MMP-3 Single Nucleotide Polymorphisms Research Articles

MMP3 single-nucleotide polymorphisms are associated with noncontact ACL injuries in competing high-level athletes.

Matrix metalloproteinases (MMPs) play an important role in matrix remodeling, as well as in ligament integrity. Anterior cruciate ligament (ACL) rupture is a severe and frequent knee injury in sports. The aim of this study was to investigate polymorphisms within the MMP3 gene with the predisposition for noncontact ACL rupture in the Croatian professional athletes. One hundred eighty-seven (95 with ACL rupture occurring through a noncontact mechanism and 92 asymptomatic controls) unrelated Caucasians were recruited between 2016 and 2017. All participants were genotyped for three single-nucleotide polymorphisms (SNP) within the MMP3 gene: rs591058 C/T, rs650108 A/G, and rs679620 G/A using the pyrosequencing method. For all three investigated SNPs, genotype frequencies have significantly differed between cases and controls. The MMP3 rs591058 TT (p = 0.0012, odds ratio [OR] = 38.541, 95% confidence interval [CI] = 1.7024-8.7254), rs650108 GG (p = 0.0051, OR = 23.338, 95% CI = 1.2899-4.2226) and rs679620 AA (p = 0.0030, OR = 34.750, 95% CI = 1.5266-7.9101) genotypes, as well as haplotype variant T-G-A (p = 0.0104, OR = 1.71, 95% CI = 1.13-2.59) were significantly overrepresented in cases compared to controls. These results support association between functional variants within the MMP3 gene and the risk of ACL rupture. Still, further research is needed to corroborate these results in a larger population.

Association of Promoter Polymorphism of MMP-1 rs1799750 and MMP-3 rs3025058 with circulating levels of MMP-1 and MMP-3 in patients with Rheumatoid Arthritis

The genetic background of Rheumatoid arthritis (RA) is only partly understood and several genes seem to be involved. Matrix metalloproteinases (MMPs) are involved in joint destruction in rheumatoid arthritis (RA). MMP1 (interstitial collagenase) and MMP3 (stromelysin 1) as most studied enzymes in RA. In the present study, we have investigated the genotypic and haplotypic relationships of the MMP-1 and MMP-3 genes with circulating levels of these MMPs. Functional relevance in single-nucleotide polymorphisms (SNPs)in rs1799750 (1G/2G, MMP-1 promoter) and rs3025058 (5A/6A, MMP-3 promoter) genotyped in 60 RA patients and 60 healthy control is used to determine association of polymorphisms with the severity of the disease. The MMP-3 SNPs were associated with serum MMP-3 level (P <0.05) and were associated with disease activity score (DAS28). We observed that MMP-1 SNPs were lacking in association with disease activity. Our findings conclude that several closely linked polymorphisms in the MMP-1–MMP-3 loci have an important role in determining the circulating levels of these MMPs in RA and that MMP-3 polymorphism is associated with the disease severity.

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 effect of gender and genetic polymorphisms on matrix metalloprotease (MMP) and tissue inhibitor (TIMP) plasma levels in different infectious and non-infectious conditions.

Matrix metalloproteases (MMPs) are increased in different infections due to their role in controlling immune responses and are regulated by tissue inhibitors (TIMPs). Different MMP promoter single nucleotide polymorphisms (SNPs) induce changes in MMP genes, mRNA and protein expression. Gender might also modify MMP plasma levels. In order to determine the weight of these variables on MMP secretion we studied MMP-1, -2, -3, -8, -9, -10, -13 and TIMP-1, -2, -4 plasma levels in 90 patients with severe bacterial sepsis, 102 with anti-retroviral (ARV)-treated HIV monoinfection, 111 with ARV-treated HIV-hepatitis C virus (HCV) co-infection and 86 non-infected controls (45 stroke and 41 trauma patients). MMP-1(-1607 1G/2G), MMP-3(-1612 5A/6A), MMP-8(-799C/T), MMP-9(-1562 C/T) and MMP-13(-77A/G) SNPs were genotyped. MMP-3 plasma levels were significantly higher in men than in women in each diagnostic group, and MMP-3 SNP allele 6A carriers also had higher levels than allele 5A carriers, an effect that was magnified by sepsis. Independent predictors of higher MMP-3 levels were male gender (P = 0.0001), MMP-3(-1612 5A/6A) SNP (P = 0.001), higher levels of TIMP-4 (P = 0.004) and MMP-8 (P = 0.006) and lower levels of MMP-1 (P = 0.03) by multivariate analysis. No strong associations with gender or SNPs were observed for other MMPs or TIMPs. In conclusion, male gender and MMP-3(-1612 5A/6A) 6A allele carriage increased MMP-3 plasma levels significantly, especially in patients with severe bacterial sepsis. This confounding gender effect needs to be addressed when evaluating MMP-3 plasma levels in any infectious or non-infectious condition.

Association of Genetic Polymorphisms With Histological Grading of Necroinflammation, Staging of Fibrosis, and Liver Function in Mexicans With Chronic Hepatitis C Virus Infection

Background/AimThe aim of this work was to establish an association between the single-nucleotide polymorphisms (SNPs) of TGFB1 (rs1800471), AT (rs3789679), MMP-1 (rs17886084), MMP-3 (rs35068180), and PAI-1 (rs1799889) and the histological...

Left ventricular function influenced by MMP3 gene 5A/6A polymorphism (rs3025058): a gated-SPECT study

The evaluation of left ventricular function is important to identify individuals at high risk for cardiovascular disease. The genetic differences underlying variability in the expression of ventricular function are not totally elucidated. This knowledge will provide a methodology for treatment more selective in retardation myocardial dysfunction. The aim of this study was to identify the relationship between metalloproteinase 3 (MMP3) 5A/6A and metalloproteinase 9 (MMP9) C/T single nucleotide polymorphisms (SNPs) with left ventricular function parameters considered normal and pathologic and to identify the contribution of the polymorphisms on left ventricle ejection fraction (LVEF) variance. Two hundred and five patients underwent myocardial perfusion scintigraphy (MPS) with 99mTc-tetrofosmin, and the left ventricular function parameters were determined. Patients without evidence of ischaemic heart disease which was confirmed with the study of negative MPS were included in Group I and patients with history of ischaemic heart disease which was confirmed with the study of positive MPS to myocardial ischaemia were included in Group II. The MMP3 and MMP9 genotypes were amplified by polymerase chain reaction and were identified by restriction fragment length polymorphism. Individuals carrying the 6A6A genotype (5A/6A MMP3 SNP) had mean values higher left ventricle end systolic volume and left ventricle end diastolic volume and lower LVEF than those carrying the 5A allele (stress: 6A6A: 115 ± 56 ml; 5A allele: 99 ± 44 ml, p = 0.02; 6A6A: 65 ± 51 ml; 5A allele: 49 ± 39 ml, p = 0.04; 6A6A: 49 ± 14%; 5A allele: 55 ± 14%, p = 0.02, respectively), the expression of regional wall thickening and motion abnormalities (p < 0.05) was also more frequent. The frequency of threshold values to predict cardiovascular disease was lesser in heterozygotes than in homozygotes. In Group II, in all the carriers of the 6A6A genotype, abnormal alterations in the LV wall thickening and motion were identified, 17.4% of the carriers of the 5A allele had normal wall thickening and 18.8% had normal wall motion. When the two polymorphisms were included in multiple regression model, the MMP3 5A/6A genetic variant emerged as an independent variable of LVEF (β = − 0.18, p = 0.01). And still, the accumulative effect of two genetic variants (MMP3 5A/6A and MMP9 C/T) had a significant unique contribution to the LVEF variation, in addition to the age and gender (β = 0.14, p = 0.04). The MMP3 5A/6A polymorphism contributes to the variability in the left ventricular function expression. The combined MMP3 5A/6A and MMP9 C/T polymorphisms can be associated with LVEF variance.

Influence of variations across the MMP-1 and -3 genes on the serum levels of MMP-1 and -3 and disease activity in rheumatoid arthritis

Matrix metalloproteinases (MMPs) are involved in joint destruction in rheumatoid arthritis (RA), and are strongly associated with levels of inflammation. To understand the relationship between MMP-1 and -3 variants and MMP levels in RA, we investigated the genotypic and haplotypic relationships of the MMP-1 and -3 genes with circulating levels of these MMPs. The genotypes of single-nucleotide polymorphisms (SNPs) rs1799750 (1G/2G, MMP-1 promoter), rs495366 (G/A, intergene), rs679620 (A/G, MMP-3 coding region) and rs3025058 (5A/6A, MMP-3 promoter) were determined in 430 RA patients. Each polymorphism was associated with serum levels of MMP-1 (P trend <0.0001 for each SNP), with haplotype 1G-G-A-5A associated with the highest level. The intergenic and MMP-3 SNPs were associated with MMP-1 levels independent of the MMP-1 promoter SNP. The MMP-3 SNPs were associated with serum MMP-3 level (P trend <0.0001 for each SNP), and were each associated with mean time-averaged disease activity (DAS28) in patients followed up for 2 years (P=0.003). Our findings indicate that several closely linked polymorphisms in the MMP-1-MMP-3 loci have an important role in determining the circulating levels of these MMPs in RA, and that MMP-3 polymorphism is associated with the level of disease activity over time.

Abstract 4727: TERT SNPs and ovarian cancer risk

Abstract There is increasing evidence that neighboring stromal cells are not uninvolved bystanders in the pathway to cancer. We hypothesized that SNPs in genes expressed as a consequence of interactions between ovarian cancer cells and the host micro-environment could contribute to ovarian cancer susceptibility. We therefore used a two-stage approach to comprehensively evaluate common single nucleotide polymorphisms (SNPs) in the Ovarian Cancer Association Consortium (OCAC) for 173 genes involved in stromal-epithelial interactions. Cases with epithelial ovarian cancer (n=675) and controls (n=1,162) were genotyped at 1536 SNPs using an Illumina GoldenGate™ BeadArray array. Logistic regression was used to estimate odds ratios (ORs) and adjust for potential confounders. Based on Positive Predictive Value estimates, three SNPs - PODXL rs1013368, ITGA6 rs13027811 and MMP3 rs522616 - were selected for replication using TaqMan genotyping in 3,734 serous invasive cases and 10,067 controls from 16 OCAC case-control studies. An additional 18 SNPs with Pper-allele &amp;lt;0.05 in the test set, and which fitted into an iPLEX design, were selected for replication by a subset of five OCAC studies (n=1771 serous invasive cases; n=4022 controls). The associations observed in the test set for the PODXL, ITGA6 and MMP3 SNPs were completely attenuated in the replication set (adj. Pper-allele ≥0.5). However, TERT rs7726159 showed evidence of a log additive association with ovarian cancer risk in the replication study (Pper-allele =0.03). Combined analysis of the test and replication sets for this SNP showed a significant association with risk of serous ovarian cancer among non-Hispanic whites [adj. ORper-allele 1.14 (1.04 - 1.24) p = 0.003]. A stronger association was observed for serous invasive cases when data for all ethnicities were included [adj. ORper-allele 1.18 (1.09 - 1.28) p = 2.46 × 10−5]. Stratification by histological subtype and malignant potential showed that TERT rs7726159 was also associated with risk of serous borderline tumors, but not with any other subtypes. Although TERT variants have not been previously reported to be associated with ovarian cancer, multiple genome-wide association studies have reported associations with this locus and risk of glioma, basal cell carcinoma, and several cancer types that are known to originate in the epithelium, including lung, bladder, prostate and cervical cancer. Further analysis of this locus is necessary to definitively identify the causal SNP(s). Our study adds to the growing evidence that, as well as 8q24, the TERT locus at 5p15.33, is a general cancer susceptibility locus. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4727.

No Association betweenMatrix Metalloproteinase-1orMatrix Metalloproteinase-3Polymorphisms and Breast Cancer Susceptibility: A Report from the Shanghai Breast Cancer Study

Matrix metalloproteinase (MMP)-1 (interstitial collagenase) and MMP-3 (stromelysin) are structurally related multifunctional enzymes that are involved in physiologic and pathologic tissue remodeling ([1][1], [2][2]). Known to contribute to breast cancer invasion and metastasis ([3][3]-[5][4]), roles

Multiple-polymorphism associations of 7 matrix metalloproteinase and tissue inhibitor metalloproteinase genes with myocardial infarction and angiographic coronary artery disease

Single nucleotide polymorphisms (SNPs) in matrix metalloproteinase (MMP) genes may be associated with myocardial infarction (MI) and coronary artery disease (CAD), but studies of multiple MMP genes and their tissue inhibitors (TIMPs) are scarce. Furthermore, differentiation of predictive ability by end point (MI vs CAD) has not been addressed. This study evaluated the association with MI of SNPs in genes encoding MMPs 1, 2, 3, and 9 and TIMPs 1, 2, and 3. Genotypes of patients (N = 5148) with MI (n = 1693) and angiographically defined CAD (> or = 1 lesion of > or = 70% stenosis, n = 1967) were compared with MI-free (n = 3455) and non-CAD patients (n = 1122), respectively. Because of linkage disequilibrium, MMP-1 and MMP-3 SNPs (chromosome 11) were combined, as were the 2 MMP-9 SNPs. For MI, only MMP-9 group CT/RQ (odds ratio [OR] 1.25, P = .007 vs wild-type CC/RR) had greater MI risk, with TT/QQ having a weak trend (OR 1.43, P = .10). These findings remained (CT/RQ) or were strengthened (TT/QQ) after full adjustment. For CAD, association was found for MMP-1/MMP-3 groups 2G1G/6A6A (OR 1.45, P = .022), 2G1G/6A5A (OR = 1.49, P = .001), 2G1G/5A5A (OR 1.64, P = .003), and 1G1G/5A5A (OR 1.35, P = .035) compared to wild type. Composite MMP-9 genotypes but not other SNPs were associated with MI, whereas MMP-1/MMP-3 genotypes were CAD-associated. The largest MMP/TIMP gene study to date, this study suggests care in selection and definition of clinical phenotypes. Furthermore, this suggests that the evaluated SNPs only approximately account for intragenic variation in these genes and that comprehensive evaluation of all variations in these genes should better elucidate associations with MI and CAD phenotypes.

Role of matrix metalloproteinase, tissue inhibitor of metalloproteinase and tumor necrosis factor-α single nucleotide gene polymorphisms in inflammatory bowel disease

To study the (functional) relevance of single nucleotide polymorphisms (SNPs) in genes encoding matrix metalloproteinases (MMP)-1, -2, -3, -9, tissue inhibitors of metalloproteinases (TIMP)-1, -2 and tumor necrosis factor (TNF)-alpha in the etiopathogenesis of inflammatory bowel diseases (IBD), that may enhance susceptibility and/or disease severity. Genomic DNA from 134 Crohn' s disease (CD), 111 ulcerative colitis (UC) patients and 248 control subjects was isolated from resected intestinal tissue or blood. Allelic composition at SNP loci was determined by PCR-RFLP or tetra primer ARMS PCR. The TIMP-1 genotype TT in women and T in men at SNP +372 T/C was found to increase CD susceptibility (39% vs 23.8%, P = 0.018 and 67.9% vs 51.6%, P = 0.055, respectively), while women with this genotype were less prone to development of fistulae during follow-up (41.4% vs 68.3%, P = 0.025). Male IBD or CD patients carrying the TIMP-1 +372 T-allele expressed lower levels of TIMP-1 in surgically resected macroscopically inflamed tissue (0.065 < P < 0.01). The 5T5T genotype at MMP-3 SNP -1613 5T/6T increased the chance of stenotic complications in CD during follow-up (91.2% vs 71.8%, P = 0.022) but seemed to protect against colonic involvement of this disease at first endoscopic/radiologic examination (35.3% vs 59.5%, P = 0.017). Allelic composition at the examined SNPs in genes coding for TIMP-1 and MMP-3 affect CD susceptibility and/or phenotype, i.e., fistulizing disease, stricture pathogenesis and first disease localisation. These findings reinforce the important role of these proteins in IBD.

Polymorphisms in the MMP1 and MMP3 promoter and non-small cell lung carcinoma in North China

Matrix metalloproteinases (MMPs) are proteolytic enzymes that regulate various cell behaviors in cancer biology, via their basic function of degradation of proteins. Genetic variations in several MMP promoters may influence transcription and expression of MMPs. The aim of this study is to assess the effects of the two single nucleotide polymorphisms (SNPs), the guanine insertion polymorphism in the MMP1 promoter and the adenosine insertion polymorphism in the MMP3 promoter, on risk of the development and lymphatic metastasis of non-small cell lung carcinoma (NSCLC). The MMP1 and MMP3 SNPs were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis in 243 NSCLC patients and 350 control subjects in North China. The overall genotype and allelotype distribution of both the variants in cancer patients and controls was not significantly different (all P values are above 0.05). However, stratification analysis showed that smoking individuals with the MMP3 5A allele had a >1.5-fold increased risk to develop NSCLC, compared with those harboring the 6A homozygous [the age and gender adjusted odds ratio (OR) = 1.68, 95% confidence interval (CI) = 1.04-2.70]. In addition, the frequency of the MMP3 5A homozygote in NSCLC patients with lymphatic metastasis was significantly higher than that in lymph node negative ones (5.7 versus 0%, P = 0.04). Moreover, the MMP 1G/5A haplotype significantly increased the risk of lymphatic metastasis (OR = 3.36, 95% CI = 1.42-7.94), compared with the 2G/6A haplotype. The present result suggested that the MMP3 promoter polymorphism may modify susceptibility to NSCLC, and the MMP 1G/5A haplotype may predicate the risk of lymphatic metastasis of this tumor.

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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.