MMP-2 Single Nucleotide Polymorphisms Research Articles

The relationship between MMP-2 rs243865, MMP-9 rs398242 and CXCL-12 rs1801157 gene polymorphisms with Japanese encephalitis disease and disease outcome in North Indian population.

Japanese encephalitis virus (JEV) is one of the most important causes of acute and uncontrolled inflammatory disease in Asia. Matrix metalloproteinases (MMPs) and chemokines play a detrimental role in the host response to JE disease, aetiology, and disease outcome. Evidently, MMPs are widely circulated in the brain and regulate various process including microglial activation, inflammation, blood-brain barrier disruption as well as affects central nervous system (CNS). The present study was to assess the association of single nucleotide polymorphisms of MMP-2, MMP-9 and chemokine (CXCL-12/SDF1-3') in the north Indian population. We performed case-control study comprising of 125 patients and 125 healthy controls in north Indian population. Genomic DNA was extracted from whole blood and gene polymorphism have been determined by PCR-RFLP method. MMP-2, MMP-9 and CXCL-12 gene was not significantly associated with JE disease, but homozygous (T/T) genotype of MMP-2 was statically associated with disease outcome (p=0.05, OR=0.110). A/G and G/G genotype of CXCL-12 was significantly associated with severity of disease. (p=0.032, OR=5.500, p=0.037, OR= 9.167). The serum level of MMP-2 was observed significantly increased in JE patients with homozygous (T/T) genotype whereas increased MMP-9 level was associated with heterozygous genotype. MMP-2, MMP-9 and CXCL-12 gene polymorphism were not associated with JE susceptibility, but MMP-2 may be contributed to disease protection. CXCL-12 was associated with disease severity. In our concern this is the first report from northern India.

P3641Matrix Metalloproteinase-2 polymorphisms are associated with prognosis of patients with symptomatic coronary artery disease

Abstract Background Matrix Metalloproteinase-2 (MMP-2) is involved in regulation and proliferation of vascular and endothelial cells and is therefore an important component of atherosclerotic vessels. Inhibition of MMP-2 activity is associated with improvement of cardiac function in animal models after myocardial infarction. MMP-2 single nucleotide polymorphisms (SNPs) might alter MMP-2 expression and therefore influence prognosis in patients with symptomatic coronary artery disease (CAD). Methods and results Genotyping for selected MMP-2 SNPs variants (rs2241145, rs2285053, rs2287076, rs243865, rs7201) was performed in 943 consecutive patients with symptomatic CAD. All patients were followed-up for all-cause death (ACD), myocardial infarction (MI) and ischemic stroke (IS) for 360 days. The primary combined endpoint (CE) consisted of either first occurrence of ACD, and/or MI, and/or IS. Secondary endpoints were defined as the single events of ACD or MI. Homozygous carriers of major allele (rs2241145, rs2287076) showed significantly better event-free survival than carriers of the minor allele for CE (Log rank = 0.022 and Log rank= 0.015, respectively). Furthermore, homozygous carriers of major allele (rs2241145, rs2285053, rs2287076) showed significantly better event-free survival for ACD (Log rank= 0.047, Log rank= 0.006 and Log rank= 0.023, respectively). In multivariate analysis, MMP-2 rs2241145, rs2287076 and rs2285053 were significantly and independently associated with CE and ACD. Figure 1 Conclusions MMP-2 rs2241145, rs2287076 and rs2285053 are associated with prognosis and might be valuable for further risk stratification in CAD patients. Acknowledgement/Funding DFG, KFO 274, CRC TR 240

Matrix metalloproteinase-2 gene polymorphisms are associated with ischemic stroke in a Hainan population.

Ischemic stroke is a complex vascular disease, which has become 1 of the major causes of morbidity and mortality worldwide. More and more data showed that matrix metalloproteinases (MMPs), in particular, MMP-2 are deleterious after ischaemic stroke. This study investigated the relationship between MMP-2 and stroke risk in the Southern Chinese population.We evaluated single nucleotide polymorphisms (SNP) of MMP-2 in stroke patients in an association study using a case-control design. Six SNPs of MMP2 were selected and genotyped by Agena MassARRAY. SNPStats, Haploview was used to analyze genetic data.Two SNPs in the MMP-2 gene were significantly associated with stroke risk.For rs1132896 (C versus G allele), the C allele was significantly reduced stroke risk (OR = 0.56, 95% confidence intervals [95% CI] = 0.39–0.81, P = .002). The effect of the T allele of rs243849 was IS risk according to an additive genetic model (OR = 0.67, 95% CI = 0.47–0.96, P = .028). We did not found any strong linkage between the six SNPs (rs1132896, rs1053605, rs243849, rs243847, rs243832, rs7201)The results presented strongly indicate that MMP-2 genetic variants are an important mediator of stroke risk.

PP.23.11] MATRIX METALLOPROTEINASE 2 GENE POLYMORPHISM ASSOCIATES WITH RESISTANT HYPERTENSION

Objective: The lack of blood pressure (BP) control (>140/90 mmHg) – even in the presence of three or more antihypertensive drugs of different classes - define the hypertensive patients at high cardiovascular (CV) risk and high incidence of target organ damage (TOD) as resistant hypertensives (RH). Studies suggest the involvement of metalloproteinase 2 (MMP-2) in hypertension and in CV remodeling associated with TOD. Hypertension is a multifactorial condition in which BP heritability and genetic factors may have a large contribution in the development of the disease. MMP-2 single nucleotide polymorphisms (SNPs) have been associated with the predisposition of CV alterations. Few studies have evaluated the impact of MMP-2 polymorphisms on clinical conditions and their influence in RH is unknown. The aim of this study is to analyze the influence of MMP-2 SNPs in RH, as well as their association with TOD in this high CV risk group. Design and method: 119 RH patients and 136 mild to moderate hypertensives (HT) were included and submitted to clinical and laboratorial evaluations. We assessed genotypes by allelic discrimination assay using real time polymerase chain reaction. We compare clinical and laboratorial characteristics according to SNPs genotypes/haplotypes (rs243865, rs243866 and rs2285053). TOD were categorized by left ventricular mass index (women >95 g/m2 and men >115 g/m2) and arterial stiffness (PWV>10m/s). Results: We did not find association of studied SNPs with TOD and clinical features. However, the allelic and genotype frequencies of rs2285053 showed to be different between RH and HT subjects (C vs T, p = 0.02; CC vs CT vs TT, p = 0.04, respectively), with high prevalence of C allele in the RH group. Moreover, haplotype frequencies were also different (GCC vs GCT vs ATC, p = 0.03) between groups. Finally, regression analysis demonstrated that haplotype was associated with resistance to treatment, as well as age, gender, race, BMI, LVH and aldosterone levels. Conclusions: We conclude that only the SNP rs2285053 may be associated with RH when compared to controlled counterparts. Our finding suggests that the presence of C allele may have some bearing in the resistance to antihypertensive process.

Associations of rs3918242 and rs2285053 MMP-9 and MMP-2 polymorphisms with the risk, severity, and short- and long-term complications of degenerative mitral valve diseases: a 4.8-year prospective cohort study.

Degenerative forms of mitral valve diseases (MVDs) are very complex pathologies. Thus, it is difficult to make generalizations about the disease pathways or genetic risk factors contributing to these diseases. However, a key role of metalloproteinases (MMPs) in their pathophysiology is emerging. Thus, we performed for the first time a perspective study to assess eventual associations of some functional single nucleotide polymorphisms (SNPs) in MMP-2 and MMP-9 genes with the MVD risk, symptom severity, and short- and long-term (4.8 years) complications. For this purpose, 90 patients and two control groups were genotyped for rs3918242, rs243865, and rs2285053 MMP-2 and MMP-9 gene SNPs, and systemic levels of pro-atrial natriuretic peptide (pro-ANP) and two enzymes were quantified and correlated to genotypes of MMP-2 and MMP-9 SNPs studied. In addition, associations between these SNPs and symptom severity and short- and long-term (4.8 years) complications were evaluated. Interestingly, rs3918242 MMP-9 and rs2285053 MMP-2 SNPs were significantly represented in cases than two control groups and were associated with a higher MVD risk, as demonstrated using dominant/recessive models. Cases stratified for NYHA symptoms and particularly those NYHA III+IV with rs3918242 CT+TT MMP-9 and rs2285053CT+TT genotypes also showed higher severity related to significant higher systemic levels of MMP enzymes and pro-ANP at enrolment and 4.8 follow-up times. In addition, cases with these genotypes and particularly those NYHA III+IV had a very significant percentage of complications, particularly at the 4.8 follow-up. Surprisingly, 20% of patient controls developed MVD at 4.8-year follow-up and were carriers of these genotypes. Thus, the associations observed seem to suggest that the two SNPs might represent useful biomarkers and targets for preventing and monitoring MVDs and developing personalized treatments, consenting a more appropriate management and outcome.

Association study for the role of Matrix metalloproteinases 2 and 3 gene polymorphisms in dental caries susceptibility

ObjectiveVarious exogenous and endogenous risk factors have been described as contributing to dental caries susceptibility. In the last decade it has been established that both pro and active forms of host derived Matrix metalloproteinases (MMPs) are present in the oral cavity. MMPs role in caries development has been hypothesized. The aim of this study was to analyse MMP2 (rs2287074) and MMP3 (rs679620) single nucleotide polymorphisms (SNPs) and their role in caries susceptibility. DesignThe two SNPs were analysed by PCR- restriction fragment length polymorphism (RFLP) in a sample of 102 ethnic Bulgarian volunteers (42 males and 60 females), all students in Sofia Medical University. ResultsStatistical analysis of the MMP2 SNP showed significant differences for the genotype frequencies between the caries free (CF, DMFT=0) and low caries experience (LCE, DMFT≤5) groups. Analysis for the non-synonymous MMP3 SNP found significant differences between both CF vs caries experience groups (LCE+ high caries experience (HCE, DMFT≥5)) and LCE vs HCE groups. The presence of allele G decreased the risk of HCE about 4 times. ConclusionsMMP2 and MMP3 genes are likely to be involved in caries susceptibility in our population. However, as dental caries is a multifactorial disorder and several genes are likely to have influence on it, it is reasonable to expect that SNPs, even those proven to be functional like rs679620, potentially play a significant, but not major role in the disease outcome.

The GC + CC genotype at position -418 in TIMP-2 promoter and the -1575GA/-1306CC genotype in MMP-2 is genetic predisposing factors for prevalence of moyamoya disease.

BackgroundTo investigate the association of single-nucleotide polymorphisms (SNPs) in matrix metalloproteinases (MMPs)-2, -3, and -9 and tissue inhibitor of metalloproteinase (TIMP)-2 with moyamoya disease (MMD). We conducted a case-control study of MMD patients by assessing the prevalence of six SNPs of MMP-2 -1575G > A [rs243866], MMP-2 -1306C > T [rs243865], MMP-3 -1171 5a/6a [rs3025058], MMP-9 -1562C > T [rs3918242], MMP-9 Q279R [rs17576], and TIMP-2 -418G > C [rs8179090].MethodsKorean patients with MMD (n = 107, mean age, 20.9 ± 15.9 years; 66.4% female) and 243 healthy control subjects (mean age, 23.0 ± 16.1 years; 56.8% female) were included. The subjects were divided into pediatric and adult groups. The genotyping of six well-known SNPs (MMP-2 -1575G > A, MMP-2 -1306C > T, MMP-3 -1171 5a/6a, MMP-9 -1562C > T, MMP-9 Q279R, and TIMP-2 -418G > C) in MMP and TIMP genes was performed by polymerase chain reaction-restriction fragment length polymorphism assays.ResultsA significantly higher frequency of the GC genotype for TIMP-2 -418 G > C was found in MMD patients. The MMP-9 Q279R GA + AA genotype showed a protective effect for MMD. The GA/CC MMP-2 -1575/-1306 genotype was significantly more prevalent in MMD patients.ConclusionsOur findings demonstrate that TIMP-2 -418 GC + CC and MMP-2 -1575GA/-1306CC genotypes could be genetic predisposing factors for MMD development.Electronic supplementary materialThe online version of this article (doi:10.1186/s12883-014-0180-5) contains supplementary material, which is available to authorized users.

MMP-2 and MMP-9 in normal mucosa are independently associated with outcome of colorectal cancer patients

Background:Upregulation of the matrix metalloproteinases MMP-2 and MMP-9 in various cancers has been associated with worse survival of the patients.Methods:We assessed MMP-2 and MMP-9 levels in normal colorectal mucosa from colorectal cancer patients in relation to the course of the disease.Results:A high protein expression of MMP-2 as well as MMP-9 in normal mucosa was found to be correlated with worse 5-year survival. The combination of both parameters was an even stronger prognostic factor. These protein levels were found not to be related to the corresponding single nucleotide polymorphisms of MMP-2 (−1306C>T) and MMP-9 (−1562C>T). Multivariate analyses indicated that the MMP-2 and MMP-9 levels in normal mucosa are prognostic for survival, independent of TNM classification.Conclusion:MMP-2 and MMP-9 levels in normal mucosa are indicative of the course of disease in colorectal cancer patients.

E0065 The association between the single nucleotide polymorphisms of matrix metalloproteinases and the carotid atherosclerosis in patients with essential hypertension

ObjectiveTo investigate the relationship between the single nucleotide polymorphisms (SNP) of matrix metallo proteases (MMP-2 -735C/T; MMP-3 -1171 5A/6A) and the carotid atherosclerosis (CAS) in Chinese Han and Uygur populations...

Polymorphisms of MMP-2 Gene are Associated With Systolic Heart Failure Risk in Han Chinese

BackgroundMatrix metalloproteinases (MMPs) are a family of proteolytic enzymes responsible for protein degradation. MMP-2 has been demonstrated to play a pivotal role in myocardial remodeling process that occurs in congestive heart failure (HF). We hypothesized that MMP-2 genetic variations could be associated with systolic HF risk. MethodsTo test the association of single nucleotide polymorphisms of MMP-2 with systolic HF risk, we performed a hospital-based, case-control study of 605 patients with systolic HF and 689 controls without HF. Three single nucleotide polymorphisms of MMP-2 (rs243864, rs243866, and rs17859821) were genotyped by restriction fragment length polymorphism methods. ResultsThe genotype frequencies of MMP-2 rs243866 AA and AG in the control group were significantly higher than that in the case group (24.7% versus 17.9%, P < 0.01). Compared with the GG homozygotes, MMP-2 rs243866 A allele carriers had a significantly lower risk of systolic HF (adjusted OR 0.69, 95% CI 0.49-0.98; P=0.035). Haplotype analysis indicated the haplotype GGG (rs243864-rs17859821-rs243866) was associated with higher risk of systolic HF (adjusted OR 2.05, 95% CI 1.08-3.89; P=0.028). ConclusionThe findings of the current study suggest that MMP-2 rs243866 A allele was associated with lower risk of systolic HF in Han Chinese.

MATRIX METALLOPROTEINASE-2 POLYMORPHISM IS ASSOCIATED WITH PROGNOSIS IN PROSTATE CANCER

Objective: Prostate cancer (PCa) is the most frequent tumor in males in Brazil. Single nucleotide polymorphisms (SNP) have been demonstrated in the promoter region of matrix metalloproteinases (MMPs) genes and have been associated with development and progression of some cancers. In this study, our aim was to investigate a possible relation between polymorphism of the promoter region of the MMP2 gene and classical prognostic parameters in prostate cancer. Materials and methods: Genomic DNA was extracted using conventional protocols. The DNA sequence containing the polymorphic site was amplified by real-time polymerase chain reaction, using fluorescent probes (TaqMan). Results: In patients with tumors of a higher stage (pT3), a polymorphic allele in the MMP2 gene was more frequent (P 0.026) than in patients with lower tumor stage. A polymorphic allele in the MMP2 gene was more frequent in Gleason 7 than in Gleason 6( P 0.042). Conclusions: We conclude that MMP2 polymorphism can be used together with pathological stage and Gleason score to identify patients with worse prognosis. Our results illustrate the potential use of MMP2 SNP as a molecular marker for prostate cancer. © 2010 Elsevier Inc. All rights reserved.

Matrix metalloproteinase-2 polymorphism is associated with prognosis in prostate cancer

Objective Prostate cancer (PCa) is the most frequent tumor in males in Brazil. Single nucleotide polymorphisms (SNP) have been demonstrated in the promoter region of matrix metalloproteinases ( MMPs) genes and have been associated with development and progression of some cancers. In this study, our aim was to investigate a possible relation between polymorphism of the promoter region of the MMP2 gene and classical prognostic parameters in prostate cancer. Materials and methods Genomic DNA was extracted using conventional protocols. The DNA sequence containing the polymorphic site was amplified by real-time polymerase chain reaction, using fluorescent probes (TaqMan). Results In patients with tumors of a higher stage (pT3), a polymorphic allele in the MMP2 gene was more frequent ( P = 0.026) than in patients with lower tumor stage. A polymorphic allele in the MMP2 gene was more frequent in Gleason ≥ 7 than in Gleason ≤ 6 ( P = 0.042). Conclusions We conclude that MMP2 polymorphism can be used together with pathological stage and Gleason score to identify patients with worse prognosis. Our results illustrate the potential use of MMP2 SNP as a molecular marker for prostate cancer.

Single-Nucleotide Polymorphisms of MMP-2 Gene in Stroke Subtypes

Background: Matrix metalloproteinases (MMP) are expressed after ischemic stroke. These proteases are responsible for a higher incidence of hemorrhages, are correlated to size of infarction and influence the effects of recombinant tissue plasminogen activator treatment. We therefore evaluated single nucleotide polymorphisms (SNP) of MMP-2 in different subtypes of stroke patients in an association study using a case-control design. Methods: 197 stroke patients were divided according to modified TOAST criteria (small vessel disease, large vessel disease, hemorrhagic stroke and asymptomatic carotid artery stenosis) and compared to 143 controls. Clinical data like age, sex, risk factors and diagnostic results including MRI or cranial CT scans and ultrasound evaluations of intra- and extracranial arteries were obtained. Genotypes of MMP-2 (12 SNP) were compared to controls and DNA samples were analyzed by matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) analysis. Logistic regression analysis was performed for small vessel disease to test for interactions between markers and defined clinical risk factors. Additionally, MMP-2 serum levels obtained in the first 24 h after stroke were measured. Results: From the MMP-2 gene, 5 markers (rs1030868, rs2241145, rs2287074, rs2287076, rs7201) showed a significant association with small vessel infarcts (p < 0.05) and rs7201:g.C was identified as an independent risk factor by multivariable logistic regression analysis. MMP-2 protein levels were significantly lower in this group (174 ± 48 ng/dl) versus controls (214 ± 56 ng/dl). For other stroke subtypes, no significant association with MMP-2 SNP could be found. Conclusion: Our study demonstrates an association of the MMP-2 gene with the development of lacunar stroke, and no association of MMP-2 with other stroke subtypes.

Clinical impact of MMP and TIMP gene polymorphisms in gastric cancer

Gastric cancers express enhanced levels of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). Single-nucleotide polymorphisms (SNPs) in MMP and TIMP genes may be associated with disease susceptibility and might also affect their antigen expression. We studied the genotype distribution and allele frequencies of SNPs of MMP-2, -7, -8 and -9 and TIMP-1 and -2 in gastric cancer patients in relation to tumour progression, patient survival and tissue antigen expression. The genotype distribution and allele frequencies were similar in gastric cancer patients and controls, except for MMP-7−181A>G. In addition, the genotype distribution of MMP-7−181A>G was associated with Helicobacter pylori status (χ2 7.8, P=0.005) and tumour-related survival of the patients. Single-nucleotide polymorphism TIMP-2303C>T correlated significantly with the WHO classification (χ2 5.9, P=0.03) and also strongly with tumour-related survival (log rank 11.74, P=0.0006). Single-nucleotide polymorphisms of MMP-2, -8, -9 and TIMP-1 were not associated with tumour-related survival. Only the gene promoter MMP-2−1306C>T polymorphism correlated significantly with the protein level within the tumours. First-order dendrogram cluster analysis combined with Cox analysis identified the MMP-7−181A>G and TIMP-2303C>T polymorphism combination to have a major impact on patients survival outcome. We conclude that MMP-related SNPs, especially MMP-7−181A>G and TIMP-2303C>T, may be helpful in identifying gastric cancer patients with a poor clinical outcome.

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Various exogenous and endogenous risk factors have been described as contributing to dental caries susceptibility. In the last decade it has been established that both pro and active forms of host derived Matrix metalloproteinases (MMPs) are present in the oral cavity. MMPs role in caries development has been hypothesized. The aim of this study was to analyse MMP2 (rs2287074) and MMP3 (rs679620) single nucleotide polymorphisms (SNPs) and their role in caries susceptibility.The two SNPs were analysed by PCR- restriction fragment length polymorphism (RFLP) in a sample of 102 ethnic Bulgarian volunteers (42 males and 60 females), all students in Sofia Medical University.Statistical analysis of the MMP2 SNP showed significant differences for the genotype frequencies between the caries free (CF, DMFT = 0) and low caries experience (LCE, DMFT ≤ 5) groups. Analysis for the non-synonymous MMP3 SNP found significant differences between both CF vs caries experience groups (LCE+ high caries experience (HCE, DMFT ≥ 5)) and LCE vs HCE groups. The presence of allele G decreased the risk of HCE about 4 times.MMP2 and MMP3 genes are likely to be involved in caries susceptibility in our population. However, as dental caries is a multifactorial disorder and several genes are likely to have influence on it, it is reasonable to expect that SNPs, even those proven to be functional like rs679620, potentially play a significant, but not major role in the disease outcome.