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Association between the Matrix Metalloproteinase-9 rs3918242 Polymorphism and Ischemic Stroke Susceptibility: A Meta-Analysis
ARTICLE IN PRESS
Association between the Matrix Metalloproteinase-9 rs3918242 Polymorphism and Ischemic Stroke Susceptibility: A Meta-Analysis Tao He,
MS,*
Jie Wang,
MS,†
Xiao-Li Wang, MS,‡ Wen-Shuai Deng, Peng Sun, PhD*
PhD,*
and
Background: In recent years, dozens of case-control studies showed that matrix metalloproteinase (MMP)-9 rs3918242 variants were associated with ischemic stroke (IS) susceptibility. However, the conclusions of case-control studies that evaluated the relationship between MMP-9 rs3918242 variants and the risk of IS were still equivocal. Herein, we conducted a comprehensive meta-analysis to investigate the association between MMP-9 rs3918242 variants and the risk of IS. Methods: We searched 5 databases (PubMed, EMBASE, Google Scholar, Web of Science, and Chinese Biomedical Literature Database) to identify the eligible studies up to October of 2016. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to evaluate the association of MMP-9 rs3918242 variants with IS susceptibility under the allelic model (T versus C) and the dominant model (TT + CT versus CC). Results: A total of 14 studies with 3233 cases and 3123 controls were included in this meta-analysis. Our meta-analysis indicated that MMP-9 rs3918242 variants were associated with significantly increased risk of IS in overall populations (T versus C: OR = 1.43, 95% CI = 1.20-1.71, P < .001; TT + CT versus CC: OR = 1.39, 95% CI = 1.16-1.67, P < .001). Subgroup analysis based on ethnicity (Chinese and Caucasian) suggested that MMP-9 rs3918242 variants contributed to increase the risk of IS in Chinese population; However, no association was detected between MMP-9 rs3918242 variants and the risk of IS in Caucasian population. Conclusion: Therefore, our meta-analysis suggested that MMP-9 rs3918242 variants (T allele, TT and CT genotypes) contributed to significantly increase the risk of IS in the Chinese population. Key Words: MMP-9—metaanalysis—polymorphism—ischemic stroke. © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved.
From the *Department of Neurosurgery, Affiliated Hospital of Qingdao University, Qingdao, China; †Department of Gerontology, Affiliated Hospital of Qingdao University, Qingdao, China; and ‡Department of Neurology, Affiliated Hospital of Qingdao University, Qingdao, China. Received December 8, 2016; revision received December 25, 2016; accepted December 31, 2016. Grant support: This work was supported by the National Natural Science Foundation of China (Grant No. 81671305) and the Key Development Projects of Shandong Province (Grant No. 2015GSF118177). Address correspondence to Peng Sun, PhD, Department of Neurosurgery, Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Qingdao 266003, China. E-mail: [email protected]. 1052-3057/$ - see front matter © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2016.12.036
Introduction Ischemic stroke (IS), a multifactorial vascular disease, still remains a major reason of morbidity and mortality worldwide. The exact etiology and pathogenesis of IS are not well understood; However, environmental factors (such as diabetes, hypertension, atrial fibrillation, and dyslipidemia) have been confirmed as important factors for risk of IS.1-4 In addition, genetic factors were also correlated with occurrence and progress of IS because not all individuals were exposed to the abovementioned environmental factors. Large amount of studies showed that inflammation has an important role in the risk of IS. Matrix metalloproteinases (MMPs), which belong to a family of zinc-dependent
Journal of Stroke and Cerebrovascular Diseases, Vol. ■■, No. ■■ (■■), 2017: pp ■■–■■
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proteolytic enzymes, are an important inflammatory mediator and play a vital role in degrading the extracellular matrix in both physiological and pathologic processes.5 MMPs, produced by endothelial cells, microglia, neurons, and astrocytes, are involved in the progress of atherosclerosis by activating migration and proliferation of smooth muscle cells and inducting destabilization of atherosclerotic plaques.6,7 In clinical conditions, imbalanced MMP activity has been shown to be associated with cardiovascular and cerebrovascular diseases.6,8,9 MMP-9 is one of the important members of the MMP family, and several MMP-9 gene polymorphisms regulated the MMP-9 activity.10-12 Currently, studies have identified MMP-91562 C > T (rs3918242) polymorphism within the promoter of the MMP-9 gene.12 In 2009, Zhang et al13 found that T-1562 allele-to-C-1562 allele transition led to a higher promoter activity of MMP-9. In particular, MMP-9 exhibited higher expression levels in human brain tissues of IS, indicating that MMP-9 may contribute to ischemic brain injury.14 In 2014, 2 meta-analysis were performed to assess the association of MMP-9 rs3918242 polymorphism with IS susceptibility, but no association was detected in their meta-analysis.15,16 In recent years, increasing evidence has indicated that MMP-9 rs3918242 variants were associated with risk of IS. Although the studies have reported the association of MMP-9 rs3918242 variants with IS susceptibility, the results still remain controversial. Therefore, we performed a comprehensive meta-analysis including 14 studies to provide more reliable conclusions on the associations between MMP-9 rs3918242 variants and the risk of IS.
Materials and Methods Literature Search To identify the available studies that evaluated the relationship between MMP-9 rs3918242 polymorphism and the risk of IS for meta-analysis, 5 databases (PubMed, EMBASE, Google Scholar, Web of Science, and Chinese Biomedical Literature Database) were searched independently by 2 investigators (T.H. and J.W.) using the following items: “MMP-9 or matrix metalloproteinase-9 or 92-kDa type IV collagenase or gelatinase B” and “ischemic stroke or IS or cerebral infarction” from inception to October 2016; only Chinese and English language studies were included. Moreover, we reviewed reference lists of selected studies for other eligible studies.
were provided to calculate odds ratios (ORs) and 95% confidence intervals (95% CI); (3) When studies reported the overlapping samples, only larger samples or recent studies were given precedence; (4) Studies must have full-text publications; (5) Genotype distributions of the healthy controls must accord with Hardy–Weinberg equilibrium. In addition, studies were excluded if they had incomplete genotype distributions, were animal studies, did not have a case-control or cohort design, or were case reports, reviews, and meta-analysis.
Data Extraction Data extraction was performed independently by 2 investigators (T.H. and J.W.) from all selected studies and any disagreements were resolved by the third investigator (X.L.W.). The following information was extracted: first author, year of publication, genotyping methods, ethnicity, gender, age, the number of patients and healthy controls, diagnostic criteria, genotype frequencies, and Hardy–Weinberg equilibrium.
Statistical Analysis ORs and its 95% CIs were used to estimate the association between MMP-9 rs3918242 variants and IS susceptibility based on the methods of the study by Woolf.17 Considering the low frequency of risk allele (T), we used allele model (T versus C) and dominant model (TT + CT versus CC) to assess the risks of the genotypes on IS. Heterogeneity across individual studies was determined by I2-statistics.18,19 Heterogeneity was considered statistically significant if I2 was greater than or equal to 50% (no heterogeneity: I2 <25%; moderate heterogeneity: I2 = 25%-50%).20 If I2 was greater than or equal to 50%, the random effect model was used in this metaanalysis; otherwise, the fixed effect model was adopted.21 The visual inspection of funnel plots and P value for Begg’s test were used to weigh the publication bias, and the symmetric plot or P value >.05 was considered no publication bias.22 To evaluate the stability of the results, sensitivity analysis was conducted by omitting each individual study in turn from all available studies and reanalyzing the remaining studies. Moreover, stratified analysis was conducted based on ethnicity. The overall analysis and stratified analysis were performed by Stata software version 12.0 (StataCorp, College Station, TX).
Results Inclusion and Exclusion Criteria Studies that estimated the association between MMP-9 rs3918242 polymorphism and the risk of IS were included in our meta-analysis if they matched the following inclusion criteria: (1) Study design must be a casecontrol or cohort study; (2) Sufficient genotype frequencies
Characteristics of Eligible Studies Figure 1 graphically describes the flow diagram of study identification and selection process. Three hundred and eighty-six studies were identified. Finally, a total of 14 studies23-36 with 3233 cases and 3123 controls that evaluated the correlation of MMP-9 rs3918242 variants with
ARTICLE IN PRESS MMP-9 RS3918242 POLYMORPHISM AND ISCHEMIC STROKE SUSCEPTIBILITY
Figure 1.
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Flow diagram for the process of selecting articles.
the risk of IS were included in our meta-analysis. Of these, 323,24,36 studies with 801 cases and 877 controls involved Caucasian population, and 1125-35 studies with 2432 cases and 2246 controls focused on Chinese population. The primary characteristics of all studies included are listed in Table 1.
Association between MMP-9 rs3918242 Variants and Risk of IS A total of 14 studies with 3233 cases and 3123 controls examined the relationship between MMP-9 rs3918242 variants and the risk of IS. The main results of our metaanalysis and heterogeneity test are listed in Table 2. Overall, significant association was identified in allelic and dominant models (Table 2, Fig 2). In addition, stratified analysis based on ethnicity (Chinese and Caucasian) indicated MMP-9 rs3918242 variants were associated with increased risk of IS in the Chinese population. However, no association was found between MMP-9 rs3918242 variants and the risk of IS in the Caucasian population (Table 2, Fig 2).
Sensitivity Analysis and Publication Bias The sensitivity analysis was performed by sequential omission of any single study in turn. The results showed that pooled OR and 95% CI were not materially altered (Fig 3). Publication bias was assessed by the shape of funnel plots and P value for Begg’s test. The shape of funnel plots and the P value >.05 (T versus C: P = .189; TT + CT versus CC: P = .352) showed no significant publication bias (Fig 4).
Discussion IS, caused by a sudden, reduced or interrupted blood flow to the brain, still remains a leading cause of morbidity and mortality worldwide, with an approximated 9.9% of deaths in overall populations.37 Although the pathogenesis of IS was still elusive, an enormous body of evidence suggested that genetic factors were closely related to the risk of IS. MMP-9, also called 92-kDa type IV collagenase or gelatinase B, is one of the members of the MMP family. The promoter region of the MMP-9 gene contains a
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Table 1. Basic characteristics of the 14 case-control studies included
First author
Year
Ethnicity
Buraczynska24 Li25 Zhao26 Nie27 Hao28 Liu29 Zhang30 Shi31 Zhou32 Yue33 Zhou34 Hou35 Szczudlik23 Montaner36
2015 2013 2015 2014 2015 2011 2008 2011 2008 2014 2009 2009 2010 2003
Caucasian Chinese Chinese Chinese Chinese Chinese Chinese Chinese Chinese Chinese Chinese Chinese Caucasian Caucasian
322/410 302/308 335/335 396/400 317/317 232/235 114/80 224/112 101/114 284/226 70/60 57/59 418/408 61/59
Control
CT
TT
CC
CT
TT
Diagnostic criteria
Male of case/control
Age distribution in case/control
174 132 252 50 223 64 305 62 214 59 181 48 95 16 186 38 87 14 227 50 46 22 46 10 315 89 44 17
16 0 48 29 44 3 3 0 0 7 2 1 14 0
283 119 271 37 254 71 338 41 242 66 204 29 63 15 92 20 99 13 195 28 50 8 47 12 291 111 47 12
8 0 10 21 9 2 2 0 2 3 2 0 6 0
CT and/or MRI CT and/or MRI CT and/or MRI WHO Diagnostic Criteria CT and/or MRI CT and/or MRI CT and/or MRI CT and/or MRI MRI CT and/or MRI CT and/or MRI CT TOAST CT
156/217 165/140 194/194 279/276 180/180 146/144 82/54 126/54 46/51 163/124 40/35 39/52 205/195 27/NA
64.3 ± 12.7/NA 65.71 ± 9.8/63.21 ± 8.19 63.65 ± 9.40/64.45 ± 9.15 64.9 ± 8.9/64.1 ± 9.7 62.13 ± 10.25/62.50 ± 9.85 62.07 ± 4.88/60.86 ± 9.92 66.0 ± 10.9/64.0 ± 13.6 64.5 ± 10.95/66.93 ± 10.87 61.6 ± 11.5/59.6 ± 10.9 67.52 ± 13.28/67.86 ± 11.74 57.7 ± 10.2/54.2 ± 9.4 68 ± 10/63 ± 9 66.4 ± 12.3/64.4 ± 18.4 71 ± 9.3/NA
CC
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Case No. of case/control
Genotyping method HWE PCR–RFLP PCR–RFLP PCR–RFLP PCR–RFLP PCR–RFLP PCR–RFLP PCR–RFLP PCR–RFLP PCR–RFLP PCR–RFLP PCR–RFLP PCR–RFLP PCR–RFLP PCR–RFLP
Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
Abbreviations: CT, computed tomography; HWE, Hardy–Weinberg equilibrium; MRI, magnetic resonance imaging; NA, not available; PCR, polymerase chain reaction; RFLP, restricted fragment length polymorphism; TOAST, Trial of Org 10172 in Acute Stroke Treatment; WHO, World Health Organization.
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Table 2. Meta-analysis of MMP-9 rs3918242 polymorphism on IS susceptibility T versus C
TT+CT versus CC
Ethnicity
N
OR (95% CI)
I2 (%)
P
OR (95% CI)
I2 (%)
P
Overall Chinese Caucasian
14 11 3
1.43 (1.20-1.71) 1.60 (1.41-1.82) 1.30 (.79-2.13)
58.10 39.10 82.10
<.001 <.001 .305
1.39 (1.16-1.67) 1.48 (1.28-1.71) 1.30 (.68-2.49)
51.40 4.50 86.50
<.001 <.001 .423
Abbreviations: CI, confidence interval; IS, ischemic stroke; MMP, matrix metalloproteinase; OR, odds ratio.
-1562C/T polymorphism (rs3918242), and this polymorphism is located on chromosome 20q12.2-13.1. It was reported that carrying the -1562T allele has a higher transcriptional activity of MMP-9 compared to -1562C allele carriers.38 Several studies have also shown plasma protein levels were higher in T allele carriers than C allele carriers.39 At present, the mechanism of rs3918242 polymorphism regulating expression of MMP-9 is not fully clear. Loftus et al40 found MMP-9 was highly expressed in unstable carotid plaques compared to stable carotid plaques. Gu et al41 showed that abnormal hyperactivity of MMP-9 can directly cause programmed neuronal death and brain damage. In our meta-analysis, we found MMP-9 rs3918242 variants were associated with significantly increased risk of IS.
Several case-control studies have been focused on the association between MMP-9 rs3918242 polymorphism and the risk of IS. Montaner et al36 firstly conducted a casecontrol study in a Spanish population, and they showed that there was no association of MMP-9 rs3918242 variants with IS susceptibility. Another study was performed in a Polish population, and they also showed no correlation between MMP-9 rs3918242 variants and the risk of IS. In recent years, significant associations between MMP-9 rs3918242 variants and increased risk of IS were found in some case-control studies.24,26-28 The inconclusive or conflicting results may be due to the genetic or environmental factors. Therefore, we conducted a comprehensive meta-analysis to gain more reliable conclusions.
Figure 2. Forest plot for the association of MMP-9 rs3918242 variants with IS susceptibility (TT + CT versus CC). Abbreviations: IS, ischemic stroke; MMP, matrix metalloproteinase.
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Figure 3.
Sensitivity analysis of the summary OR coefficients in the overall population (TT + CT versus CC). Abbreviation: OR, odds ratio.
In this study, we found MMP-9 rs3918242 variants were associated with increased risk of IS under the allelic and dominant models. Our conclusions were not consistent with the previous meta-analysis.15,16 Only 3 case-control studies that involved cervical artery dissection (CAD) and IS were included in 1 meta-analysis.16 We noted that CAD is just as an etiology for occurrence of IS, and CAD did not mean IS, and these studies’ conclusions may thus be disputable. The other meta-analysis15 including 6 case-
control studies with 1176 IS patients and 1051 controls showed no association of MMP-9 rs3918242 variants with IS susceptibility. To date, we performed a comprehensive meta-analysis including 14 case-control studies with 3233 cases and 3123 controls, and the results showed MMP-9 rs3918242 variants were associated with increased risk of IS in overall populations. In the stratified analysis, we found that MMP-9 rs3918242 variants contributed to increase the risk of IS in the Chinese population;
Figure 4. Begg’s funnel plot of MMP-9 rs3918242 variants with IS susceptibility in overall populations (TT + CT versus CC). Abbreviations: IS, ischemic stroke; MMP, matrix metalloproteinase.
ARTICLE IN PRESS MMP-9 RS3918242 POLYMORPHISM AND ISCHEMIC STROKE SUSCEPTIBILITY
However, no association was detected between MMP-9 rs3918242 variants and IS susceptibility in the Caucasian population. In addition, no publication bias was found in our meta-analysis. In all, our meta-analysis suggested that MMP-9 rs3918242 variants T allele may contribute to increase the risk of IS in the Chinese population. Interestingly, Zhang et al42 found that T allele may be a protective factor against hemorrhagic transformation of IS in the Chinese population. Because of insufficient data, the association between MMP-9 rs3918242 variants and hemorrhagic transformation was not included in our meta-analysis. This association should be analyzed in future studies. Some potential limitations of our meta-analysis should be emphasized. Firstly, only published studies were included in this meta-analysis. Therefore, the publication bias may exist in our meta-analysis. Secondly, association between the MMP-9 3918242 polymorphism and IS risk might be due to the synergistic interactions with other genes. In addition, significant heterogeneity was observed in the Caucasian population. However, there were only 3 studies that estimated the association between MMP-9 variants and risk of IS in the Caucasian population, which may limit further analysis. In a word, our meta-analysis of 14 case-control studies showed MMP-9 rs3918242 variants were associated with increased risk of IS. Moreover, considering the 3 limitations mentioned above, well-designed studies with larger sample sizes are still required to validate the association between MMP-9 rs3918242 polymorphism and risk of IS. Acknowledgment: We would like to acknowledge the investigators for their helpful comments on this paper.
References 1. Ghilardi G, Biondi ML, DeMonti M, et al. Matrix metalloproteinase-1 and matrix metalloproteinase-3 gene promoter polymorphisms are associated with carotid artery stenosis. Stroke 2002;33:2408-2412. 2. Kalb R. Spontaneous dissection of the carotid and vertebral arteries. N Engl J Med 2001;6:467. 3. Brandt T, Orberk E, Weber R, et al. Pathogenesis of cervical artery dissections: association with connective tissue abnormalities. Neurology 2001;57:24-30. 4. Lin RT, Chen CH, Tsai PC, et al. Sex-specific effect of matrix metalloproteinase-9 functional promoter polymorphism on carotid artery stiffness. Atherosclerosis 2012;223:416-420. 5. Visse R, Nagase H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res 2003;92:827-839. 6. Galis ZS, Khatri JJ. Matrix metalloproteinases in vascular remodeling and atherogenesis: the good, the bad, and the ugly. Circ Res 2002;90:251-262. 7. Katakami N, Takahara M, Kaneto H, et al. Accumulation of gene polymorphisms related to plaque disruption and thrombosis is associated with cerebral infarction in subjects with type 2 diabetes. Diabetes Care 2010;33:390-395.
7
8. Siefert SA, Sarkar R. Matrix metalloproteinases in vascular physiology and disease. Vascular 2012;20:210-216. 9. Chen Q, Jin M, Yang F, et al. Matrix metalloproteinases: inflammatory regulators of cell behaviors in vascular formation and remodeling. Mediators Inflamm 2013;2013: 928315. 10. Kaplan RC, Smith NL, Zucker S, et al. Matrix metalloproteinase-3 (MMP3) and MMP9 genes and risk of myocardial infarction, ischemic stroke, and hemorrhagic stroke. Atherosclerosis 2008;201:130-137. 11. Fornage M, Mosley TH, Jack CR, et al. Family-based association study of matrix metalloproteinase-3 and -9 haplotypes with susceptibility to ischemic white matter injury. Hum Genet 2007;120:671-680. 12. 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. 13. Zhang B, Henney A, Eriksson P, et al. Genetic variation at the matrix metalloproteinase-9 locus on chromosome 20q12.2-13.1. Hum Genet 1999;105:418-423. 14. Rosell A, Ortega-Aznar A, Alvarez-Sabín J, et al. Increased brain expression of matrix metalloproteinase-9 after ischemic and hemorrhagic human stroke. Stroke 2006;37: 1399-1406. 15. Fan ZZ, Ge ZM, Cai HB, et al. Association between the MMP-9-1562 C>T polymorphism and the risk of stroke: a meta-analysis. Mol Biol Rep 2014;41:6787-6794. 16. Wen D, Du X, Nie SP, et al. Association between matrix metalloproteinase family gene polymorphisms and ischemic stroke: a meta-analysis. Mol Neurobiol 2014; 50:979-985. 17. Woolf B. On estimating the relation between blood group and disease. Ann Hum Genet 1955;19:251-253. 18. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002;21:1539-1558. 19. Zintzaras E, Ioannidis JP. Heterogeneity testing in meta-analysis of genome searches. Genet Epidemiol 2005;28:123-137. 20. Lau J, Ioannidis JP, Schmid CH. Quantitative synthesis in systematic reviews. Ann Intern Med 1997;127:820826. 21. Martin WJ. Statistical aspects of poliomyelitis in England and Wales in recent years. Mon Bull Minist Health Public Health Lab Serv 1959;18:54-64. 22. Egger M, Davey SG, Schneider M, et al. Bias in metaanalysis detected by a simple, graphical test. BMJ 1997;315:629-634. 23. Szczudlik P, Borratyn´ska A. Association between the -1562 C/T MMP-9 polymorphism and cerebrovascular disease in a Polish population. Neurol Neurochir Pol 2010;44:350357. 24. Buraczynska K, Kurzepa J, Ksiazek A, et al. Matrix metalloproteinase-9 (MMP-9) gene polymorphism in stroke patients. Neuromolecular Med 2015;17:385-390. 25. Li JY, Wu HR, Li HX, et al. Association between gene polymorphism of ALOX5AP, COX-2, MPP-9 and ischemic stroke. Med J Qiulu 2013;28:321-324. 26. Zhao JH, Xu YM, Xing HX, et al. Associations between matrix metalloproteinase gene polymorphisms and the development of cerebral infarction. Genet Mol Res 2016;14:19418-19424. 27. Nie SW, Wang XF, Tang ZC. Correlations between MMP-2/MMP-9 promoter polymorphisms and ischemic stroke. Int J Clin Exp Med 2014;7:400-404. 28. Hao Y, Tian S, Sun M, et al. Association between matrix metalloproteinase gene polymorphisms and development
ARTICLE IN PRESS T. HE ET AL.
8
29.
30.
31.
32.
33.
34.
35.
36.
of ischemic stroke. Int J Clin Exp Pathol 2015;8:1164711652. Liu D, Sun HY, Yang Y, et al. Polymorphisms of matrix metalloproteinase-2 C735T and-9 C1562T are associated with stroke and its subtype large artery atherosclerotic stroke, but not associated with the prognosis in patients with ischemic stroke. Int J Cerebrovasc Dis 2011;19:503-509. Zhang L, Zhang YD, Li JY, et al. Relationship between the gene polymorphism of matrix metalloproteinase-9 C1562T and ischemic stroke. J Clin Neurol 2008;21. Shi N, Wang L, Song LY, et al. A study of the association between polymorphism of MMP-9 gene and atherosclerosis and cerebral infarction. Chin J Clin Neurosci 2011;19:476-480. Zhou YL, Jin XP, Zhu M, et al. Relationship between matrix metalloproteinase-9 polymorphism and acute cerebral infarction. Chin J Neurol 2008;41:97-101. Yue YH, Bai XD, Zhang XN, et al. Correlation between serum matrix metalloproteinase-9 levels and its gene -1562C>T polymorphism to ischemic stroke subtypes in Uygur nationality. Chin J Arterioscler 2014;22:55-60. Zhou J, Liu J. Matrix metalloproteinase-9 polymorphism (C1562T) in patients with cerebral infarction. China J Modern Med 2009;12:1829-1831. Hou LH, Liu XE, Li H, et al. Polymorphism of matrix metalloproteinase-9 related to cerebral infarction. Chin Remedies Clin 2009;9:575-577. Montaner J, Fernández-Cadenas I, Molina CA, et al. Safety profile of tissue plasminogen activator treatment among
37.
38.
39.
40.
41.
42.
stroke patients carrying a common polymorphism (C-1562T) in the promoter region of the matrix metalloproteinase-9 gene. Stroke 2003;34:2851-2855. Truelsen T, Heuschmann PU, Bonita R, et al. Standard method for developing stroke registers in low-income and middle-income countries: experiences from a feasibility study of a stepwise approach to stroke surveillance (STEPS Stroke). Lancet Neurol 2007;6:134139. Blankenberg S, Rupprecht HJ, Poirier O, et al. Plasma concentrations and genetic variation of matrix metalloproteinase 9 and prognosis of patients with cardiovascular disease. Circulation 2003;107:1579-1585. Buss A, Pech K, Roelver S, et al. Functional polymorphisms in matrix metalloproteinases -1, -3, -9 and -12 in relation to cervical artery dissection. BMC Neurol 2009;9: 40. Loftus IM, Naylor AR, Goodall S, et al. Increased matrix metalloproteinase-9 activity in unstable carotid plaques. A potential role in acute plaque disruption. Stroke 2000;31:40-47. Gu Z, Cui J, Brown S, et al. A highly specific inhibitor of matrix metalloproteinase-9 rescues laminin from proteolysis and neurons from apoptosis in transient focal cerebral ischemia. J Neurosci 2005;25:6401-6408. Zhang X, Cao X, Xu X, et al. Correlation between the -1562C/T polymorphism in the matrix metalloproteinase-9 gene and hemorrhagic transformation of ischemic stroke. Exp Ther Med 2015;9:1043-1047.
Association between the Matrix Metalloproteinase-9 rs3918242 Polymorphism and Ischemic Stroke Susceptibility: A Meta-Analysis Tao He,
MS,*
Jie Wang,
MS,†
Xiao-Li Wang, MS,‡ Wen-Shuai Deng, Peng Sun, PhD*
PhD,*
and
Background: In recent years, dozens of case-control studies showed that matrix metalloproteinase (MMP)-9 rs3918242 variants were associated with ischemic stroke (IS) susceptibility. However, the conclusions of case-control studies that evaluated the relationship between MMP-9 rs3918242 variants and the risk of IS were still equivocal. Herein, we conducted a comprehensive meta-analysis to investigate the association between MMP-9 rs3918242 variants and the risk of IS. Methods: We searched 5 databases (PubMed, EMBASE, Google Scholar, Web of Science, and Chinese Biomedical Literature Database) to identify the eligible studies up to October of 2016. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to evaluate the association of MMP-9 rs3918242 variants with IS susceptibility under the allelic model (T versus C) and the dominant model (TT + CT versus CC). Results: A total of 14 studies with 3233 cases and 3123 controls were included in this meta-analysis. Our meta-analysis indicated that MMP-9 rs3918242 variants were associated with significantly increased risk of IS in overall populations (T versus C: OR = 1.43, 95% CI = 1.20-1.71, P < .001; TT + CT versus CC: OR = 1.39, 95% CI = 1.16-1.67, P < .001). Subgroup analysis based on ethnicity (Chinese and Caucasian) suggested that MMP-9 rs3918242 variants contributed to increase the risk of IS in Chinese population; However, no association was detected between MMP-9 rs3918242 variants and the risk of IS in Caucasian population. Conclusion: Therefore, our meta-analysis suggested that MMP-9 rs3918242 variants (T allele, TT and CT genotypes) contributed to significantly increase the risk of IS in the Chinese population. Key Words: MMP-9—metaanalysis—polymorphism—ischemic stroke. © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved.
From the *Department of Neurosurgery, Affiliated Hospital of Qingdao University, Qingdao, China; †Department of Gerontology, Affiliated Hospital of Qingdao University, Qingdao, China; and ‡Department of Neurology, Affiliated Hospital of Qingdao University, Qingdao, China. Received December 8, 2016; revision received December 25, 2016; accepted December 31, 2016. Grant support: This work was supported by the National Natural Science Foundation of China (Grant No. 81671305) and the Key Development Projects of Shandong Province (Grant No. 2015GSF118177). Address correspondence to Peng Sun, PhD, Department of Neurosurgery, Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Qingdao 266003, China. E-mail: [email protected]. 1052-3057/$ - see front matter © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2016.12.036
Introduction Ischemic stroke (IS), a multifactorial vascular disease, still remains a major reason of morbidity and mortality worldwide. The exact etiology and pathogenesis of IS are not well understood; However, environmental factors (such as diabetes, hypertension, atrial fibrillation, and dyslipidemia) have been confirmed as important factors for risk of IS.1-4 In addition, genetic factors were also correlated with occurrence and progress of IS because not all individuals were exposed to the abovementioned environmental factors. Large amount of studies showed that inflammation has an important role in the risk of IS. Matrix metalloproteinases (MMPs), which belong to a family of zinc-dependent
Journal of Stroke and Cerebrovascular Diseases, Vol. ■■, No. ■■ (■■), 2017: pp ■■–■■
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proteolytic enzymes, are an important inflammatory mediator and play a vital role in degrading the extracellular matrix in both physiological and pathologic processes.5 MMPs, produced by endothelial cells, microglia, neurons, and astrocytes, are involved in the progress of atherosclerosis by activating migration and proliferation of smooth muscle cells and inducting destabilization of atherosclerotic plaques.6,7 In clinical conditions, imbalanced MMP activity has been shown to be associated with cardiovascular and cerebrovascular diseases.6,8,9 MMP-9 is one of the important members of the MMP family, and several MMP-9 gene polymorphisms regulated the MMP-9 activity.10-12 Currently, studies have identified MMP-91562 C > T (rs3918242) polymorphism within the promoter of the MMP-9 gene.12 In 2009, Zhang et al13 found that T-1562 allele-to-C-1562 allele transition led to a higher promoter activity of MMP-9. In particular, MMP-9 exhibited higher expression levels in human brain tissues of IS, indicating that MMP-9 may contribute to ischemic brain injury.14 In 2014, 2 meta-analysis were performed to assess the association of MMP-9 rs3918242 polymorphism with IS susceptibility, but no association was detected in their meta-analysis.15,16 In recent years, increasing evidence has indicated that MMP-9 rs3918242 variants were associated with risk of IS. Although the studies have reported the association of MMP-9 rs3918242 variants with IS susceptibility, the results still remain controversial. Therefore, we performed a comprehensive meta-analysis including 14 studies to provide more reliable conclusions on the associations between MMP-9 rs3918242 variants and the risk of IS.
Materials and Methods Literature Search To identify the available studies that evaluated the relationship between MMP-9 rs3918242 polymorphism and the risk of IS for meta-analysis, 5 databases (PubMed, EMBASE, Google Scholar, Web of Science, and Chinese Biomedical Literature Database) were searched independently by 2 investigators (T.H. and J.W.) using the following items: “MMP-9 or matrix metalloproteinase-9 or 92-kDa type IV collagenase or gelatinase B” and “ischemic stroke or IS or cerebral infarction” from inception to October 2016; only Chinese and English language studies were included. Moreover, we reviewed reference lists of selected studies for other eligible studies.
were provided to calculate odds ratios (ORs) and 95% confidence intervals (95% CI); (3) When studies reported the overlapping samples, only larger samples or recent studies were given precedence; (4) Studies must have full-text publications; (5) Genotype distributions of the healthy controls must accord with Hardy–Weinberg equilibrium. In addition, studies were excluded if they had incomplete genotype distributions, were animal studies, did not have a case-control or cohort design, or were case reports, reviews, and meta-analysis.
Data Extraction Data extraction was performed independently by 2 investigators (T.H. and J.W.) from all selected studies and any disagreements were resolved by the third investigator (X.L.W.). The following information was extracted: first author, year of publication, genotyping methods, ethnicity, gender, age, the number of patients and healthy controls, diagnostic criteria, genotype frequencies, and Hardy–Weinberg equilibrium.
Statistical Analysis ORs and its 95% CIs were used to estimate the association between MMP-9 rs3918242 variants and IS susceptibility based on the methods of the study by Woolf.17 Considering the low frequency of risk allele (T), we used allele model (T versus C) and dominant model (TT + CT versus CC) to assess the risks of the genotypes on IS. Heterogeneity across individual studies was determined by I2-statistics.18,19 Heterogeneity was considered statistically significant if I2 was greater than or equal to 50% (no heterogeneity: I2 <25%; moderate heterogeneity: I2 = 25%-50%).20 If I2 was greater than or equal to 50%, the random effect model was used in this metaanalysis; otherwise, the fixed effect model was adopted.21 The visual inspection of funnel plots and P value for Begg’s test were used to weigh the publication bias, and the symmetric plot or P value >.05 was considered no publication bias.22 To evaluate the stability of the results, sensitivity analysis was conducted by omitting each individual study in turn from all available studies and reanalyzing the remaining studies. Moreover, stratified analysis was conducted based on ethnicity. The overall analysis and stratified analysis were performed by Stata software version 12.0 (StataCorp, College Station, TX).
Results Inclusion and Exclusion Criteria Studies that estimated the association between MMP-9 rs3918242 polymorphism and the risk of IS were included in our meta-analysis if they matched the following inclusion criteria: (1) Study design must be a casecontrol or cohort study; (2) Sufficient genotype frequencies
Characteristics of Eligible Studies Figure 1 graphically describes the flow diagram of study identification and selection process. Three hundred and eighty-six studies were identified. Finally, a total of 14 studies23-36 with 3233 cases and 3123 controls that evaluated the correlation of MMP-9 rs3918242 variants with
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Figure 1.
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Flow diagram for the process of selecting articles.
the risk of IS were included in our meta-analysis. Of these, 323,24,36 studies with 801 cases and 877 controls involved Caucasian population, and 1125-35 studies with 2432 cases and 2246 controls focused on Chinese population. The primary characteristics of all studies included are listed in Table 1.
Association between MMP-9 rs3918242 Variants and Risk of IS A total of 14 studies with 3233 cases and 3123 controls examined the relationship between MMP-9 rs3918242 variants and the risk of IS. The main results of our metaanalysis and heterogeneity test are listed in Table 2. Overall, significant association was identified in allelic and dominant models (Table 2, Fig 2). In addition, stratified analysis based on ethnicity (Chinese and Caucasian) indicated MMP-9 rs3918242 variants were associated with increased risk of IS in the Chinese population. However, no association was found between MMP-9 rs3918242 variants and the risk of IS in the Caucasian population (Table 2, Fig 2).
Sensitivity Analysis and Publication Bias The sensitivity analysis was performed by sequential omission of any single study in turn. The results showed that pooled OR and 95% CI were not materially altered (Fig 3). Publication bias was assessed by the shape of funnel plots and P value for Begg’s test. The shape of funnel plots and the P value >.05 (T versus C: P = .189; TT + CT versus CC: P = .352) showed no significant publication bias (Fig 4).
Discussion IS, caused by a sudden, reduced or interrupted blood flow to the brain, still remains a leading cause of morbidity and mortality worldwide, with an approximated 9.9% of deaths in overall populations.37 Although the pathogenesis of IS was still elusive, an enormous body of evidence suggested that genetic factors were closely related to the risk of IS. MMP-9, also called 92-kDa type IV collagenase or gelatinase B, is one of the members of the MMP family. The promoter region of the MMP-9 gene contains a
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Table 1. Basic characteristics of the 14 case-control studies included
First author
Year
Ethnicity
Buraczynska24 Li25 Zhao26 Nie27 Hao28 Liu29 Zhang30 Shi31 Zhou32 Yue33 Zhou34 Hou35 Szczudlik23 Montaner36
2015 2013 2015 2014 2015 2011 2008 2011 2008 2014 2009 2009 2010 2003
Caucasian Chinese Chinese Chinese Chinese Chinese Chinese Chinese Chinese Chinese Chinese Chinese Caucasian Caucasian
322/410 302/308 335/335 396/400 317/317 232/235 114/80 224/112 101/114 284/226 70/60 57/59 418/408 61/59
Control
CT
TT
CC
CT
TT
Diagnostic criteria
Male of case/control
Age distribution in case/control
174 132 252 50 223 64 305 62 214 59 181 48 95 16 186 38 87 14 227 50 46 22 46 10 315 89 44 17
16 0 48 29 44 3 3 0 0 7 2 1 14 0
283 119 271 37 254 71 338 41 242 66 204 29 63 15 92 20 99 13 195 28 50 8 47 12 291 111 47 12
8 0 10 21 9 2 2 0 2 3 2 0 6 0
CT and/or MRI CT and/or MRI CT and/or MRI WHO Diagnostic Criteria CT and/or MRI CT and/or MRI CT and/or MRI CT and/or MRI MRI CT and/or MRI CT and/or MRI CT TOAST CT
156/217 165/140 194/194 279/276 180/180 146/144 82/54 126/54 46/51 163/124 40/35 39/52 205/195 27/NA
64.3 ± 12.7/NA 65.71 ± 9.8/63.21 ± 8.19 63.65 ± 9.40/64.45 ± 9.15 64.9 ± 8.9/64.1 ± 9.7 62.13 ± 10.25/62.50 ± 9.85 62.07 ± 4.88/60.86 ± 9.92 66.0 ± 10.9/64.0 ± 13.6 64.5 ± 10.95/66.93 ± 10.87 61.6 ± 11.5/59.6 ± 10.9 67.52 ± 13.28/67.86 ± 11.74 57.7 ± 10.2/54.2 ± 9.4 68 ± 10/63 ± 9 66.4 ± 12.3/64.4 ± 18.4 71 ± 9.3/NA
CC
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Case No. of case/control
Genotyping method HWE PCR–RFLP PCR–RFLP PCR–RFLP PCR–RFLP PCR–RFLP PCR–RFLP PCR–RFLP PCR–RFLP PCR–RFLP PCR–RFLP PCR–RFLP PCR–RFLP PCR–RFLP PCR–RFLP
Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
Abbreviations: CT, computed tomography; HWE, Hardy–Weinberg equilibrium; MRI, magnetic resonance imaging; NA, not available; PCR, polymerase chain reaction; RFLP, restricted fragment length polymorphism; TOAST, Trial of Org 10172 in Acute Stroke Treatment; WHO, World Health Organization.
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Table 2. Meta-analysis of MMP-9 rs3918242 polymorphism on IS susceptibility T versus C
TT+CT versus CC
Ethnicity
N
OR (95% CI)
I2 (%)
P
OR (95% CI)
I2 (%)
P
Overall Chinese Caucasian
14 11 3
1.43 (1.20-1.71) 1.60 (1.41-1.82) 1.30 (.79-2.13)
58.10 39.10 82.10
<.001 <.001 .305
1.39 (1.16-1.67) 1.48 (1.28-1.71) 1.30 (.68-2.49)
51.40 4.50 86.50
<.001 <.001 .423
Abbreviations: CI, confidence interval; IS, ischemic stroke; MMP, matrix metalloproteinase; OR, odds ratio.
-1562C/T polymorphism (rs3918242), and this polymorphism is located on chromosome 20q12.2-13.1. It was reported that carrying the -1562T allele has a higher transcriptional activity of MMP-9 compared to -1562C allele carriers.38 Several studies have also shown plasma protein levels were higher in T allele carriers than C allele carriers.39 At present, the mechanism of rs3918242 polymorphism regulating expression of MMP-9 is not fully clear. Loftus et al40 found MMP-9 was highly expressed in unstable carotid plaques compared to stable carotid plaques. Gu et al41 showed that abnormal hyperactivity of MMP-9 can directly cause programmed neuronal death and brain damage. In our meta-analysis, we found MMP-9 rs3918242 variants were associated with significantly increased risk of IS.
Several case-control studies have been focused on the association between MMP-9 rs3918242 polymorphism and the risk of IS. Montaner et al36 firstly conducted a casecontrol study in a Spanish population, and they showed that there was no association of MMP-9 rs3918242 variants with IS susceptibility. Another study was performed in a Polish population, and they also showed no correlation between MMP-9 rs3918242 variants and the risk of IS. In recent years, significant associations between MMP-9 rs3918242 variants and increased risk of IS were found in some case-control studies.24,26-28 The inconclusive or conflicting results may be due to the genetic or environmental factors. Therefore, we conducted a comprehensive meta-analysis to gain more reliable conclusions.
Figure 2. Forest plot for the association of MMP-9 rs3918242 variants with IS susceptibility (TT + CT versus CC). Abbreviations: IS, ischemic stroke; MMP, matrix metalloproteinase.
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Figure 3.
Sensitivity analysis of the summary OR coefficients in the overall population (TT + CT versus CC). Abbreviation: OR, odds ratio.
In this study, we found MMP-9 rs3918242 variants were associated with increased risk of IS under the allelic and dominant models. Our conclusions were not consistent with the previous meta-analysis.15,16 Only 3 case-control studies that involved cervical artery dissection (CAD) and IS were included in 1 meta-analysis.16 We noted that CAD is just as an etiology for occurrence of IS, and CAD did not mean IS, and these studies’ conclusions may thus be disputable. The other meta-analysis15 including 6 case-
control studies with 1176 IS patients and 1051 controls showed no association of MMP-9 rs3918242 variants with IS susceptibility. To date, we performed a comprehensive meta-analysis including 14 case-control studies with 3233 cases and 3123 controls, and the results showed MMP-9 rs3918242 variants were associated with increased risk of IS in overall populations. In the stratified analysis, we found that MMP-9 rs3918242 variants contributed to increase the risk of IS in the Chinese population;
Figure 4. Begg’s funnel plot of MMP-9 rs3918242 variants with IS susceptibility in overall populations (TT + CT versus CC). Abbreviations: IS, ischemic stroke; MMP, matrix metalloproteinase.
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However, no association was detected between MMP-9 rs3918242 variants and IS susceptibility in the Caucasian population. In addition, no publication bias was found in our meta-analysis. In all, our meta-analysis suggested that MMP-9 rs3918242 variants T allele may contribute to increase the risk of IS in the Chinese population. Interestingly, Zhang et al42 found that T allele may be a protective factor against hemorrhagic transformation of IS in the Chinese population. Because of insufficient data, the association between MMP-9 rs3918242 variants and hemorrhagic transformation was not included in our meta-analysis. This association should be analyzed in future studies. Some potential limitations of our meta-analysis should be emphasized. Firstly, only published studies were included in this meta-analysis. Therefore, the publication bias may exist in our meta-analysis. Secondly, association between the MMP-9 3918242 polymorphism and IS risk might be due to the synergistic interactions with other genes. In addition, significant heterogeneity was observed in the Caucasian population. However, there were only 3 studies that estimated the association between MMP-9 variants and risk of IS in the Caucasian population, which may limit further analysis. In a word, our meta-analysis of 14 case-control studies showed MMP-9 rs3918242 variants were associated with increased risk of IS. Moreover, considering the 3 limitations mentioned above, well-designed studies with larger sample sizes are still required to validate the association between MMP-9 rs3918242 polymorphism and risk of IS. Acknowledgment: We would like to acknowledge the investigators for their helpful comments on this paper.
References 1. Ghilardi G, Biondi ML, DeMonti M, et al. Matrix metalloproteinase-1 and matrix metalloproteinase-3 gene promoter polymorphisms are associated with carotid artery stenosis. Stroke 2002;33:2408-2412. 2. Kalb R. Spontaneous dissection of the carotid and vertebral arteries. N Engl J Med 2001;6:467. 3. Brandt T, Orberk E, Weber R, et al. Pathogenesis of cervical artery dissections: association with connective tissue abnormalities. Neurology 2001;57:24-30. 4. Lin RT, Chen CH, Tsai PC, et al. Sex-specific effect of matrix metalloproteinase-9 functional promoter polymorphism on carotid artery stiffness. Atherosclerosis 2012;223:416-420. 5. Visse R, Nagase H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res 2003;92:827-839. 6. Galis ZS, Khatri JJ. Matrix metalloproteinases in vascular remodeling and atherogenesis: the good, the bad, and the ugly. Circ Res 2002;90:251-262. 7. Katakami N, Takahara M, Kaneto H, et al. Accumulation of gene polymorphisms related to plaque disruption and thrombosis is associated with cerebral infarction in subjects with type 2 diabetes. Diabetes Care 2010;33:390-395.
7
8. Siefert SA, Sarkar R. Matrix metalloproteinases in vascular physiology and disease. Vascular 2012;20:210-216. 9. Chen Q, Jin M, Yang F, et al. Matrix metalloproteinases: inflammatory regulators of cell behaviors in vascular formation and remodeling. Mediators Inflamm 2013;2013: 928315. 10. Kaplan RC, Smith NL, Zucker S, et al. Matrix metalloproteinase-3 (MMP3) and MMP9 genes and risk of myocardial infarction, ischemic stroke, and hemorrhagic stroke. Atherosclerosis 2008;201:130-137. 11. Fornage M, Mosley TH, Jack CR, et al. Family-based association study of matrix metalloproteinase-3 and -9 haplotypes with susceptibility to ischemic white matter injury. Hum Genet 2007;120:671-680. 12. 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. 13. Zhang B, Henney A, Eriksson P, et al. Genetic variation at the matrix metalloproteinase-9 locus on chromosome 20q12.2-13.1. Hum Genet 1999;105:418-423. 14. Rosell A, Ortega-Aznar A, Alvarez-Sabín J, et al. Increased brain expression of matrix metalloproteinase-9 after ischemic and hemorrhagic human stroke. Stroke 2006;37: 1399-1406. 15. Fan ZZ, Ge ZM, Cai HB, et al. Association between the MMP-9-1562 C>T polymorphism and the risk of stroke: a meta-analysis. Mol Biol Rep 2014;41:6787-6794. 16. Wen D, Du X, Nie SP, et al. Association between matrix metalloproteinase family gene polymorphisms and ischemic stroke: a meta-analysis. Mol Neurobiol 2014; 50:979-985. 17. Woolf B. On estimating the relation between blood group and disease. Ann Hum Genet 1955;19:251-253. 18. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002;21:1539-1558. 19. Zintzaras E, Ioannidis JP. Heterogeneity testing in meta-analysis of genome searches. Genet Epidemiol 2005;28:123-137. 20. Lau J, Ioannidis JP, Schmid CH. Quantitative synthesis in systematic reviews. Ann Intern Med 1997;127:820826. 21. Martin WJ. Statistical aspects of poliomyelitis in England and Wales in recent years. Mon Bull Minist Health Public Health Lab Serv 1959;18:54-64. 22. Egger M, Davey SG, Schneider M, et al. Bias in metaanalysis detected by a simple, graphical test. BMJ 1997;315:629-634. 23. Szczudlik P, Borratyn´ska A. Association between the -1562 C/T MMP-9 polymorphism and cerebrovascular disease in a Polish population. Neurol Neurochir Pol 2010;44:350357. 24. Buraczynska K, Kurzepa J, Ksiazek A, et al. Matrix metalloproteinase-9 (MMP-9) gene polymorphism in stroke patients. Neuromolecular Med 2015;17:385-390. 25. Li JY, Wu HR, Li HX, et al. Association between gene polymorphism of ALOX5AP, COX-2, MPP-9 and ischemic stroke. Med J Qiulu 2013;28:321-324. 26. Zhao JH, Xu YM, Xing HX, et al. Associations between matrix metalloproteinase gene polymorphisms and the development of cerebral infarction. Genet Mol Res 2016;14:19418-19424. 27. Nie SW, Wang XF, Tang ZC. Correlations between MMP-2/MMP-9 promoter polymorphisms and ischemic stroke. Int J Clin Exp Med 2014;7:400-404. 28. Hao Y, Tian S, Sun M, et al. Association between matrix metalloproteinase gene polymorphisms and development
ARTICLE IN PRESS T. HE ET AL.
8
29.
30.
31.
32.
33.
34.
35.
36.
of ischemic stroke. Int J Clin Exp Pathol 2015;8:1164711652. Liu D, Sun HY, Yang Y, et al. Polymorphisms of matrix metalloproteinase-2 C735T and-9 C1562T are associated with stroke and its subtype large artery atherosclerotic stroke, but not associated with the prognosis in patients with ischemic stroke. Int J Cerebrovasc Dis 2011;19:503-509. Zhang L, Zhang YD, Li JY, et al. Relationship between the gene polymorphism of matrix metalloproteinase-9 C1562T and ischemic stroke. J Clin Neurol 2008;21. Shi N, Wang L, Song LY, et al. A study of the association between polymorphism of MMP-9 gene and atherosclerosis and cerebral infarction. Chin J Clin Neurosci 2011;19:476-480. Zhou YL, Jin XP, Zhu M, et al. Relationship between matrix metalloproteinase-9 polymorphism and acute cerebral infarction. Chin J Neurol 2008;41:97-101. Yue YH, Bai XD, Zhang XN, et al. Correlation between serum matrix metalloproteinase-9 levels and its gene -1562C>T polymorphism to ischemic stroke subtypes in Uygur nationality. Chin J Arterioscler 2014;22:55-60. Zhou J, Liu J. Matrix metalloproteinase-9 polymorphism (C1562T) in patients with cerebral infarction. China J Modern Med 2009;12:1829-1831. Hou LH, Liu XE, Li H, et al. Polymorphism of matrix metalloproteinase-9 related to cerebral infarction. Chin Remedies Clin 2009;9:575-577. Montaner J, Fernández-Cadenas I, Molina CA, et al. Safety profile of tissue plasminogen activator treatment among
37.
38.
39.
40.
41.
42.
stroke patients carrying a common polymorphism (C-1562T) in the promoter region of the matrix metalloproteinase-9 gene. Stroke 2003;34:2851-2855. Truelsen T, Heuschmann PU, Bonita R, et al. Standard method for developing stroke registers in low-income and middle-income countries: experiences from a feasibility study of a stepwise approach to stroke surveillance (STEPS Stroke). Lancet Neurol 2007;6:134139. Blankenberg S, Rupprecht HJ, Poirier O, et al. Plasma concentrations and genetic variation of matrix metalloproteinase 9 and prognosis of patients with cardiovascular disease. Circulation 2003;107:1579-1585. Buss A, Pech K, Roelver S, et al. Functional polymorphisms in matrix metalloproteinases -1, -3, -9 and -12 in relation to cervical artery dissection. BMC Neurol 2009;9: 40. Loftus IM, Naylor AR, Goodall S, et al. Increased matrix metalloproteinase-9 activity in unstable carotid plaques. A potential role in acute plaque disruption. Stroke 2000;31:40-47. Gu Z, Cui J, Brown S, et al. A highly specific inhibitor of matrix metalloproteinase-9 rescues laminin from proteolysis and neurons from apoptosis in transient focal cerebral ischemia. J Neurosci 2005;25:6401-6408. Zhang X, Cao X, Xu X, et al. Correlation between the -1562C/T polymorphism in the matrix metalloproteinase-9 gene and hemorrhagic transformation of ischemic stroke. Exp Ther Med 2015;9:1043-1047.