HomeLarge Type Edition
HOME ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Services
Right arrow Download to citation manager
PubMed
Right arrow PubMed Citation
The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 61:1065-1069 (2006)
© 2006 The Gerontological Society of America

Analysis of Functional Polymorphisms of Metalloproteinase Genes in Persons With Vascular Dementia and Alzheimer's Disease

Andrea Flex, Eleonora Gaetani, Anna S. Proia, Giovanni Pecorini, Giuseppe Straface, Federico Biscetti, Giuseppe Fioroni, Alexandra Sabusco, Roberto Flore, Paolo Tondi, Paolo Pola and Roberto Pola

Laboratory of Vascular Biology and Genetics, 2 Department of Medicine and Angiology, and 3 Department of Internal Medicine and Geriatrics, A. Gemelli University Hospital, Catholic University School of Medicine, Rome, Italy.
4 IRCCS Associazione Oasi Maria SS, Institute for Research on Mental Retardation and Brain Aging, Troina, Italy.

Address correspondence to Roberto Pola, MD, PhD, Istituto di Medicina Interna e Geriatria, Policlinico A. Gemelli, Università Cattolica del Sacro Cuore, L.go A. Gemelli 8, 00168 Rome, Italy. E-mail: rob_pola{at}hotmail.com


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
Background. Vascular dementia (VAD) and Alzheimer's disease (AD) may share common neuropathological mechanisms. Matrix metalloproteinases (MMPs) may induce destruction of the extracellular matrix, neuronal dysfunction, and death. Increased expression of these molecules has been found in a number of neurological diseases, including cerebral ischemia and AD. Expression and activity of MMPs may be genetically influenced by common polymorphisms in the promoter regions of the corresponding genes. The purpose of this study was to evaluate whether functional polymorphisms of MMP genes are associated with dementia.

Methods. This is a cross-sectional study including a total of 599 individuals: 193 with VAD, 183 with AD, and 223 controls. Polymorphisms of the MMP-1, MMP-3, and MMP-9 genes were studied.

Results. MMP-1 2G2G, MMP-1 1G2G, MMP-3 5A5A, and MMP-9 TT genotypes were significantly and independently associated with VAD (odds ratio [OR] 2.5, 95% confidence interval [CI] 1.4–4.4, OR = 1.7, 95% CI, 1.0–2.7, OR = 2.9, 95% CI, 1.5–5.9, and OR = 6.8, 95% CI, 1.3–35.1, respectively). MMP-1 2G2G and MMP-3 5A5A genotypes were associated with increased risk of AD only in persons who carry the apolipoprotein E (APOE) {varepsilon}4 allele (OR = 6.0, 95% CI, 2.3–15.5, and OR = 14.3, 95% CI, 3.2–63.0, respectively). Interestingly, the odds of VAD and AD was further increased in persons concomitantly carrying more than one MMP gene variation, compared to individuals that only had one high-risk genotype.

Conclusions. Our study suggests that MMP gene polymorphisms are associated with VAD and AD, although these results need to be treated with caution until replicated. MMP genotypes may influence the risk of dementia and merit further investigation as potential genetic markers of disease.

IN recent years, there has been increasing appreciation of the fact that, although the initial events triggering neurodegenerative processes in vascular dementia (VAD) versus Alzheimer's disease (AD) may be different, these two forms of dementia may share common neuropathological mechanisms, ranging from inflammation to autoimmune processes and dysregulation of cytokine systems. In both diseases, neuronal injury results in the initiation of a similar cascade of cytokine production, which is eventually involved in crucial pathological phenomena, including amyloidogenesis, amyloid accumulation in blood vessels, white matter lesions, and angiogenesis (1). In this respect, it is interesting to note that white matter infarcts and cerebrovascular pathology are often present in the brain of persons with AD, and senile plaques may be found in patients with VAD (2). In addition, ischemic insults of the brain, such as in VAD, may increase neurofibrillary tangle formation and amyloid precursor protein accumulation, which typically occur in AD (3,4).

Matrix metalloproteinases (MMPs) are a related family of metal-dependant proteases, the function of which is the remodeling of the extracellular matrix during tissue injury and repair (5). MMPs are released from astrocytes, neurons, and microglia, as well as leukocytes and macrophages, and their target compounds include collagen, gelatin, fibronectin, laminin, elastin, and proteoglycans. In the central nervous system, MMPs may lead to extracellular matrix destruction, neuronal dysfunction, and death. Increased expression of these molecules has been found in a number of neurological diseases, including stroke and AD (5–8).

Genetic research is beginning to identify susceptibility genes that may influence the inflammatory process in AD and VAD. Polymorphisms in genes encoding interleukins, adhesion molecules, cytokines, and chemokines have been associated to different extents with either AD or VAD (9–13). In this respect, it is interesting to note that also the expression and activity of MMPs may be genetically controlled (14). For instance, the plasma levels of MMP-1, MMP-3, and MMP-9 are significantly influenced by common polymorphisms in the promoter regions of the corresponding genes (15–17). These genetic variations may be clinically important, as indicated by the reported associations between MMP polymorphisms and a number of pathologic conditions, ranging from different types of cancer to chronic inflammatory and cardiovascular diseases (18–23). In the present study, we investigated whether the MMP-1 1G/2G, MMP-3 5A/6A, and MMP-9 C/T gene polymorphisms are associated with dementia.


   METHODS
Top
 Abstract
 Methods
Results
 Discussion
 References
 
Participants
The individuals enrolled in this study were recruited from persons consecutively admitted to our Department of Medicine from January 2001 through May 2004. Diagnosis of probable VAD was performed by using the National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche et l'Enseignement en Neurosciences (NINDS-AIREN ) criteria (24). Diagnosis of probable AD was made in accordance with the National Institute for Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) guidelines (25). No cases of familial AD were included in this study. The Hachinski Ischemic Score was also used to aid in distinguishing between VAD and dementia from neurological disorders (26).

Controls were persons matched for age and sex, admitted to the same Department of Medicine in the same period of time, without dementia, and with no history of cerebrovascular diseases. They had no relationship with patients and no family history of dementia.

In both patients and controls, cognitive function was studied by using formal neuropsychological testing. Brain imaging evaluation was performed in all participants by computed tomography (CT) scan and/or magnetic resonance imaging (MRI). Carotid arteries were examined by two independent operators, by B-mode ultrasonography. Hypertension was defined as a systolic blood pressure > 140 mmHg, a diastolic blood pressure > 90 mmHg, or current treatment with an antihypertensive drug. Hypercholesterolemia was defined as either a need for hypolipidemic drugs or total plasma cholesterol level > 5.18 mmol/L. A diagnosis of coronary artery disease (CAD) was performed according to the medical history of the patients, the use of anti-anginal drugs, and the presence of electrocardiographic signs of myocardial ischemia and/or necrosis.

Patients with suspected mixed dementia (VAD and AD) were excluded from this study. We also excluded patients with possible metabolic and/or systemic causes of cognitive deterioration, such as deficiency of vitamin B12 and/or folic acid, endocrine diseases (with the exception of type 2 diabetes), anemia, electrolyte disturbances, respiratory diseases, heart failure, and psychiatric diseases. Participants affected by tumors, chronic inflammatory diseases, and autoimmune diseases were excluded as well. At the end of the recruitment period, a total of 310 individuals were excluded from the study as they presented one or more of the above-mentioned exclusion criteria, and a total of 599 participants were enrolled: 193 were affected by VAD, 183 by AD, and 223 were controls. The study protocol was accepted by the Ethics Committee of our University Hospital.

Genetic Testing
DNA was extracted from peripheral blood and assayed, as previously described, by polymerase chain reaction (PCR) and restriction enzyme analysis, for the detection of the MMP-1 1G/2G, MMP-3 5A/6A, and MMP-9 C/T gene polymorphisms (27–29). All the analyses were performed twice by blinded independent investigators. Error rates were 2.3%, 1.9%, and 2.9% for MMP-1, MMP-3, and MMP-9 gene polymorphism, respectively.

Statistical Analyses
Demographic and clinical data between groups were compared by chi-square test and by t test. Genotype and allele frequencies were compared by chi-square test. Associations were calculated assuming a dominant or recessive relationship between the number of high-risk alleles and the prevalence of diseases. Odds ratios (ORs) were calculated with 95% confidence interval (CI). Statistical significance was established at p <.05.


   RESULTS
Top
 Abstract
 Methods
 Results
Discussion
 References
 
The demographic and clinical characteristics of the studied population are shown in Table 1. VAD patients and controls did not significantly differ in terms of age, sex, smoking status, and hypercholesterolemia. In contrast, hypertension, diabetes, CAD, and peripheral arterial occlusive disease (PAOD) were significantly more frequent in patients with VAD than in controls. AD subjects did not significantly differ from controls in terms of age, sex, smoking status, hypercholesterolemia, and diabetes. Hypertension and PAOD were significantly more frequent in controls than in patients with AD.


View this table:
[in this window]
[in a new window]
  		Table 1. Demographic and Clinical Data in Control, VAD, and AD Participants.

 
Table 2 shows the distribution of MMP-1, MMP-3, and MMP-9 genotypes and alleles in all participants. Genotypes were in Hardy–Weinberg equilibrium. In both VAD and AD patients, the frequency of the MMP-1 2G2G genotype was significantly higher than in controls (p =.0008 and p =.0001, respectively). Likewise, allele distribution was statistically different between groups (p <.0001). Also, the MMP-3 5A5A genotype was significantly more common in VAD and AD patients than in controls (p =.009). The 5A allele frequency was 46.9% and 48.6% in VAD and AD participants, respectively, whereas only 39.7% controls carried this allele. The analysis of the MMP-9 gene polymorphism revealed that the TT genotype was significantly more frequent in individuals with VAD than in controls (p =.03), whereas the distribution of the MMP-9 TT, CT, and CC genotypes was not statistically different between AD patients and controls. Finally, no difference was found in the MMP-9 T/C allele distribution between the three studied groups.


View this table:
[in this window]
[in a new window]
  		Table 2. Genotype and Allele Frequencies in Control, VAD, and AD Participants.

 
To assess whether these gene polymorphisms were independently associated with dementia, we used a logistic regression model and adjusted for potential confounding factors. The analyses were conducted assuming a recessive or a dominant relationship between the high-risk alleles and the presence of the disease. After correcting for age, sex, presence of hypertension, hypercholesterolemia, diabetes, CAD, PAOD, and smoking status, we found that increased risk of VAD was significantly and independently associated with the 2G2G and 2G1G genotypes of the MMP-1 gene polymorphism (OR, 2.5; 95% CI, 1.4–4.4; p =.001 and OR, 1.7; 95% CI, 1.0–2.7; p =.03, respectively), the 5A5A genotype of the MMP-3 gene polymorphism (OR, 2.9; 95% CI, 1.5–5.9; p =.002), and the TT genotype of the MMP-9 gene polymorphism (OR, 6.8; 95% CI, 1.3–35.1; p =.02) (Table 3).


View this table:
[in this window]
[in a new window]
  		Table 3. Association Between MMP Genotypes and VAD.

 
A similar logistic regression model was used to investigate the association between the MMP gene polymorphisms and AD. Increased risk of the disease was significantly and independently associated with the MMP-1 2G2G genotype of the MMP-1 gene polymorphism and the 5A5A genotype of the MMP-3 gene polymorphism. In contrast, no increased risk for AD was associated with the presence of the TT genotype of the MMP-9 gene polymorphism (Table 4).


View this table:
[in this window]
[in a new window]
  		Table 4. Association Between MMP Genotypes and AD.

 
To further investigate the role of these gene variations in AD, we also considered the presence of the {varepsilon}4 allele of the apolipoprotein E (APOE) gene polymorphism, which is a well known genetic risk factor for AD (Table 5). In the AD group, 80 participants (43.7%) were positive and 103 (56.3%) were negative for the presence of the APOE {epsilon}4 allele. In the control group, the ratio between APOE {epsilon}4-positive and -negative participants was 28:195 (12.5%:87.5%). We found that the presence of MMP-1 2G2G homozygosity was not associated with increased risk for AD in persons who do not carry the APOE {epsilon}4 allele. In contrast, the OR for AD was increased in participants who concomitantly carried the MMP-1 2G2G genotype and the APOE {varepsilon}4 allele (OR, 6.0; 95% CI, 2.3–15.5; p <.0001). Similarly, an increased OR for AD was found in participants carrying the APOE {epsilon}4 allele in combination with the MMP-3 5A5A genotype (OR, 14.3; 95% CI, 3.2–63.0; p <.0001). No role for the TT genotype of the MMP-9 gene polymorphism was found in AD participants independently on the presence or the absence of the APOE {epsilon}4 allele.


View this table:
[in this window]
[in a new window]
  		Table 5. ORs for AD According to the Interaction Between MMP and APOE Genotypes.

 
Finally, we tested whether the risk of dementia could be influenced by the presence of multiple MMP high-risk genotypes (Table 6). We found that participants who concomitantly carried the MMP-1 2G allele (2G+ individuals) and the MMP-3 5A5A genotype had an increased OR for VAD (OR, 4.0; 95% CI, 1.9–8.2; p <.0001), compared to individuals who only had one of these two gene variations. Likewise, the MMP-1 2G+/MMP-9 TT genotypic combination was associated with increased OR for VAD (OR, 7.7; 95% CI, 1.3–65.3; p =.04), compared to that observed when only one of these high-risk genotypes was present. The MMP-3 5A5A/MMP-9 TT genotypic combination was observed only in five individuals, and all of them (100.0%) were affected by VAD (data not shown). Similarly, the triple 2G+/5A5A/TT combination was found only in five persons, and all of them were affected by VAD (data not shown). A stronger association with AD was also found in participants who concomitantly carried the MMP-1 2G2G and MMP-3 5A5A genotypes (OR, 5.1; 95% CI, 1.9–13.3; p =.001), compared to those who separately exhibited only one of them.


View this table:
[in this window]
[in a new window]
  		Table 6. MMP Genotypic Combinations and Risk of Dementia.

 

   DISCUSSION
Top
 Abstract
 Methods
 Results
 Discussion
References
 
This is the first study investigating the association between two different forms of dementia (VAD and AD) and three functionally important polymorphisms of the MMP-1, MMP-3, and MMP-9 genes. We found that the odds for VAD are increased by the 2G2G and 2G1G genotypes of the MMP-1 gene polymorphism, as well as by the 5A5A genotype of the MMP-3 gene polymorphism and the TT genotype of the MMP-9 gene polymorphism.

In addition, we found an increased risk of AD in association with the MMP-1 2G2G and MMP-3 5A5A genotypes. Importantly, this effect was observed only in persons who also carried the high-risk {varepsilon}4 allele of the APOE gene polymorphism, which is a well-known genetic risk factor for AD. However, it has to be pointed out that the CIs and power of the study are insufficient to establish whether a true gene–gene interaction is present.

The biological significance of these results depends on the fact that the gene polymorphisms investigated in this study are functionally important. Indeed, it has been clearly demonstrated that the MMP-1 1G/2G polymorphism contributes to the regulation of the expression of the MMP-1 gene and, in particular, it has been shown that the presence of the 2G allele is associated with enhanced transcriptional gene activity (30). Similarly, the 5A allele of the MMP-3 gene polymorphism has a higher promoter activity than the 6A allele (12), and transient transfection experiments and DNA–protein interaction assays have indicated that the T allele of the MMP-9 C/T gene polymorphism has a higher promoter activity than the C allele, apparently due to preferential binding of a putative transcription repressor protein to the C allelic promoter (19). Our findings are consistent with the concept that MMP gene polymorphisms may be clinically important, as suggested by several previous studies that have reported a positive association between MMP-1, MMP-3, and MMP-9 gene variations and a number of diseases (18–23). Our data are also consistent with the study of Saarela and colleagues (6), which found an interaction between the MMP-3 5A and APOE 4 alleles and increased risk of AD in a cohort of Finnish individuals. More recently, a lack of association between common polymorphisms of the MMP-3 and MMP-9 genes and AD has instead been reported in a Japanese cohort (31).

A major finding of this study is the observation that there is an increased risk of dementia in persons who concomitantly carry more MMP high-risk genotypes. In particular, we found that, in participants carrying the 2G allele of the MMP-1 gene polymorphism (MMP-1 2G+ individuals), the OR for VAD is further increased by the concomitant presence of either the MMP-3 5A5A genotype or the MMP-9 TT genotype. Likewise, the MMP-1 2G2G and MMP-3 5A5A genotypes contribute to increase the OR for this form of dementia. Our results are consistent with the concept that, although individual single nucleotide polymorphism identification may provide a framework for genetic susceptibility, the characterization of single gene polymorphisms is insufficient to describe the overall effects of genetics on the phenotypic state of complex diseases. Studies have shown that optimal understanding of phenotypic expression will require knowledge of haplotype expression and gene additive effects.

This study has some potential limitations. It is a case–control study, and recruitment and survival bias cannot be excluded. We studied a selected sample of patients admitted to a Department of Medicine for reasons not necessarily related to dementia, and this population might be not representative of the general population. In addition, the participants included in this study had a number of concomitant diseases, and comorbidity might represent a confounding factor. The size of the studied population is relatively small, and our findings need to be confirmed in larger samples and should be tested in groups of different ethnic origin. Also, as this study only included persons affected by sporadic AD, the results should be confirmed in the future in samples that also include familial cases of AD. Finally, we cannot exclude that the observed associations depend on the effect of genes in linkage disequilibrium with the genes investigated in this study.

Conclusion
This is the first study evaluating the role of the MMP-1 1G/2G, MMP-3 5A/6A, and MMP-9 C/T gene polymorphisms in VAD and AD. The risk of dementia may be influenced by the presence of specific MMP genotypes and by reciprocal interactions between them. MMP gene variations might merit further investigation as potential markers of dementia.


   Footnotes
Top
 Abstract
 Methods
 Results
 Discussion
 References
 
Decision Editor: Luigi Ferrucci, MD, PhD

Received September 23, 2005

Accepted April 18, 2006


   References
Top
 Abstract
 Methods
 Results
 Discussion
 References
 

  1. Tarkowski E, Liljeroth AM, Minthon L, Tarkowski A, Wallin A, Blennow K. Cerebral pattern of pro- and anti-inflammatory cytokines in dementias. Brain Res Bull. 2003;61:255-260.[Medline]
  2. Leys D, Erkinjuntti T, Desmond DW, et al. Vascular dementia: the role of cerebral infarcts. Alzheimer Dis Assoc Disord. 1999;(suppl 3):S38–S48.
  3. Wen Y, Yang S, Liu R, Simpkins JW. Transient cerebral ischemia induces site-specific hyperphosphorylation of tau protein. Brain Res. 2004;1022:30-38.[Medline]
  4. Wen Y, Onyewuchi O, Yang S, Liu R, Simpkins JW. Increased beta-secretase activity and expression in rats following transient cerebral ischemia. Brain Res. 2004;1009:1-8.[Medline]
  5. Clark AW, Krekoski CA, Bou SS, Chapman KR, Edwards DR. Increased gelatinase A (MMP-2) and gelatinase B (MMP-9) activities in human brain after focal ischemia. Neurosci Lett. 1997;238:53-56.[Medline]
  6. Saarela MS, Lehtimaki T, Rinne JO, et al. Interaction between matrix metalloproteinase 3 and the epsilon4 allele of apolipoprotein E increases the risk of Alzheimer's disease in Finns. Neurosci Lett. 2004;367:336-339.[Medline]
  7. Asahi M, Wang X, Mori T, et al. Effects of matrix metalloproteinase-9 gene knock-out on the proteolysis of blood-brain barrier and white matter components after cerebral ischemia. J Neurosci. 2001;21:7724-7732.[Abstract/Free Full Text]
  8. Leake A, Morris CM, Whateley J. Brain matrix metalloproteinase 1 levels are elevated in Alzheimer's disease. Neurosci Lett. 2000;291:201-203.[Medline]
  9. Pola R, Flex A, Gaetani E, et al. The –174 G/C polymorphism of the interleukin-6 gene promoter is associated with Alzheimer's disease in an Italian population. Neuroreport. 2002;13:1645-1647.[Medline]
  10. Pola R, Flex A, Gaetani E, et al. Intercellular adhesion molecule-1 K469E gene polymorphism and Alzheimer's disease. Neurobiol Aging. 2003;24:385-387.[Medline]
  11. Pola R, Flex A, Gaetani E, et al. Monocyte chemoattractant protein-1 (MCP-1) gene polymorphism and risk of Alzheimer's disease in Italians. Exp Gerontol. 2004;39:1249-1252.[Medline]
  12. Pola R, Gaetani E, Flex A, et al. –174 G/C interleukin-6 gene polymorphism and increased risk of multi-infarct dementia: a case-control study. Exp Gerontol. 2002;7:949-955.
  13. Pola R, Flex A, Gaetani E, et al. Association between intercellular adhesion molecule-1 E/K gene polymorphism and probable vascular dementia in humans. Neurosci Lett. 2002;326:171-174.[Medline]
  14. Medley TL, Cole TJ, Dart AM, Gatzka CD, Kingwell BA. Matrix metalloproteinase-9 genotype influences large artery stiffness through effects on aortic gene and protein expression. Arterioscler Thromb Vasc Biol. 2004;24:1479-1484.[Abstract/Free Full Text]
  15. Zhu Y, Spitz MR, Lei L, Mills GB, Wu X. A single nucleotide polymorphism in the matrix metalloproteinase-1 promoter enhances lung cancer susceptibility. Cancer Res. 2001;61:7825-7829.[Abstract/Free Full Text]
  16. Ye S, Eriksson P, Hamsten A, Kurkinen M, Humphries SE, Henney AM. Progression of coronary atherosclerosis is associated with a common genetic variant of the human stromelysin-1 promoter which results in reduced gene expression. J Biol Chem. 1996;271:13055-13060.[Abstract/Free Full Text]
  17. Zhang B, Ye S, Herrmann SM, et al. Functional polymorphism in the regulatory region of gelatinase B gene in relation to severity of coronary atherosclerosis. Circulation. 1999;99:1788-1794.[Abstract/Free Full Text]
  18. Ye S. Polymorphism in matrix metalloproteinase gene promoters: implication in regulation of gene expression and susceptibility of various diseases. Matrix Biol. 2000;19:623-629.[Medline]
  19. Hirata H, Okayama N, Naito K, et al. Association of a haplotype of matrix metalloproteinase (MMP)-1 and MMP-3 polymorphisms with renal cell carcinoma. Carcinogenesis. 2004;25:2379-2384.[Abstract/Free Full Text]
  20. Satsangi J, Chapman RW, Haldar N, et al. A functional polymorphism of the stromelysin gene (MMP-3) influences susceptibility to primary sclerosing cholangitis. Gastroenterology. 2001;121:124-130.[Medline]
  21. Mattey DL, Nixon NB, Dawes PT, Ollier WE, Hajeer AH. Association of matrix metalloproteinase 3 promoter genotype with disease outcome in rheumatoid arthritis. Genes Immun. 2004;5:147-149.[Medline]
  22. Lanfear DE, Marsh S, Cresci S, Shannon WD, Spertus JA, McLeod HL. Genotypes associated with myocardial infarction risk are more common in African Americans than in European Americans. J Am Coll Cardiol. 2004;44:165-167.[Abstract/Free Full Text]
  23. Ye S, Gale CR, Martyn CN. Variation in the matrix metalloproteinase-1 gene and risk of coronary heart disease. Eur Heart J. 2003;24:1668-1671.[Abstract/Free Full Text]
  24. Roman GC, Tatemichi TK, Erkinjuntti T, et al. Vascular dementia: diagnostic criteria for research studies. Neurology. 2003;43:259-260.
  25. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology. 1984;34:939-344.[Abstract/Free Full Text]
  26. Hachinski VC, Iliff LD, Zilhka E, et al. Cerebral blood flow in dementia. Arch Neurol. 1975;32:632-637.[Abstract/Free Full Text]
  27. Lee YH, Kim HJ, Rho YH, Choi SJ, Ji JD, Song GG. Functional polymorphisms in matrix metalloproteinase-1 and monocyte chemoattractant protein-1 and rheumatoid arthritis. Scand J Rheumatol. 2003;32:235-239.[Medline]
  28. Gnasso A, Motti C, Irace C, et al. Genetic variation in human stromelysin gene promoter and common carotid geometry in healthy male subjects. Arterioscler Thromb Vasc Biol. 2000;20:1600-1605.[Abstract/Free Full Text]
  29. Jones GT, Phillips VL, Harris EL, Rossaak JI, van Rij AM. Functional matrix metalloproteinase-9 polymorphism (C-1562T) associated with abdominal aortic aneurysm. J Vasc Surg. 2003;38:1363-1367.[Medline]
  30. Rutter JL, Mitchell TI, Buttice G, et al. A single nucleotide polymorphism in the matrix metalloproteinase-1 promoter creates an Ets binding site and augments transcription. Cancer Res. 1998;58:5321-5325.[Abstract/Free Full Text]
  31. Shibata N, Ohnuma T, Higashi S, et al. Genetic association between matrix metalloproteinase MMP-9 and MMP-3 polymorphisms and Japanese sporadic Alzheimer's disease. Neurobiol Aging. 2005;26:1011-1014.[Medline]




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Services
Right arrow Download to citation manager
PubMed
Right arrow PubMed Citation

HOME ARCHIVE SEARCH TABLE OF CONTENTS