Human Molecular Genetics, 2002, Vol. 11, No. 5 569-576
© 2002 Oxford University Press
The role of matrix metalloproteinase polymorphisms in the rate of decline in lung function
University of British Columbia McDonald Research Laboratories/iCAPTURE Center, St Paul’s Hospital, 1081 Burrard Street, Vancouver, British Columbia V6Z 1Y6, Canada, 1Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN, USA and 2Faculty of Medicine, University of Manitoba, Winnipeg, MB, Canada
Received November 14, 2001; Revised and Accepted January 8, 2002.
 |
ABSTRACT |
|---|
 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
|---|
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 negatively associated with a fast rate of decline (P = 0.02). 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.
|
INTRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
|---|
Chronic obstructive pulmonary disease (COPD) is characterized by decreased expiratory flow rates, increased pulmonary resistance and hyperinflation of the lung. Cigarette smoking is the most important risk factor for the development of COPD but only a minority of smokers develop symptoms (1). Smoking leads to two pathophysiologic processes in the lung. The first is proteolytic destruction of the lung parenchyma, which results in permanent enlargement of airspaces (emphysema) and, consequently, loss of lung elastic recoil. The second is inflammatory narrowing of peripheral airways, which is characterized by edema, mucus hypersecretion and fibrosis of peripheral airways. Evidence of both pathophysiologic processes is usually found in an individual COPD patient.
A proteinase–antiproteinase imbalance has been the most widely accepted theory for the pathogenesis of pulmonary emphysema since the discovery of 
-1-antitrypsin deficiency (2). Matrix metalloproteinases (MMPs) comprise a structurally and functionally related family of at least 20 proteolytic enzymes, which play an essential role in tissue remodeling and repair associated with development and inflammation (3). MMP genes have been mapped to chromosomes 11, 14, 16, 20 and 22, with several of them being clustered within the long arm of chromosome 11 (4). Overexpression of metalloproteinases has been associated with several pathological conditions, including the irreversible degradation of tissues in arthritis (5) and the degradation of collagens in tumor invasion and metastasis leading to poorer prognosis in patients with higher expression of MMPs (6,7). Several studies in animals and humans have provided evidence that MMP1 (interstitial collagenase), MMP12 (human macrophage elastase) and MMP9 (gelatinase B) are important in airway inflammation and the development of emphysema. In 1992, D’Armiento et al. (8) demonstrated that transgenic mice over-expressing human MMP1 in their lungs developed morphologic changes strikingly similar to human pulmonary emphysema. MMP12 knockout mice did not develop emphysema following exposure to cigarette smoke compared to wild–type mice (9), suggesting that the presence of MMP12 is critical in smoke-induced lung injury. Smokers with airway obstruction show increased expression of MMP1 and MMP9 compared to smokers without COPD and non-smokers (10,11).
Lung function normally increases to a maximal value at adulthood and begins to decline 10–15 years later (12). COPD can develop because of a reduced maximal lung function, an earlier age of onset of decline or an accelerated rate of decline. The latter is thought to be related to genetic susceptibility to cigarette smoke (1). Family (13) and twin (14) studies have provided evidence that there is a genetic susceptibility for the development of COPD. There are a number of function-altering polymorphisms within the promoters of MMP genes (15–17). Furthermore, we describe a novel polymorphism in the coding region of the MMP12 gene.
The aim of this study was to investigate the association of MMP polymorphisms with rate of decline of lung function in smokers. We selected 590 study subjects who had either a rapid decline or no decline in lung function over a period of 5 years. We hypothesized that polymorphisms that lead to increased expression of MMP genes or increased activity of the enzymes would be associated with a rapid rate of decline in lung function.
|
RESULTS |
|---|
|
TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
|---|
The characteristics of the 590 smokers are given in Table 1. There were significant differences in several potentially confounding variables between the rapid and non-decliner groups. Therefore, the frequencies of the genotypes between groups were analyzed by binary logistic regression to adjust for these variables. Allele frequencies in our Caucasian study population (Table 2) were similar to those described previously (6,16–18). The overall observed distribution of homozygotes and heterozygotes for each polymorphism conformed to expectations based on Hardy–Weinberg analysis.
|
|
The frequency distribution of the MMP9 (CA-repeat) polymorphism showed a bimodal distribution of alleles (Table 2). Therefore, for further analyses we divided the alleles into two subclasses according to the numbers of CA repeats. Alleles with (CA)
16 were designated as ‘small’ and alleles with CA repeats (CA)
17 were designated as ‘large’. The –1607GG allele was negatively associated with a fast rate of decline [odds ratio (OR) = 0.76, 95% confidence interval (95% CI) 0.60–0.96, P = 0.02]. There was no association with rate of decline of lung function with any genotype (Table 3). However, there was a trend for an association (P = 0.05) between MMP1 (G–1607GG) containing genotypes and rate of decline of lung function. Possession of either one or two copies of the –1607GG allele was negatively associated with a fast rate of decline (OR = 0.62, 95% CI 0.42–0.92, P = 0.02). This association remained significant after adjustment for smoking history, age, sex and initial level of lung function (adjusted OR = 0.62, 95% CI 0.41–0.94, P = 0.02).
|
There was strong linkage disequilibrium (LD) between the C allele of MMP9 (C–1562T) and small variants of the MMP9 (CA-repeat) (D/Dmax = 0.96, P < 0.00001). There was also strong LD between the MMP1 (G–1607GG) and MMP12 (A–82G) alleles (D/Dmax = 0.76, P < 0.0001). The MMP1 and MMP12 genes are both located on chromosome 11q22–q23 (4). In contrast, the two MMP12 polymorphisms were not in LD.
Haplotype analysis of the two MMP12 and the two MMP9 polymorphisms did not reveal an association with rate of decline of lung function (data not shown). Similarly, MMP1 (G–1607GG)/MMP12 (A–82G) haplotypes were not associated with rate of decline of lung function. However, there was an association of MMP1 (G–1607GG) and MMP12 (Asn357Ser) haplotypes with rate of decline of lung function (Table 4). If these data are adjusted for multiple comparisons (five allele frequency comparisons, five genotype frequency comparisons and four haplotype frequency comparisons) by the Bonferroni approach, this association remains significant (P = 0.0007 x 14 = 0.0098). However, this correction is probably over-conservative given that the alleles, genotypes and haplotypes at each locus and in some cases between loci are not independent of each other.
|
|
DISCUSSION |
|---|
|
TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
|---|
In this study, we investigated the role of common polymorphisms within several MMP gene promoters in smoking-induced lung injury. We were able to exclude a major contribution of these polymorphisms individually on rate of decline in lung function of smokers. We describe a novel polymorphism in MMP12, and a novel assay for rapid genotyping of MMP1. Furthermore, we demonstrated that MMP1/MMP12 haplotypes were associated with rate of decline of lung function.
MMPs are interesting candidate genes for emphysema because of their role in tissue remodeling. There has been considerable interest in MMPs and a large number of studies have shown an involvement of MMPs in inflammatory airway disease (11,19–28). Overexpression of human MMP1 resulted in emphysema in transgenic mice (8), and deletion of MMP12 in knockout mice prevented smoking-related lung injury (9). While the relevance of these animal models to human disease has not been proven, they suggest a critical role of these proteinases in lung tissue destruction.
Most of the investigated polymorphisms have previously been shown to alter gene expression (6,15–17,29). The insertion of a G at position –1607 in the promoter of the MMP1 gene creates a binding site for the transcription factor, ETS-1 (15). Expression studies of reporter gene constructs (15) and ovarian tumor tissue samples (6) demonstrated that the –1607GG allele was associated with higher levels of gene expression.
The T allele of the MMP9 C–1562T polymorphism was associated with higher levels of gene expression in a reporter gene assay and this may be because the T allele has a lower binding affinity for a repressor of transcription (16). Reporter gene assays were also used to demonstrate that gene expression was negatively correlated to the length of a CA repeat in the MMP9 promoter (29). CA repeat sequences have been shown to bind nuclear proteins and therefore the length of a CA repeat may have implications for transcriptional regulation (30).
The A allele of the MMP12 A–82G polymorphism shows a higher affinity for the transcription factor activator protein-1 (AP-1) and higher gene expression in reporter gene assays (17). The effect of the Asn357Ser polymorphism in MMP12 on the function of the protein is not known. However, this is a non-conservative amino acid substitution that replaces an amino acid with an acidic side chain (Asn) with one that has a hydroxylic side chain (Ser) and therefore may have consequences on the catalytic activity of the protein. The Asn residue at this position is conserved in the mouse and rat, but not the rabbit orthologs of this gene. In other MMPs, both in humans and in other species, this position is invariant but it is glycine rather than asparagine (http://www.ncbi.nlm.nih.gov/). Overall, these data do not provide strong support for a function-changing role for this polymorphism.
The MMP1 (G–1607GG) variant has been associated with ovarian cancer (6), endometrial carcinoma (7) and severity of melanoma (31). MMP9 polymorphisms have been linked to coronary artery disease (16) and intracranial aneurysms (32). There was a weak association of an MMP12 polymorphism with coronary artery diameters in diabetic patients (17). A small study done in Eastern Europe failed to show a significant association with MMP9 (C–1582T) and asthma (33).
Paradoxically, the frequency of the MMP1 –1607G allele was increased in the fast decliners (0.51) compared with the non-decliners (0.44) (Table 2). The –1607G allele is associated with decreased MMP1 gene expression and therefore would be expected to be protective against a rapid decline in lung function. A possible explanation for this result is that the association is not due to the –1607G allele but is due to an allele in a nearby gene in LD with it.
The association of the MMP1 G–1607GG/MMP12 Asn357Ser haplotypes with rate of decline of lung function is not simply a consequence of the association of MMP1 –1607G with rapid decline, since there is no LD between the two polymorphisms. Comparison of the haplotypes that were significantly increased or decreased in the fast decliners confirms that it is the combination of alleles rather than a single locus that is responsible for the association. MMP1 –1607G in combination with MMP12 Asn357 was significantly increased in the fast decliners, whereas MMP1 –1607G with MMP12 Ser357 was significantly decreased in the fast decliners. This suggests that MMP1 –1607G, by itself, is not the causal allele for this association. MMP12 Asn357Ser genotype was not associated with rate of decline of lung function (Table 3) suggesting that, by itself, this polymorphism is not causal. However, the haplotypes were associated with rate of decline of lung function suggesting an interaction between the alleles. Alternatively, the haplotypes may be a marker for, and in LD with, the true causative allele that is in the immediate chromosomal vicinity. Other metalloproteinase genes are located in the 11q22–q23 region and are found in the following order; MMP7–MMP20–MMP8–MMP10–MMP1–MMP3–MMP12–MMP13 (GenBank accession no. NT_009151). However, apart from MMP1 and MMP12, none of these metalloproteinases has been implicated in the pathogenesis of COPD.
The lack of association in this study strongly suggests that the investigated MMP9 polymorphisms do not contribute to the pathogenesis of smoking-related decline in lung function. We had excellent power to detect an association of these polymorphisms with the rate of decline of lung function in the two groups of smokers. We could detect an OR of 1.7 or greater for MMP9 CA repeat and MMP9 C–1562T with a power of >80% given the size of our study. Therefore, we were able to conclude that the studied polymorphisms are unlikely to have even a minor influence on rate of decline of lung function.
In summary, this is the first study to address the influence of the majority of known function-altering polymorphisms within the MMP1, MMP9 and MMP12 genes on rate of decline of lung function in smokers. Our 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 LD with such factors.
|
MATERIALS AND METHODS |
|---|
|
TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
|---|
Subjects
Subjects were selected from the participants in the National Heart, Lung and Blood Institute, Lung Health Study. The design of this multi-center, randomized clinical trial is described more extensively elsewhere (34). Study participants were healthy current smokers, 35–60 years of age, who had mild to moderate airflow obstruction based on forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) lung function measurements (FEV1 = 55–90% of predicted and FEV1/FVC
0.70). Exclusion criteria included serious illnesses such as cancer, heart attack or stroke or other important conditions that required medical treatment. The primary outcome was rate of decline of FEV1 over a follow-up period of 5 years. The two extremes of the distribution of rate of decline were utilized in this study: individuals with a rapid decline of lung function (decline in FEV1 > 3.0% of predicted value per year) and individuals with an absence of decline over the same period (increase in FEV1 > 0.4% of predicted value per year). Of the 3216 persistent smokers in this cohort, 303 were chosen for their rapid decline of lung function and 324 were selected because of absence of decline. Of this group, 595 were Caucasians and 32 were of other ethnic groups. Due to the potential for false positive associations in ethnically stratified populations we studied the Caucasian participants separately. There were insufficient individuals in the other ethnic groups to provide statistically meaningful comparisons. Genotypic data for any of the polymorphisms were unavailable in four of the Caucasian participants.
Genotyping
DNA was extracted from blood samples using a standard phenol/chloroform protocol (35). The DNA sequence flanking the polymorphic region of each gene was amplified by PCR. Negative controls without DNA template were included with each set of reactions. All analyses were performed blinded with respect to subject characteristics. Genotypes were confirmed by a second person not directly involved in the study, and by dideoxynucleotide sequencing for a representative number of samples of each genotype.
MMP12 (Asn357Ser), MMP12 (A–82G), MMP9 (C–1562T). The primers used to amplify the DNA sequences containing the MMP12 (Asn357Ser), MMP12 (A–82G) and MMP9 (C–1562T) single nucleotide polymorphisms are summarized in Table 5. Restriction enzyme digestion was used to analyze for presence of the mutation within the PCR products (Table 5). Digested PCR products were loaded on a 3% (MMP12) or 2% (MMP9) agarose gel containing ethidium bromide and visualized in UV light (Fig. 1).
|
|
MMP1 (G–1607GG). The following primers flanking the MMP1 (G–1607GG) insertion/deletion polymorphism were used to amplify the sequence by PCR: 5'-TGC CAC TTA GAT GAC CAA ATT G-3' (sense) and 5'-GAT TCC TGT TTT CTT TCT GCG T-3' (antisense). PCR conditions were as follows: 30 cycles of 94°C for 30 s, 60°C for 30 s and 72°C for 20 s. The presence of the insertion/deletion alleles was assayed by heteroduplex analysis. Figure 2 shows the sequence of the induced heteroduplex generator. After amplification, 4 µl of 6x sucrose loading buffer (0.25% bromophenol blue, 0.25% xylene cyanol FF, 40% sucrose in water), 10 µl of PCR product and 10 µl of the amplified heteroduplex generator were denatured at 94°C for 10 min. The samples were allowed to cool slowly on the PCR machine heating block for 30 min to allow renaturation and formation of the heteroduplexes. Electrophoresis was performed on a 15% polyacrylamide gel. Bands were visualized by a UV transilluminator after staining of the gel with ethidium bromide.
|
250 and 300 bp, GG allele), two lower bands (MMP9 (CA-repeat). To determine the numbers of the (CA)n repeats in the MMP9 promoter region, PCR products were generated using a fluorescently labeled (6-FAM) forward primer (5'-GTG GAG AGA GGA GGA GGT GGT GTA AGC-3') and an unlabeled reverse primer (5'-TGG TGA GGG CAG AGG TGT CTG ACT GC-3'), which were designed according to the published sequence (GenBank accession no. M68343) (36). The PCR was performed over 30 cycles of 94°C for 20 s, 59°C for 40 s and 72°C for 20 s. Following PCR amplification, products were mixed with an internal standard (Rox-350, Applied Biosystems, Mississauga, ON). Alleles were separated by a laser-based automated DNA sequencer (ABI PRISM 3700). The sizes of the fluorescently labeled PCR products were calculated from a standard curve made using the internal standards. DNA standards containing 14, 17, 21 and 23 CA repeats were identified by direct sequencing and were included in each experiment as positive controls.
Statistical analysis
The results are presented as genotype and allele frequencies for both fast and non-decliners among the Lung Health Study participants. 
2 tests for statistical significance were performed on allele and genotype frequencies with the exception of the MMP9 CA repeat allele frequencies. Due to the large number of rare alleles, we performed a Monte Carlo test (37). In this test, 10 000 random simulations were performed to generate tables having the same marginal totals as the observed data, and the number occurrences of a 2 value greater than or equal to the 2 value associated with the real table was counted. The associations were also analyzed by binary logistic regression to adjust for potential confounding factors. Factors included in the analyses were smoking history, age, sex and initial level of lung function (pre-bronchodilator predicted FEV1 percentage). Unpaired t-tests were used to compare baseline values. All tests were performed using the JMP Statistics software package (SAS Institute Inc.)
Haplotype frequencies were estimated using the expectation-maximization (EM) algorithm (37), since haplotypes cannot be discerned directly from double heterozygotes. The EM algorithm begins by setting the haplotype frequencies in the double heterozygotes to the values that would be observed under linkage equilibrium. The values are then regarded as real data and used to calculate haplotype frequencies in the entire population. These revised haplotype frequencies are used to obtain revised expected values in the double heterozygotes. This cycle is repeated until the changes in haplotype frequencies from one iteration to the next become negligible and this yields maximum likelihood estimates of the haplotype frequencies. The Arlequin software package was used to perform these estimations, to test for LD and for Hardy–Weinberg equilibrium (38). LD was calculated in order to help interpret the haplotype data. For example, an association of a haplotype, composed of two alleles not in LD, with rate of decline of lung function suggests an interaction between the alleles. In the presence of LD, only one allele in a haplotype may be causal and the other alleles simply in LD with the causal allele.
|
ACKNOWLEDGEMENTS |
|---|
We thank Dr N.Wood for the synthesis of the induced heteroduplex generator. This study was supported by the Canadian Institutes of Health Research. The Lung Health Study was supported by a grant from the Division of Lung Diseases of the National Heart, Lung and Blood Institute. L.J. was supported by the Swiss National Science Foundation, Novartis Research Foundation, Uarda-Frutiger Foundation and the Swiss Society of Pneumology. A.J.S. was supported by a Parker B. Francis Fellowship and is a recipient of a Canadian Research Chair.
|
FOOTNOTES |
|---|
+ To whom correspondence should be addressed. Tel: +1 604 806 9008; Fax: +1 604 806 8351; Email: asandford@mrl.ubc.ca
|
REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
|---|
1 Fletcher,C. and Peto,R. (1977) The natural history of chronic airflow obstruction. Br. Med. J., 1, 1645–1648.
2
Laurell,C.C. and Eriksson,S. (1963) The electrophorectic 1-globulin pattern of serum in 1-antitrypsin deficiency. Scand. J. Clin. Lab. Invest., 15, 132–140.[ISI]
3
Nagase,H. and Woessner,J.F.Jr (1999) Matrix metalloproteinases. J. Biol. Chem., 274, 21491–21494.
4 Pendas,A.M., Santamaria,I., Alvarez,M.V., Pritchard,M. and Lopez-Otin,C. (1996) Fine physical mapping of the human matrix metalloproteinase genes clustered on chromosome 11q22.3. Genomics, 37, 266–268.[Medline]
5 Okada,Y., Nagase,H. and Harris,E.D.Jr (1987) Matrix metalloproteinases 1, 2, and 3 from rheumatoid synovial cells are sufficient to destroy joints. J. Rheumatol., 14, 41–42.
6
Kanamori,Y., Matsushima,M., Minaguchi,T., Kobayashi,K., Sagae,S., Kudo,R., Terakawa,N. and Nakamura,Y. (1999) Correlation between expression of the matrix metalloproteinase-1 gene in ovarian cancers and an insertion/deletion polymorphism in its promoter region. Cancer Res., 59, 4225–4227.
7 Nishioka,Y., Kobayashi,K., Sagae,S., Ishioka,S., Nishikawa,A., Matsushima,M., Kanamori,Y., Minaguchi,T., Nakamura,Y., Tokino,T. et al. (2000) A single nucleotide polymorphism in the matrix metalloproteinase-1 promoter in endometrial carcinomas. Jpn. J. Cancer Res., 91, 612–615.[ISI][Medline]
8 D’Armiento,J., Dalal,S.S., Okada,Y., Berg,R.A. and Chada,K. (1992) Collagenase expression in the lungs of transgenic mice causes pulmonary emphysema. Cell, 71, 955–961.[ISI][Medline]
9
Hautamaki,R.D., Kobayashi,D.K., Senior,R.M. and Shapiro,S.D. (1997) Requirement for macrophage elastase for cigarette smoke-induced emphysema in mice. Science, 277, 2002–2004.
10 Finlay,G.A., Russell,K.J., McMahon,K.J., D’Arcy E.M., Masterson,J.B., FitzGerald,M.X. and O’Connor,C.M. (1997) Elevated levels of matrix metalloproteinases in bronchoalveolar lavage fluid of emphysematous patients. Thorax, 52, 502–506.[Abstract]
11
Segura-Valdez,L., Pardo,A., Gaxiola,M., Uhal,B.D., Becerril,C. and Selman,M. (2000) Upregulation of gelatinases A and B, collagenases 1 and 2, and increased parenchymal cell death in COPD. Chest, 117, 684–694.
12 Tager,I.B., Segal,M.R., Speizer,F.E. and Weiss,S.T. (1988) The natural history of forced expiratory volumes. Effect of cigarette smoking and respiratory symptoms. Am. Rev. Respir. Dis., 138, 837–849.[ISI][Medline]
13
Givelber,R.J., Couropmitree,N.N., Gottlieb,D.J., Evans,J.C., Levy,D., Myers,R.H. and O’Connor,G.T. (1998) Segregation analysis of pulmonary function among families in the Framingham Study. Am. J. Respir. Crit. Care Med., 157, 1445–1451.
14 Redline,S., Tishler,P.V., Lewitter,F.I., Tager,I.B., Munoz,A. and Speizer,F.E. (1987) Assessment of genetic and nongenetic influences on pulmonary function. A twin study. Am. Rev. Respir. Dis., 135, 217–222.[ISI][Medline]
15
Rutter,J.L., Mitchell,T.I., Buttice,G., Meyers,J., Gusella,J.F., Ozelius,L.J. and Brinckerhoff,C.E. (1998) A single nucleotide polymorphism in the matrix metalloproteinase-1 promoter creates an ETS binding site and augments transcription. Cancer Res., 58, 5321–5325.
16
Zhang,B., Ye,S., Herrmann,S.M., Eriksson,P., de Maat,M., Evans,A., Arveiler,D., Luc,G., Cambien,F., Hamsten,A. et al. (1999) Functional polymorphism in the regulatory region of gelatinase B gene in relation to severity of coronary atherosclerosis. Circulation, 99, 1788–1794.
17
Jormsjo,S., Ye,S., Moritz,J., Walter,D.H., Dimmeler,S., Zeiher,A.M., Henney,A., Hamsten,A. and Eriksson,P. (2000) Allele-specific regulation of matrix metalloproteinase-12 gene activity is associated with coronary artery luminal dimensions in diabetic patients with manifest coronary artery disease. Circ. Res., 86, 998–1003.
18 Nelissen,I., Vandenbroeck,K., Fiten,P., Hillert,J., Olsson,T., Marrosu,M.G.. and Opdenakker,G. (2000) Polymorphism analysis suggests that the gelatinase B gene is not a susceptibility factor for multiple sclerosis. J. Neuroimmunol., 105, 58–63.[Medline]
19
Finlay,G.A., O’Driscoll,L.R., Russell,K.J., D’Arcy,E.M., Masterson,J.B., FitzGerald,M.X. and O’Connor,C.M. (1997) Matrix metalloproteinase expression and production by alveolar macrophages in emphysema. Am. J. Respir. Crit. Care Med., 156, 240–247.
20 Cataldo,D., Munaut,C., Noel,A., Frankenne,F., Bartsch,P., Foidart,J.M. and Louis,R. (2000) MMP-2- and MMP-9-linked gelatinolytic activity in the sputum from patients with asthma and chronic obstructive pulmonary disease. Int. Arch. Allergy Immunol., 123, 259–267.[ISI][Medline]
21 Cataldo,D., Munaut,C., Noel,A., Frankenne,F., Bartsch,P., Foidart,J.M. and Louis,R. (2001) Matrix metalloproteinases and TIMP-1 production by peripheral blood granulocytes from COPD patients and asthmatics. Allergy, 56, 145–151.[ISI][Medline]
22
Kumagai,K., Ohno,I., Okada,S., Ohkawara,Y., Suzuki,K., Shinya,T., Nagase,H., Iwata,K. and Shirato,K. (1999) Inhibition of matrix metalloproteinases prevents allergen-induced airway inflammation in a murine model of asthma. J. Immunol., 162, 4212–4219.
23 Ohnishi,K., Takagi,M., Kurokawa,Y., Satomi,S. and Konttinen,Y.T. (1998) Matrix metalloproteinase-mediated extracellular matrix protein degradation in human pulmonary emphysema. Lab. Invest., 78, 1077–1087.[ISI][Medline]
24
Bosse,M., Chakir,J., Rouabhia,M., Boulet,L.P., Audette,M. and Laviolette,M. (1999) Serum matrix metalloproteinase-9: tissue inhibitor of metalloproteinase-1 ratio correlates with steroid responsiveness in moderate to severe asthma. Am. J. Respir. Crit. Care Med., 159, 596–602.
25
Imai,K., Dalal,S.S., Chen,E.S., Downey,R., Schulman,L.L., Ginsburg,M. and D’Armiento,J. (2001) Human collagenase (matrix metalloproteinase-1) expression in the lungs of patients with emphysema. Am. J. Respir. Crit. Care Med., 163, 786–791.
26
Lemjabbar,H., Gosset,P., Lamblin,C., Tillie,I., Hartmann,D., Wallaert,B., Tonnel,A.B. and Lafuma,C. (1999) Contribution of 92 kDa gelatinase/type IV collagenase in bronchial inflammation during status asthmaticus. Am. J. Respir. Crit. Care Med., 159, 1298–1307.
27
Rajah,R., Nachajon,R.V., Collins,M.H., Hakonarson,H., Grunstein,M.M. and Cohen,P. (1999) Elevated levels of the IGF-binding protein protease MMP-1 in asthmatic airway smooth muscle. Am. J. Respir. Cell Mol. Biol., 20, 199–208.
28
Vignola,A.M., Riccobono,L., Mirabella,A., Profita,M., Chanez,P., Bellia,V., Mautino,G., D’Accardi,P., Bousquet,J. and Bonsignore,G. (1998) Sputum metalloproteinase-9/tissue inhibitor of metalloproteinase-1 ratio correlates with airflow obstruction in asthma and chronic bronchitis. Am. J. Respir. Crit. Care Med., 158, 1945–1950.
29 Shimajiri,S., Arima,N., Tanimoto,A., Murata,Y., Hamada,T., Wang,K.Y. and Sasaguri,Y. (1999) Shortened microsatellite d(CA)21 sequence down-regulates promoter activity of matrix metalloproteinase 9 gene. FEBS Lett., 455, 70–74.[ISI][Medline]
30 Epplen,J.T., Kyas,A. and Maueler,W. (1996) Genomic simple repetitive DNAs are targets for differential binding of nuclear proteins. FEBS Lett., 389, 92–95.[ISI][Medline]
31
Ye,S., Dhillon,S., Turner,S.J., Bateman,A.C., Theaker,J.M., Pickering,R.M., Day,I. and Howell,W.M. (2001) Invasiveness of cutaneous malignant melanoma is influenced by matrix metalloproteinase 1 gene polymorphism. Cancer Res., 61, 1296–1298.
32
Peters,D.G., Kassam,A., St Jean,P.L., Yonas,H. and Ferrell,R.E. (1999) Functional polymorphism in the matrix metalloproteinase-9 promoter as a potential risk factor for intracranial aneurysm. Stroke, 30, 2612–2616.
33 Holla,L.I., Vasku,A., Stejskalova,A. and Znojil,V. (2000) Functional polymorphism in the gelatinase B gene and asthma. Allergy, 55, 900–901.[ISI][Medline]
34 Connett,J.E., Kusek,J.W., Bailey,W.C., O’Hara,P. and Wu,M. (1993) Design of the Lung Health Study: a randomized clinical trial of early intervention for chronic obstructive pulmonary disease. Control. Clin. Trials, 14, 3S–19S.[Medline]
35 Sambrook,J., Fritsch,E.F. and Maniatis,T. (1989) Molecular Cloning. A Laboratory Manual. 2nd edn. Cold Spring Harbor Press, Cold Spring Harbor, NY.
36
Huhtala,P., Chow,L.T. and Tryggvason,K. (1990) Structure of the human type IV collagenase gene. J. Biol. Chem., 265, 11077–11082.
37 Sham,P. (1998) Statistics in Human Genetics. Arnold, London, UK.
38 Schneider,S., Roessli,D. and Excoiffier,L. (2000) Arlequin ver. 2.000: a software for population genetics data analysis. Genetics and Biometry Laboratory, University of Geneva, Switzerland.
39 O’Connor,G.T., Sparrow,D. and Weiss,S.T. (1995) A prospective longitudinal study of methacholine airway responsiveness as a predictor of pulmonary-function decline: the Normative Aging Study. Am. J. Respir. Crit. Care Med., 152, 87–92.[Abstract]
40 Rijcken,B., Schouten,J.P., Xu,X., Rosner,B. and Weiss,S.T. (1995) Airway hyperresponsiveness to histamine associated with accelerated decline in FEV1. Am. J. Respir. Crit. Care Med., 151, 1377–1382.[Abstract]
41 Tracey,M., Villar,A., Dow,L., Coggon,D., Lampe,F.C. and Holgate,S.T. (1995) The influence of increased bronchial responsiveness, atopy, and serum IgE on decline in FEV1. A longitudinal study in the elderly. Am. J. Respir. Crit. Care Med., 151, 656–662.[Abstract]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  J-Q. He, K. Shumansky, J. E. Connett, N. R. Anthonisen, P. D. Pare, and A. J. Sandford Association of genetic variations in the CSF2 and CSF3 genes with lung function in smoking-induced COPD Eur. Respir. J., July 1, 2008; 32(1): 25 - 34. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Ammous, N. R. Hackett, M. W. Butler, T. Raman, I. Dolgalev, T. P. O'Connor, B.-G. Harvey, and R. G. Crystal Variability in Small Airway Epithelial Gene Expression Among Normal Smokers Chest, June 1, 2008; 133(6): 1344 - 1353. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. P. Hersh, D. L. DeMeo, and E. K. Silverman National Emphysema Treatment Trial State of the Art: Genetics of Emphysema Proceedings of the ATS, May 1, 2008; 5(4): 486 - 493. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. V. Cockle, N. Gopichandran, J. J. Walker, M. I. Levene, and N. M. Orsi Matrix Metalloproteinases and Their Tissue Inhibitors in Preterm Perinatal Complications Reproductive Sciences, October 1, 2007; 14(7): 629 - 645. [Abstract] [PDF]
|
|
|
|
|
|
W. Shi, S. Bellusci, and D. Warburton Lung Development and Adult Lung Diseases Chest, August 1, 2007; 132(2): 651 - 656. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Churg, R. Wang, X. Wang, P.-O. Onnervik, K. Thim, and J. L Wright Effect of an MMP-9/MMP-12 inhibitor on smoke-induced emphysema and airway remodelling in guinea pigs Thorax, August 1, 2007; 62(8): 706 - 713. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Marcet-Palacios, M. Ulanova, F. Duta, L. Puttagunta, S. Munoz, D. Gibbings, M. Radomski, L. Cameron, I. Mayers, and A. D. Befus The Transcription Factor Wilms Tumor 1 Regulates Matrix Metalloproteinase-9 through a Nitric Oxide-Mediated Pathway J. Immunol., July 1, 2007; 179(1): 256 - 265. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Huang, W. Mitzner, R. Rabold, B. Schofield, H. Lee, S. Biswal, and C. G. Tankersley Variation in senescent-dependent lung changes in inbred mouse strains J Appl Physiol, April 1, 2007; 102(4): 1632 - 1639. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Sampsonas, A. Kaparianos, D. Lykouras, K. Karkoulias, and K. Spiropoulos DNA sequence variations of metalloproteinases: their role in asthma and COPD Postgrad. Med. J., April 1, 2007; 83(978): 244 - 250. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. D. Shapiro Transgenic and gene-targeted mice as models for chronic obstructive pulmonary disease Eur. Respir. J., February 1, 2007; 29(2): 375 - 378. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. J. Greenlee, Z. Werb, and F. Kheradmand Matrix Metalloproteinases in Lung: Multiple, Multifarious, and Multifaceted Physiol Rev, January 1, 2007; 87(1): 69 - 98. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. G. Morris and D. Sheppard Pulmonary Emphysema: When More is Less. Physiology, December 1, 2006; 21(6): 396 - 403. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Warburton, J. Gauldie, S. Bellusci, and W. Shi Lung Development and Susceptibility to Chronic Obstructive Pulmonary Disease Proceedings of the ATS, November 1, 2006; 3(8): 668 - 672. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. M. Chatila, E. A. Hoffman, J. Gaughan, G. B. Robinswood, G. J. Criner, and for the National Emphysema Treatment Trial Researc Advanced emphysema in african-american and white patients: do differences exist? Chest, July 1, 2006; 130(1): 108 - 118. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Su, W. Zhou, K. Asomaning, X. Lin, J. C. Wain, T. J. Lynch, G. Liu, and D. C. Christiani Genotypes and haplotypes of matrix metalloproteinase 1, 3 and 12 genes and the risk of lung cancer Carcinogenesis, May 1, 2006; 27(5): 1024 - 1029. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I K Demedts, A Morel-Montero, S Lebecque, Y Pacheco, D Cataldo, G F Joos, R A Pauwels, and G G Brusselle Elevated MMP-12 protein levels in induced sputum from patients with COPD Thorax, March 1, 2006; 61(3): 196 - 201. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. G. Schwartz and J. C. Ruckdeschel Familial Lung Cancer: Genetic Susceptibility and Relationship to Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., January 1, 2006; 173(1): 16 - 22. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Ito, S. Nagai, T. Handa, S. Muro, T. Hirai, M. Tsukino, and M. Mishima Matrix Metalloproteinase-9 Promoter Polymorphism Associated with Upper Lung Dominant Emphysema Am. J. Respir. Crit. Care Med., December 1, 2005; 172(11): 1378 - 1382. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. G. Woodruff, L. L. Koth, Y. H. Yang, M. W. Rodriguez, S. Favoreto, G. M. Dolganov, A. C. Paquet, and D. J. Erle A Distinctive Alveolar Macrophage Activation State Induced by Cigarette Smoking Am. J. Respir. Crit. Care Med., December 1, 2005; 172(11): 1383 - 1392. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. P. Hersh, D. L. DeMeo, C. Lange, A. A. Litonjua, J. J. Reilly, D. Kwiatkowski, N. Laird, J. S. Sylvia, D. Sparrow, F. E. Speizer, et al. Attempted Replication of Reported Chronic Obstructive Pulmonary Disease Candidate Gene Associations Am. J. Respir. Cell Mol. Biol., July 1, 2005; 33(1): 71 - 78. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. J. Barnes Mediators of Chronic Obstructive Pulmonary Disease Pharmacol. Rev., December 1, 2004; 56(4): 515 - 548. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-Q. He, J. E. Connett, N. R. Anthonisen, P. D. Pare, and A. J. Sandford Glutathione S-Transferase Variants and Their Interaction with Smoking on Lung Function Am. J. Respir. Crit. Care Med., August 15, 2004; 170(4): 388 - 394. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Bonniaud, M. Kolb, T. Galt, J. Robertson, C. Robbins, M. Stampfli, C. Lavery, P. J. Margetts, A. B. Roberts, and J. Gauldie Smad3 Null Mice Develop Airspace Enlargement and Are Resistant to TGF-{beta}-Mediated Pulmonary Fibrosis J. Immunol., August 1, 2004; 173(3): 2099 - 2108. |