MMP-9 Polymorphisms Research Articles

MMP13 Polymorphism Decreases Risk for Dental Caries

Recent evidence suggests that genetic studies may contribute to a better understanding of individual susceptibility to caries. Matrix metalloproteinases (MMPs) and their tissue inhibitors have been suggested to be involved in the caries process. The purpose of this study was to determine if polymorphisms in MMP2 (rs243865), MMP9 (rs17576), MMP13 (rs2252070), and TIMP2 (rs7501477) were associated with caries. Eligible unrelated children and adolescents were evaluated using a cross-sectional design. Data on oral health habits was obtained through a questionnaire and caries data was collected by clinical examination. Genotyping of the selected polymorphisms was carried out by real-time PCR. Allele and genotype frequencies were compared between individuals with and without caries experience. Of 505 subjects, 212 were caries-free and most subjects (61.2%) had mixed dentition. Allele frequency of MMP2, MMP13 and TIMP2 was different between caries-affected and caries-free individuals, with significant association for MMP13 (p = 0.004). Mutant allele carriers for MMP13 demonstrated a significantly decreased risk for caries (OR = 0.538, 95% CI 0.313–0.926); this result remained significant after adjustment for candidate genes, type of dentition and dietary factors. Allelic and genotype frequencies of the polymorphism in MMP9 were similar in caries-affected and caries-free individuals. Genetic variations in MMP13 may contribute to individual differences in caries susceptibility. Our findings reinforce that susceptibility to caries results from gene-environment interactions.

Matrix metalloproteinase-1 promoter genotypes and haplotypes are associated with carotid plaque presence

ObjectivesMatrix metalloproteinase (MMP)-1 degrades fibrillar collagens suggesting important role in vascular remodeling. Data about MMP-1 promoter polymorphisms and carotid atherosclerosis (CA) are scarce. The aim of this study was to evaluate association of MMP-1 genotypes/haplotypes with carotid plaque (CP) presence in Serbian population. Design and methodsStudy enrolled a total of 702 participants: 274 controls and 428 consecutive patients with CA who underwent carotid endarterectomy. MMP-1 polymorphisms −1607 1G/2G, −519 A/G and −340 T/C were genotyped by PCR and RFLP methods. ResultsIndividuals carrying MMP-1 −1607 2G allele had significantly increased allele dose-dependent risk for CP presence (1G1G vs. 1G2G vs. 2G2G; OR=1; OR=1.87 95% CI 1.29–2.07; OR=3.49 95% CI 1.67–7.30, p=0.0009, respectively). Compared to the referent haplotype 2G−1607-T−340-A−519, the haplotypes 1G−1607-T−340-A−519, 1G−1607-T−340-G−519 and 2G−1607-C−340-A−519 had statistically significant protective effect on CP presence (OR=0.41, 95% CI 0.29–0.81, p=0.01; OR=0.56, 95% CI 0.44–0.89, p=0.01; OR=0.43, 95% CI 0.27–0.86, p=0.02, respectively). ConclusionsMMP-1 −1607 G/2G polymorphism solely and specific haplotypes of three analyzed promoter polymorphisms are significantly and independently associated with occurrence of CP. Replication studies in other populations are needed.

Functional MMP-9 polymorphisms modulate plasma MMP-9 levels in multiple sclerosis patients

We have described that MMP-9 C−1562T and (CA)n polymorphisms contribute to multiple sclerosis (MS). Here, we evaluate whether plasma MMP-9 levels are related to disease severity, drug therapy resistance and polymorphisms. For sub-study 1, 36 patients with MS and 35 controls were recruited. For sub-study 2, 88 individuals (53 patients and 35 controls) were included in a cross-sectional analysis. MS patients presented higher MMP-9 activity (1.4±0.18 versus 0.93±0.18A.U. for control, P<0.05). Drug-therapy resistant individuals exhibited increased MMP-9 activity (1.96±0.25 versus 1.21±0.09A.U. for non-resistant patients). EDSS score was also related to MMP-9 levels. The CT+TT and HH genotypes had higher MMP-9 levels as compared to patients carrying the CC and LL. Drug therapy resistance, disease severity, MMP-9 plasma activity and polymorphisms are associated with MS.

Association ofMMP3-1171(5A&gt;6A) Polymorphism with Lung Cancer in Lebanon

Matrix metalloproteinases (MMPs) are a family of enzymes that degrade extracellular matrix components and are involved in the development and progression of cancer. Lung cancer is the most commonly diagnosed cancer in Lebanon. This study was undertaken to investigate the association between -1171(5A>6A) polymorphism in the promoter of MMP3 gene and the susceptibility to lung cancer in a Lebanese population. The MMP3 polymorphism was investigated in 41 lung cancer patients and 51 unrelated healthy controls using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. We found a significant association between MMP3-1171 5A allele and lung cancer (Odds ratio [OR]=2.7, 95% [CI]=1.3-5.3; Fisher's p-value=0.005). This study may form an additional evidence for the association of MMP3 enzyme and genetic susceptibility to lung cancer.

Association of MMP3, MMP9, ADAM33, and TIMP3 polymorphisms with chronic obstructive pulmonary disease and its progression

PCR-RFLP analysis was performed for 391 cases and 514 control individuals to analyze the contribution of polymorphisms of the matrix metalloproteinase genes MMP1 (−1607 G>GG, rs1799750; −519 A>G, rs494379), MMP2 (−735 C>T, rs2285053), MMP3 (−1171 5A>6A, rs35068180), MMP9 (−1562 C>T, rs3918242; 2660A>G, rs17576), MMP12 (−82 A>G, rs2276109), the disintegrin and metalloproteinase 33 gene ADAM33 (12418 A>G, rs2280091; 13491 C>G, rs2787094), and tissue inhibitors of metalloproteinase genes TIMP2 (−418 G>C, rs8179090) and TIMP3 (−1296 T>C, rs9619311) to chronic obstructive pulmonary disease. Significant association with increased rick of chronic obstructive pulmonary disease was observed for the 6A6A genotype of the MMP3 −1171 5A>6A polymorphism (OR = 2.49, Padj = 0.003979, Pcor = 0.0358 adjusted for age, sex, smoke pack-years, ethnicity) and for the G-G haplotype of ADAM33 polymorphisms 13491 C>G and 12418 A>G (OR = 0.39, Padj = 0.0012, Pcor = 0.006). Significant interactions were detected between the smoking status and ADAM33 12418 A >G (Pinteract = 0.026) and TIMP3 −1296 T>C (Pinteract = 0.044). The risk of emphysema was increased in GG homozygotes by ADAM33 13491 C>G and a risk of emphysema was found (OR = 1.74, Padj = 0.013, Pcor = 0.117). The severity of chronic obstructive pulmonary disease was modified by MMP9 −1562 C>T in the additive model (OR = 1.883, Padj = 0.028, Pcor = 0.252). Thus, polymorphisms of MMP3, MMP9, ADAM33, and TIMP3 can be considered important risk factors for the development and progression of chronic obstructive pulmonary disease; in addition, pathogenetically significant gene-environment interactions were identified. These data contribute to the understanding of hereditary predisposition to chronic obstructive pulmonary disease.

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.

Is MMP-7 Gene Polymorphism a Possible Risk Factor for Chronic Obstructive Pulmonary Disease in Turkish Patients

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease that leads to fixed narrowing of small airways and alveolar wall destruction (emphysema). This study was performed to test the association between MMP-7 (rs155668818) and MMP-12 (rs56184183) polymorphisms in the MMP-7 gene and COPD risk and its severity in the Turkish population. MMP-7 and MMP-12 polymorphisms were genotyped in 85 patients with COPD and 73 healthy control subjects using real-time polymerase chain reaction analysis. There were significant differences in the distribution of MMP-7 genotypes but not in the frequencies of these alleles between COPD patients and controls (p=0.009, p=0.102, respectively). The MMP-7 AA genotype was found to be associated with an increased risk of COPD (p=0.004; odds ratio: 2.576; confidence interval: 1.297-5.119). The lowest values of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), FEV1/FVC in patients with GG homozygosity were determined and these values were statistically significant compared to the control subjects (p<0.001, p<0.001, p<0.001). When the present study groups were analyzed for MMP-12 polymorphism, it was found that all the subjects had wild-type genotype for this polymorphism. These findings have suggested that MMP-7 polymorphism might be associated with the risk and progression of COPD in the Turkish population.

Association between Polymorphisms in the Promoter Regions of Matrix Metalloproteinases (MMPs) and Risk of Cancer Metastasis: A Meta-Analysis

BackgroundA variety of studies have evaluated the associations between polymorphisms in the promoter regions of Matrix metalloproteinases (MMPs) and cancer metastasis. However, the results remain inconclusive. To better understand the roles of MMP polymorphisms in metastasis, we conducted a comprehensive meta-analysis.MethodsElectronic databases were searched (from January 2000 to June 2011) for any MMP genetic association studies in metastasis. Overall and subgroup analyses were performed. Odds ratio (OR) and 95% confidence interval (CI) were used to evaluate the associations between MMP polymorphisms and metastasis. Statistical analysis was performed with Review Manager 5.0 and STATA11.0.ResultsThirty-three studies addressing five MMP polymorphisms were analyzed among 10,516 cancer cases (4,059 metastasis-positive cases and 6,457 metastasis-negative cases). For MMP1 (−1607)1G/2G, genotype 2G/2G increased the overall risk of metastasis under the recessive model (OR = 1.44, 95% CI = 1.05–1.98). In subgroup analysis based on cancer type, associations were found in head/neck and breast cancer under the recessive model, and also in breast cancer under the dominant model. For MMP3 (−1171) 5A/6A, the polymorphism decreased the overall risk of metastasis under two genetic models (recessive: OR = 0.80, 95%CI = 0.64–0.99, dominant: OR = 0.72, 95%CI = 0.56–0.93). The polymorphisms of MMP7 (−181) A/G and MMP9 (−1562) C/T increased metastatic risk. However, no association was observed between MMP2 (−1306) C/T and metastasis.ConclusionsOur investigations demonstrate that polymorphisms in the promoter regions of MMP1, 3, 7 and 9 might be associated with metastasis in some cancers. Further studies with large sample size for MMP2 should be conducted.

Association of Promoter Polymorphisms in MMP2 and TIMP2 with Prostate Cancer Susceptibility in North India

The importance of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in tumor progression is well documented. MMP2/TIMP2 system has a significant impact on the development and progression of cancer and genetic polymorphisms in the promoters of MMP2 (-1306C/T, 735C/T) and TIMP2 (-418G/A, -303C/T) are correlated with decreased enzyme activity. We sought to determine whether genetic polymorphisms in MMP2 and TIMP2 polymorphisms may be associated with varying risk of prostate cancer (PCa) in men in North India. Genotyping was done by PCR-restriction fragment length polymorphism method in 190 histologically confirmed PCa patients and 200 unrelated, healthy, age-matched individuals of similar ethnicity. Patients with MMP2 (-1306) CT genotype as well as T allele were at higher risk of PCa (p = 0.018; OR = 1.68 and p = 0.015; OR = 1.52). This effect was even more evident in the case of the T allele carrier (CT + TT) (p = 0.011; OR = 1.71). MMP2 (735) C>T, TIMP2 (-418) G>C and TIMP2 (-303) C>T polymorphism demonstrated no association. However, TIMP2 (-418) GC was found to be involved in progression of PCa but not in initiation. Haplotype results demonstrated that MMP2 (1306T-735C) and TIMP2 (418G-303T) were associated with a 1.5- and 1.8-fold increased risk, respectively. Our data indicated that MMP2-1306C>T gene polymorphism contributes to PCa susceptibility. These findings suggested MMP2 variants as a predictor of PCa progression risk among North Indian men. We assume that analysis of these gene polymorphisms can help identify patient subgroups at high risk of poor disease outcome.

Matrix Metalloproteinase (MMP)-2 Genetic Variants Modify the Circulating MMP-2 Levels in End-Stage Kidney Disease

Background: Matrix metalloproteinases (MMPs) play important roles in the pathophysiology of renal diseases, and imbalanced MMP-2 and its endogenous inhibitor (the tissue inhibitor of metalloproteinases-2; TIMP-2) are implicated in the vascular alterations of end-stage kidney disease (ESKD) patients. We have examined whether MMP-2 gene polymorphisms and haplotypes modify MMP-2 and TIMP-2 levels in ESKD patients as well as the effects of hemodialysis on the concentrations of these biomarkers. Methods: We determined MMP-2 and TIMP-2 plasma levels by gelatin zymography and ELISA, respectively, in 98 ESKD patients and in 38 healthy controls. Genotypes for two relevant MMP-2 polymorphisms (C^–1306T and C^–735T in the promoter region) were determined by TaqMan® allele discrimination assay and real-time polymerase chain reaction. The software program PHASE 2.1 was used to estimate the haplotype frequencies. Results: We found increased plasma MMP-2 and TIMP-2 levels in ESKD patients compared to controls (p < 0.05), and hemodialysis decreased MMP-2 (but not TIMP-2) levels (p < 0.05). The T allele for the C^–735T polymorphism and the C-T haplotype were associated with higher MMP-2 (but not TIMP-2) levels (p < 0.05), whereas the C^–1306T had no effects. Hemodialysis decreased MMP-2 (but not TIMP-2) levels independently of MMP-2 genotypes or haplotypes (p < 0.05). Conclusions: MMP-2 genotypes or haplotypes modify MMP-2 levels in ESKD patients, and may help to identify patients with increased MMP-2 activity in plasma. Hemodialysis reduces MMP-2 levels independently of MMP-2 genetic variants.

Association Between High Serum Matrix Metalloproteinase-9 and MMP-9 (-1562C>T) Polymorphism in Patients With ST-Elevation Acute Myocardial Infarction.

BackgroundMatrix metalloproteinase (MMP)-9 is excessively expressed in frail region of atherosclerotic plaque and released in circulation following plaque rupture. High MMP-9 level associated with severity of occluded thrombus and subsequent myocardial infarction. MMP-9 (-1562C>T) polymorphism associated with acute myocardial infarction, however conflicting data present regarding impact of MMP-9 (-1562C>T) polymorphism on circulating MMP-9 level in acute myocardial infarction with ST-elevation (STEMI), clinical entity represents totally occluded coronary thrombus.MethodsWe enrolled consecutively subjects with acute coronary syndrome treated in intensive coronary care unit. Acute coronary syndrome diagnosis were classified into STEMI and non-ST-elevation acute coronary syndrome (NSTEACS). Seventy consecutive subjects were enrolled for this study, 31 subjects with STEMI and 39 subjects with NSTEACS.ResultsOn admission serum MMP-9 level, measured with sandwich enzyme immunoassay, were higher in STEMI as compared with NSTEACS (1,574.2 ± 604.1 ng/mL vs. 1,104.4 ± 591.5 ng/mL, P < 0.01). Proportion of subjects with MMP-9 (-1562C>T) polymorphism, analyzed with PCR-RFLP, were higher in STEMI as compared with NSTEACS (66.7% vs. 33.3%, P = 0.15). T allele frequency was almost twice in STEMI as compared to in NSTEACS. Almost all (83%) subjects with MMP-9 (-1562C>T) polymorphism had high serum MMP-9 level (> 1,334.5 ng/mL) during STEMI, whereas in NSTEACS all subjects had low level.ConclusionMMP-9 (-1562C>T) polymorphism associated with high serum MMP-9 level in patients with STEMI.

Preeclampsia: Molecular Mechanisms, Predisposition, and Treatment

Preeclampsia is a disorder characterised by vascular endothelial dysfunction and vasospasm that occurs after 20 weeks of gestation till 4–6 weeks postpartum. The global incidence of preeclampsia has been estimated at 2–14% of all pregnancies. Despite the advances made in the field, research is still organised to clarify the possible molecular mechanisms or predisposing factors of preeclampsia as well as the treatment options for such a significant disorder. Papers were selected on the basis of fundamental research ideas or reviews in the field. This special issue is comprising of seven papers which are focused on the better understanding of preeclapsia. One of the papers deals with the correlation of preeclampsia with hypoxia, thrombosis, and inflammation. The authors suggest that there is no accurate test for predicting preeclampsia. The role of markers such as sFLT, sEng, products of fetal and placental origin, markers of renal or endothelial damage, or markers of oxidative stress is presented by acting as secondary pathways to the pathophysiological changes that precede the clinical onset of preeclampsia. A combination of such markers is proposed in order to increase the detection accuracy earlier in the pregnancy and hopefully allow for more effective prophylactic strategies. Another paper sought to validate the use of urinary podocyte (podocyturia) as a single diagnostic marker in preeclampsia and in differentiating from other high-risk pregnancy states with similar presentations. The researchers discovered that podocyte loss is present not only in preeclampsia but in other high-risk pregnancy states. In addition, podocyturia was not found in a majority of patients diagnosed with preeclampsia. So, they realized that their findings had relatively low sensitivity and specificity, but they proposed further research regarding the predictive value of podocyturia in preeclampsia in larger studies. The authors of one of the paper investigated whether there is an association between angiotensin converting enzyme (ACE) insertion/deletion (I/D) polymorphism and preeclampsia in 236 pregnant women. They showed that there was significant difference in terms of genotype distribution between preeclampsia and controls, while it was not found any difference in allele frequency for ACE I/D polymorphism. A possible reason for the inconsistency could be the genetic basis that caused different susceptibilities among different populations. Moreover, one paper is mentioning that both women and children exposed to preeclampsia exhibit an adverse vascular phenotype, a propensity to subclinical atherosclerosis, and increased risk of adverse cardiac and vascular events in future life. They suggest that further studies into the mechanisms such as vascular dysfunction underlying the altered cardiovascular phenotype might provide unique insight into pathophysiological or molecular links between preeclampsia and cardiovascular disease which may direct us to novel treatment strategies for both conditions. Improvement in vascular function is also proposed as a valuable intermediate end point in studies aiming to reduce risk in this potentially young and generally asymptomatic population before the onset of clinical disease. F. J. Valenzuela and colleagues have recently reviewed some polymorphisms in important candidate genes involved in different pathogenic mechanisms related to preeclampsia and concluded that various studies in different populations have identified maternal polymorphisms associated with preeclampsia through candidate gene approaches. Luizon and colleagues with a Letter to the Editor add to the paper of F. J. Valenzuela et al. by further referring to candidate genes related to angiogenesis and endothelial dysfunction in preclampsia performed in the Brazilian population. Specifically, genotypes and haplotypes formed by polymorphisms of VEGF, eNOS, and MMP-9, along with an example of the interaction among these genes in the prediction of preeclampsia provide additional information with clinical relevance to its susceptibility. An additional paper is a review of the molecular mechanisms which are contributing to the pathogenesis of preeclampsia. Altered angiogenic balance, systemic inflammation, dysregulation of Renin-Angiotensin system, and placental hypoxia or ischemia are mechanisms leading to the pathogenesis of preeclampsia. However, it is unknown whether the mechanisms act independently or have synergistic effects.

Matrix metalloproteinase‐2 promoter and tissue inhibitor of metalloproteinase‐2 gene polymorphisms in non‐Hodgkin's lymphoma

Single nucleotide polymorphisms in the promoter regions of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinase (TIMP) genes are associated with an adverse outcome in some cancers. We examined three polymorphisms: -1306C/T and -735C/T in MMP-2 and -418G/C in the TIMP-2 gene, using chain reaction restriction fragment length polymorphism typing analysis in 575 patients with non-Hodgkin's lymphoma (NHL). We examined the possible correlations between the three polymorphisms (MMP-2 (-1306C/T and -735C/T) and TIMP-2 gene (-418G/C)) and the clinical significance and survival rate in patients with NHL. The incidence of the CT, TT+CT genotypes and T allele of -735C/T was significantly higher in stage III and IV patients compared to stage I and II patients. In cases with bone marrow infiltration, the TT genotypes of the -1306C/T gene were significantly less frequent compared to CC genotypes. The CT, TT and CT+TT genotypes and T allele in patients exhibiting the -1306C/T polymorphism were significantly less frequent in patients with a large tumor size compared to a smaller tumor. The TT genotypes of the -735C/T polymorphism were more common in patients with a large tumor compared to those with a smaller tumor. The frequency of the -1306C/-735T haplotype in patients with a smaller tumor size was significantly higher compared to patients with a large tumor. The -1306T/-735C and -1306C/-735C haplotypes were significantly less frequent in patients with B-symptoms compared to those without. Interestingly, patients with the -735CT genotype exhibited a lower rate of survival. Our results demonstrate that certain MMP-2 and TIMP-2 gene polymorphisms potentially effect the progression or assessment of prognosis for NHL. This research warrants further, larger scale studies.

Polymorphisms of genes involved in extracellular matrix remodeling and abdominal aortic aneurysm

Abdominal aortic aneurysm (AAA) has a multifactorial etiology and the relevance of genetic factors is getting increasing interest, in particular those related to the destructive remodeling of extracellular matrix. We performed a candidate gene association study of polymorphisms in genes coding matrix metalloproteinases (MMPs), tissue inhibitors of MMPs (TIMPs), and elastin (ELN) in AAA. DNA samples from 423 AAA patients and 423 controls were genotyped for 12 polymorphisms in 10 genes: MMP1 (-1607G/GG), MMP2 (-735C/T; -1306C/T; -1575 G/A), MMP3 (5A/6A), MMP9 (-1562C/T), MMP10 (A180G), MMP-12 (-82A/G), MMP-13 (-77A/G), TIMP1 (C434T), TIMP3 (-1296T/C), and ELN (G1355A). Genotype distribution was significantly different between patients and controls for the following polymorphisms: -1306C/T MMP2; 5A/6A MMP3; -77A/G MMP-13; G1355A ELN; and C434T TIMP1. In a multivariable logistic regression analysis adjusted for traditional cardiovascular risk factors and chronic obstructive pulmonary disease, -1306C/T MMP2 (odds ratios [OR] = 0.55 [95% confidence interval, CI .34-.85], P < .007) and G1355A ELN (OR = 0.64 ([95% CI .41-.99], P = .046) polymorphisms resulted in independent protective factors for abdominal aortic aneurysm (AAA), whereas 5A/6A MMP3 (OR = 1.82 [95% CI 1.04-3.12], P = .034) and -77 A/G MMP-13 (OR = 2.14 [95% CI 1.18-3.86], P = .012) polymorphisms resulted in independent risk factors for AAA. In a multivariable logistic regression analysis adjusted for traditional cardiovascular factors and chronic obstructive pulmonary disease, the prevalence of the contemporary presence of three or four genetic risk conditions was a strong and independent determinant of AAA disease (OR = 2.96, 95% CI 1.67-5.24, P < .0001). For those polymorphisms independently associated with AAA in this study (-1306C/T MMP2, 5A/6A MMP3, -77A/G MMP-13, and G1355A ELN polymorphisms), we performed a meta-analysis of the available data (this paper and literature data). We found a significant association with an increased risk of AAA for MMP3 (AAA patients n = 1258, controls n = 1406: OR = 1.48 [95% CI = 1.23-1.78], I(2) = 0%) and MMP-13 (AAA patients n = 800, controls n = 843: OR = 1.37 [95% CI = 1.04-1.82], I(2) = 25%) polymorphisms and a trend that did not reach the statistical significance, toward a decreased risk of AAA for MMP2 (AAA patients n = 1090, controls n = 1077: OR = 0.83 [95% CI = .60-1.15], I(2) =7 1%) and ELN (AAA patients n = 904, controls n = 1069: OR = 0.79 [95% CI = .53-1.18], I(2) = 72%) polymorphisms. These findings suggest that polymorphisms in MMP2, MMP3, MMP-13, and ELN genes may independently contribute to the pathogenesis of AAA.

Association of MMP-9 gene polymorphisms with acute coronary syndrome in the Uygur population

MethodsA case–control study composed of 361 ACS patients and 432 control subjects that underwent coronary angiography were enrolled in the study. Among the ACS patients, 162 had single-vessel disease (44.9%),...

Role of functional polymorphism of matrix metalloproteinase-2 (-1306 C/T and -168 G/T) and MMP-9 (-1562 C/T) promoter in oral submucous fibrosis and head and neck squamous cell carcinoma in an Indian population

The aim of this study was to explore the association of MMP-2 (-1306 C/T and -168 G/T) and MMP-9 (-1562 C/T) promoter polymorphisms in oral submucous fibrosis (OSMF) and head and neck squamous cell carcinoma (HNSCC) cases. These SNP were genotyped by PCR-RFLP. Total of 1260 individuals were recruited, of which 412 OSMF, 422 HNSCC and 426 were controls. In HNSCC, MMP-2 (-1306 C/T) and MMP-9 (-1562C/T) polymorphism, T allele showed strong association (p < 0.00 and p < 0.01) as compared to healthy control respectively, but not in case of OSMF and showed significant association with increasing progression of clinico-pathological grading. We concluded that SNPs in the MMP-2 and -9 promoter region may be associated with susceptibility to HNSCC not in OSMF.

Genetic Variants in Matrix Metalloproteinase-9 Gene Modify Metalloproteinase-9 Levels in Black Subjects

Altered matrix metalloproteinases (MMPs) levels are involved in cardiovascular diseases and increased MMP-9 levels enhance the cardiovascular risk in apparently healthy subjects. We investigated the effects of MMP-9 gene polymorphisms and haplotypes on the circulating MMP-9 levels in healthy black subjects and the effects of an MMP-2 polymorphism on the plasma MMP-2 concentrations. We studied 190 healthy subjects, nonsmokers, self-reported as blacks (18-63 years). Genotypes for the MMP-2 C(-1306)T polymorphism and the MMP-9 C(-1562)T, 90(CA)(14-24) and Q279R polymorphisms (rs243865, rs3918242, rs2234681, and rs17576, respectively) were determined by TaqMan(®) Allele Discrimination assay and real-time polymerase chain reaction or restriction fragment length polymorphism. Alleles for the 90(CA)(14-24) polymorphism were grouped as low (L) when there were <21 and high (H) when there were ≥21 CA repeats. The plasma levels of MMP-2 and MMP-9 were determined by gelatin zymography. The software PHASE 2.1 was used to estimate the haplotypes frequencies. Although we found no effects of the MMP-9 C(-1562)T or the Q279R polymorphisms on MMP-9 levels, higher MMP-9 levels were associated with the HH genotype for the -90(CA)(14-24) polymorphism compared with the HL or LL genotypes. Lower MMP-9 levels were found in carriers of the CRL haplotype (combining the C, R, and L alleles for the MMP-9 polymorphisms) compared with the CRH haplotype. Consistent with this finding, the CRL haplotype was more commonly found in subjects with low MMP-9 levels. The MMP-2 C(-1306)T polymorphism had no effects on the plasma MMP-2 levels. Our results show that MMP-9 genetic variations modify MMP-9 levels in black subjects and may offer biochemical evidence implicating MMP-9 in the pathogenesis of cardiovascular diseases in blacks.

Genetic variation, gene-expression and circulating levels of matrix metalloproteinase-9 in patients with stable coronary artery disease

BackgroundMediators involved in atherosclerosis and plaque rupture may have importance as risk markers for coronary artery disease (CAD). We have investigated the influence of matrix metalloproteinase (MMP)-9 genetic variations on gene- and protein expression in stable CAD patients. MethodsThe promoter −1562C/T and exon 6 R279Q A/G polymorphisms were determined in 1001 patients with angiographically verified stable CAD and in 204 healthy controls. Genotype and gene-expression were determined by real-time PCR. Serum levels of MMP-9 and its inhibitor TIMP-1were measured immunologically and by zymography (MMP-9 activity). ResultsNone of the polymorphisms associated with the presence of CAD, myocardial infarction or type 2 diabetes, whereas the variant allele of the R279Q polymorphism associated with hypertension (adjusted p=0.015). The T- and G alleles associated with lower and higher mRNA levels, respectively (p<0.005 both), also shown in an experimental ex-vivo LPS stimulated model. T-allele carriers had higher concentrations of MMP-9 (adjusted p=0.032) and the GG genotype induced lower MMP-9 gelatinolytic activity (p=0.01). Higher MMP-9 gene-expression and TIMP-1 levels were observed in patients with previous myocardial infarction, the latter also was elevated in diabetics (<0.05, all). ConclusionThe investigated MMP-9 polymorphisms influenced gene- and protein expression differently and the R279Q polymorphism associated significantly with hypertension.

Role of matrix metalloproteinase 3 gene promoter polymorphism in chronic pancreatitis

To study the role of 5A/6A polymorphism of matrix metalloproteinase (MMP-3) and their levels in the pathogenesis of chronic pancreatitis (CP). One hundred and twenty CP patients and an equal number of age and sex-matched healthy controls were included in the study. Genotypes were determined for 5A/6A allele of MMP-3 gene by allele specific PCR (AS-PCR). The serum MMP-3 levels were estimated using sandwich ELISA method. The distribution of the genotypes of the 5A/6A polymorphism in both control and study patients was similar (p = 0.523). Within the disease group, patients with older age, early onset of the disease, and addictions such as smoking and alcohol consumption had higher levels as compared to those who did not have these features. We conclude that functional polymorphism of MMP-3 (5A/6A) is not associated with CP. However, the higher levels within the disease group indicate its possible role in the disease process.

Variation of Matrix Metalloproteinase 1 and 3 Haplotypes and Their Serum Levels in Patients with Rheumatoid Arthritis and Osteoarthritis

The matrix metalloproteinases 1 and 3 (MMP1 and MMP3) are thought to be important in destructive joint changes seen in rheumatoid arthritis (RA) and osteoarthritis (OA) diseases. The aim of this study was to analyze whether functional polymorphisms in the promoter region of the MMP1 and MMP3 genes were associated with RA and OA. The MMP1 (-1607 1G/2G) and MMP3 (-1171 5A/6A) polymorphisms were screened by polymerase chain reaction-restriction fragment length polymorphism in 100 patients with (RA), 100 patients with (OA), and 100 controls. Serum MMP1 and MMP3 levels were measured by enzyme-linked immunosorbent assay. The results reported a significant difference between patients with OA and controls regarding allele distributions of MMP1 polymorphism, but not between patients with RA and controls. For MMP3 polymorphism, the 6A/6A genotype was significantly more frequent in patients with RA and OA than in controls. The haplotype 2G-6A, which carries the abnormal alleles, showed higher frequencies in the patients with RA and OA than in controls (28%, 30% and 8%, respectively). There were no significant differences in serum MMP1 and MMP3 levels between all studied groups. In conclusion, the MMP1 and MMP3 haplotypes may represent genetic determinants for RA and OA in the Egyptian population. The results suggest that MMP polymorphism genotypes may be more useful in predicting joint damage than measurement of serum concentrations of MMP1 and MMP3. Moreover, MMP1 and MMP3 polymorphisms may predict the activity and severity of these diseases.