polymorphism to the development of COPD in each gender. In this study for MMP-7-181 A/G polymorphism, GG homozygous genotype was associated with respiratory parameters of COPD patients. These COPD patients were staged according to GOLD criteria for 2006. The COPD patients were examined according to the stage distribution for MMP-7 genotypes. The patients in this study were classified as four groups according to the severity of COPD. There were no statistical differences between these stages and MMP-7 genotypes. However, an interesting finding was the increased frequency of the AA homozygous genotype in the COPD patients; in our opinion, this may be used as a marker for determining genetic susceptibility to COPD. Therefore, these findings along with additional studies in larger patient groups must be approved. To explain the role of the risk of COPD, the effect of MMP-7 polymorphisms and other variants of the MMP-7 on the other MMP family members, and their biological functions more extensive studies with larger groups are required in the future.

Footnotes

Disclosure Statement

No competing financial interests exist.

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