MMP-9 Single Nucleotide Polymorphisms Research Articles

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.

MMP9 SNP and MMP SNP-SNP interactions increase the risk for ischemic stroke in the Han Hakka population.

ObjectivesTo investigate the association of eight variants of four matrix metalloproteinase (MMP) genes with ischemic stroke (IS) and whether interactions among these single nucleotide polymorphisms (SNPs) increases the risk of IS.MethodsAmong 547 patients with ischemic stroke and 350 controls, matrix‐assisted laser desorption/ionization time of flight mass spectrometry was used to examine eight variants arising from four different genes, including MMP‐1 (rs1799750), MMP‐2 (rs243865, rs2285053, rs2241145), MMP‐9 (rs17576), and MMP‐12 (rs660599, rs2276109, and rs652438). Gene–gene interactions were employed using generalized multifactor dimensionality reduction (GMDR) methods.ResultsThe frequency of rs17576 was significantly higher in IS patients than in controls (p = .033). Logistic regression analysis revealed the AG and GG genotypes of rs17576 to be associated with a higher risk for IS, with the odds ratio and 95% confidence interval being 2.490 (1.251–4.959) and 2.494 (1.274–4.886), respectively. GMDR analysis showed a significant SNP‐SNP interaction between rs17576 and rs660599 (the testing balanced accuracy was 53.70% and cross‐validation consistency was 8/10, p = .0107). Logistic regression analysis showed the interaction between rs17576 and rs660599 to be an independent risk factor for IS with an odds ratio of 1.568 and a 95% confidence interval of 1.152–2.135.ConclusionAn MMP‐9 rs17576 polymorphism is associated with increased IS risk in the Han Hakka population and interaction between MMP‐9 rs17576 and MMP‐12 rs660599 is associated with increased IS risk as well.

Analysis of COL1A1 and MMP9 single nucleotide polymorphisms in mandibular prognathism

Mandibular prognathism (MP) belongs to malocclusions of skeletal Class III and is characterized by overgrowth of the lower jaw with or without undergrowth of the upper jaw. MP etiology is multifactorial, including both environmental and genetic factors. It is conceivable that single nucleotide polymorphisms (SNPs) in genes controlling craniofacial development might contribute to MP. The aim of the present study was to establish a potential association between COL1A1 -1997 G>T (rs1107946) and MMP9 -1562 C>T (rs3918242) SNPs and MP in Serbian population. This case-control study included 120 participants: 60 patients with MP and 60 controls with skeletal Class I. The two SNPs were analyzed by means of polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The association of gene variants with MP risk was determined by calculating odds ratios (OR) and their 95% confidence intervals (CI).There was no difference in SNPs allele frequencies, and no difference could be observed in MMP9 -1562 C>T genotypes distribution between cases and controls. However, the TT genotype of COL1A1-1997 G/T (rs1107946) polymorphism was associated with a two-fold increase of mandibular prognathism risk, though with a borderline statistical significance (OR 2.32, CI 0.97-5.53, p=0.055). COL1A1-1997 G/T (rs1107946) appears to be implicated in Class III mandibular prognathism while MMP9 -1562 C/T (rs3918242) does not seem to be a risk factor for the development of this type of craniofacial anomaly.

A polymorphism in the 3'-untranslated region of the matrix metallopeptidase 9 gene is associated with susceptibility to idiopathic calcium nephrolithiasis in the Chinese population.

ObjectiveTo investigate whether single nucleotide polymorphisms (SNPs) in the 3′ untranslated region (UTR) of the matrix metallopeptidase 9 gene (MMP9) are associated with susceptibility to calcium oxalate stones.MethodsA total of 428 patients with kidney stone disease (KSD) and 450 control individuals were enrolled. Three MMP9 SNPs (rs20544, rs9509, and rs1056628) were genotyped, and MMP9 mRNA and protein expression was determined in patients and controls. The dual luciferase reporter gene assay was conducted by transfecting HEK293 cells with miR-491-5p mimics and plasmids containing MMP9 with rs1056628 AA/CC genotypes.ResultsThe rs1056628 CC genotype was significantly increased in KSD patients compared with controls (CC vs AA: odds ratio [OR] = 2.279, 95% confidence interval [CI] = 1.048–4.956). The rs1056628 C allele frequency was higher in KSD patients than controls. The increased KSD risks associated with rs1056628 were more evident in individuals aged <30 years (OR = 3.504, 95% CI = 1.102–11.139) and men (OR = 2.522, 95% CI = 1.004–6.334). mRNA and protein levels of MMP9 were significantly higher in KSD patients with the CC genotype than in those with the AA genotype.ConclusionThis study demonstrates that MMP9 SNP rs1056628 is associated with a significant KSD risk in Chinese Han individuals.

Association of MMP2 and MMP9 gene polymorphisms with the recurrent spontaneous abortion: A meta-analysis.

Recurrent spontaneous abortion (RSA) accounts for the most common complication of early pregnancy in humans. Matrix metalloproteinases (MMPs) play important regulatory roles in implantation and placentation to ensure a successful pregnancy. Single nucleotide polymorphisms (SNPs) have been identified in the promoters of MMP2 and MMP9 genes. However, the associations between MMP2 and MMP9 SNPs and the RSA risk remain unclear. The aim of this meta-analysis was to investigate whether MMP2 (-735C>T) and MMP9 (-1562C>T) SNPs are associated with the risk of RSA. Literatures published before 17th April 2020 were screened to identify the eligible studies. Heterogeneity, sensitivity and publication bias analysis were analyzed by the STATA software. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by the Review Manager software with fixed effects model. After screening, 2 studies for MMP2 (-735C>T) (278 RSA cases and 265 controls) and 4 studies for MMP9 (-1562C>T) (520 RSA cases and 512 controls) were enrolled in this meta-analysis. Results showed that MMP2 (-735C>T) presented a statistically significant association with the risk of RSA under allelic (T vs C: OR=1.50, 95% CI=1.14-1.98, P=0.004, I2=31%), heterozygote (CT vs CC: OR=1.74, 95% CI=1.22-2.50, P=0.003, I2=41%) and dominant (TT+CT vs CC: OR=1.74, 95% CI=1.23-2.45, P=0.002, I2=40%) genetic models. MMP9 (-1562C>T) in allelic (T vs C: OR=1.34, 95% CI=1.08-1.65, P=0.007, I2=0%), heterozygote (CT vs CC: OR=1.38, 95% CI=1.06-1.79, P=0.02, I2=0%) and dominant (TT+CT vs CC: OR=1.41, 95% CI=1.10-1.82, P=0.008, I2=0%) genetic models were significantly correlated with the RSA risk. Our meta-analysis results suggest that MMP2 -735T allele and MMP9 -1562T allele have significant association with the risk of RSA.

Cervical transverse MRI in ALS diagnosis and possible link to VEGF and MMP9 single nucleotide polymorphisms. Case Report

We report the case of a patient diagnosed with ALS and presenting with a “snake eyes” sign on axial cervical MRI. Given the peculiar radiological presentation and our patient’s young age, we decided to perform a genetic analysis to better investigate the molecular mechanisms underlying the pathogenesis of his clinical phenotype. In our study, we identified different polymorphisms of interest at the level of VEGF and MMP9 promoters that we suggest could contribute to neuronal sufferance by promoting vascular abnormalities and tissue hypoxia, in accordance with previous published papers. When combined with repetitive mechanical stress at cervical level, as evident in our patient’s case, the resultant radiological image appears to be the “snake eyes” sign in the anterior horns of the cervical spinal cord, while the clinical phenotype is that of an atypical ALS case, possibly an ALS-mimic. To correctly identify and diagnose such patients, in particular when disease course and neuroradiological data do not correspond to those of a classical ALS case, we underline the importance of axial cervical MRI studies and suggest the possibility of their implementation into routine clinical practice.

MMP9 polymorphism is associated with susceptibility to non-traumatic osteonecrosis of femoral head in a Chinese Han population.

Non-traumatic osteonecrosis of femoral head (ONFH) is an orthopedic refractory disease with escalating morbidity in Chinese Han population. In our case-control study, we examined eight previously identified MMP9 single-nucleotide polymorphisms (SNPs) in 585 non-traumatic ONFH patients and 507 healthy individuals from northern China to determine whether these SNPs associated with the risk of developing non-traumatic ONFH. Genetic model and haplotype analyses were used to evaluate the association between SNPs and non-traumatic ONFH. MMP9 rs2274755 (OR, 0.740; 95% CI, 0.578-0.949; p = 0.017) was associated with a reduced risk of non-traumatic ONFH. After adjusting for age and gender, the logistic regression results showed that rs2274755 associated with a lower risk of non-traumatic ONFH in the dominant (OR=0.71, 95% CI: 0.54-0.94, p=0.016), overdominant (OR=0.73, 95% CI: 0.55-0.96, p=0.026) and log-additive (OR=0.74740; 95% CI, 0.578-0.949; p=0.017) models. In addition, the “TGC” haplotype of rs2274755 was associated with a 0.79-fold decrease in risk while the “CTC” haplotype associated with a 0.65-fold decrease risk of the non-traumatic ONFH. These results provide evidence that the MMP9 SNP at the rs2274755 locus is associated with a decreased risk of non-traumatic ONFH in a Chinese Han population.

A single-nucleotide polymorphism inMMP9is associated with decreased risk of steroid-induced osteonecrosis of the femoral head

Osteonecrosis of the femoral head (ONFH) is a common hip joint disease, and steroid-induced ONFH accounts for a large number of cases. Here, we examined eight previously-identified single-nucleotide polymorphisms (SNPs) in the MPP2 and MPP9 genes of 285 steroid-induced ONFH patients and 507 healthy controls from northern China to determine whether these SNPs were associated with the risk of developing steroid-induced ONFH. Chi-squared tests and genetic model and haplotype analyses were used to evaluate associations. The rs2274755 SNP in MMP9 was associated with a decreased risk of steroid-induced ONFH in the allele, dominant, and additive models. Additionally, the “CGC” MMP9 haplotype was associated with a 0.69-fold decrease in the risk of steroid-induced ONFH. Although additional, larger population-based studies are needed to confirm these findings, our results reveal for the first time an association between a MMP9 SNP at the rs2274755 locus and a decreased risk of steroid-induced ONFH in a northern Chinese population.

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.

Matrix metalloproteinase variants associated with risk and clinical outcome of esophageal cancer.

We conducted a case-control study to investigate the role of matrix metalloproteinase (MMP) 2, MMP3, and MMP9 single nucleotide polymorphisms on susceptibility to esophageal squamous cell carcinoma (ESCC) in a Chinese population, and their association with environmental factors. A total of 226 patients with ESCC, and 226 age- and gender-matched healthy controls were enrolled in this study. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis was carried out on MMP2 -1306 C>T (rs243865), MMP3 -1171 5A>6A (rs3025058), and MMP9 -1562 C>T (rs3918242) genotypes. Unconditional regression analysis showed that individuals carrying the MMP2 -1306 TT genotype had a decreased incidence of ESCC compared to those with the CC genotype [odds ratio (OR) = 0.32; 95% confidence interval (CI), 0.10-0.89, P value = 0.02]. Moreover, MMP9 -1562 CC carriers were associated with an increased ESCC risk compared to those with the TT genotype (OR = 2.71; 95%CI, 1.04-7.87, P value = 0.02). In the Cox proportional hazards model, after adjusting for potential confounding factors, patients carrying the MMP9 -1562 CC genotype had a significantly increased risk of death from ESCC (hazard ratio = 2.97; 95%CI, 1.25-6.87, P value = 0.005). In conclusion, this study showed that the MMP2 -1306 TT and MMP9 -1562 CC genotypes were associated with increased ESCC, and patients carrying the MMP9 -1562 CC genotype had a significantly increased risk of death from ESCC.

Role of plasma matrix-metalloproteases (MMPs) and their polymorphisms (SNPs) in sepsis development and outcome in ICU patients.

Matrix-metalloproteases (MMPs) and their tissue-inhibitors (TIMPs), modulated by different single nucleotide polymorphisms (SNPs), are critical in sepsis development. Ninety ICU severely septic and 91 ICU uninfected patients were prospectively studied. MMP-1 (−1607 1G/2G), MMP-3 (−1612 5A/6A), MMP-8 (−799 C/T), MMP-9 (−1562 C/T), and MMP-13 (−77A/G) SNPs were genotyped. Plasma MMPs (-1, -2, -3, -8, -9, -10, -13) and TIMPs (-1,-2,-4) were measured. AA homozygotes and A allele carriers of MMP-13 (−77 A/G) and 1G2G carriers of the MMP-1 (−1607 1G/2G) SNPs frequencies were different between septic and uninfected patients (p < 0.05), as well as plasma MMP-3, -8, -9 -10 and TIMP-2 levels (p < 0.04). No differences in MMPs levels among MMP-13 or MMP-1 SNPs genotypes carriers were observed. The area under the ROC curve for MMP-8 in the diagnosis of sepsis was 0.87 (95% CI 0.82–0.92), and that of CRP was 0.98 (0.94–0.998), whereas the area of MMP-9 in the detection of non-septic state was 0.73 (0.65–0.80), p < 0.0001 for all curves. Sepsis associated with increased MMP-8 and decreased MMP-9 levels in multivariate analysis (p < 0.0002). We report for the first time an association between MMP-13 and MMP-1 SNPs and sepsis. An independent association of MMP-8 and MMP-9 levels with sepsis was also observed.

Association of the polymorphisms of MMP-9 and TIMP-3 genes with thoracic aortic dissection in Chinese Han population

Thoracic aortic dissection (TAD) is the most common life-threatening disorder, and a shifted balance of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) is involved in TAD pathogenesis. The aim of this study was to evaluate the association of 4 single-nucleotide polymorphisms (SNPs) in MMP-9 and TIMP-3 genes with TAD risk in Chinese Han population. A total of 206 Chinese patients with TAD and 180 controls were included in this study. Four SNPs (rs3918249, rs2274756, rs9609643 and rs8136803) were genotyped using high-throughput MALDI-TOF mass spectrometry. Allele and genotype association analyses were conducted using PLINK. All the 4 SNPs resulted in Hardy-Weinberg equilibrium in patients and controls. The G allele frequency for the MMP-9 SNP rs2274756 was significantly higher in female TAD patients than in female controls (P=0.0099). Moreover, after adjusting for traditional cardiovascular risk factors (sex, age, hypertension, dyslipidemia, diabetes and smoking habit), the rs2274756 polymorphism (odds ratio: 0.30; 95% confidence interval: 0.11 to 0.79, P=0.015) resulted in an independent susceptibility factor for TAD in females. No associations were found between the other SNPs and TAD. The results provide strong evidence for an association between MMP-9 SNP rs2274756 and female TAD risk in Chinese Han population.

Polymorphisms in metalloproteinase-9 are associated with the risk for asthma in Mexican pediatric patients

Asthma is characterized by chronic airway inflammation, which induces airway remodelling of the extracellular matrix over time. Matrix metalloproteinases (MMPs) are involved in this process, and single-nucleotide polymorphisms (SNPs) in MMP genes may influence their mRNA expression levels or abilities to bind substrates and inhibitors, thereby contributing to asthma predisposition and severity. MMP-9 is highly expressed in airways and many studies support its involvement in asthma pathogenesis; however the contribution of MMP-9 SNPs is controversial. To investigate whether MMP-9 SNPs are associated with childhood-onset asthma in Mexican patients we conducted a case-control study including 403 children with clinical asthma diagnoses and 426 healthy controls from Mexico. The cases and controls were matched by ethnicity and gender. We found that the SNPs rs2274755, rs17577, and rs3918249 were associated with asthma risk. The most significant associations were with rs2274755 (OR=2.10, 95% CI 1.31-3.39, P=0.001) and rs17577 (OR=2.07, 95% CI 1.29-3.30, P=0.001); which were in strong linkage disequilibrium. Both SNPs were also associated with atopic asthma (OR=2.38, 95% CI 1.44-3 · 96, P=0.0005). The SNP rs3918249 exhibited a female gender-dependent association with asthma (OR=1.66, 95% CI 1.14-2.43, P=0.007). Our results suggest that MMP-9 polymorphisms could play a role in the susceptibility to childhood-onset asthma.

Abstract P106: Polymorphisms in Candidate Genes and Early Atherosclerosis: A Study of 115 Autopsy Cases of Young Adults

Atherosclerosis, a major cause of death, is a complex disease, involving both genetic and environmental factors. Chronic inflammation plays a central role in its pathogenesis; however, the influence of genetic variations on early development of atherosclerosis has been poorly investigated. We examined the relationship of five common single-nucleotide polymorphisms (SNPs) with atherosclerotic severity in the anterior descendent coronary artery (DA) in 115 consecutive individuals under 30 years autopsied at the Legal Medical Institute of Rio de Janeiro. Histological sections were stained with hematoxilin-eosin and classified for atherosclerosis lesion accordingly to the American Heart Association. DNA was extracted and genotyped for SNPs in the angiotensin conversion enzyme, tumoral necrosis factor-alpha (−308G/A and −238 G/A), interferon-gama (+874 A/T), and metalloproteinase-9 (−1562 C/T) genes by automatic sequencing. Fire weapon lesion was the major causa mortis (72%). Population mean age was 26 years, 100 male and 15 female; 35% were slims, 58% regular weight and 7% obese; 22% white, 51% non-white, and 17% blacks. Only 2 subjects had normal DA histology, while 17 presented level II lesions, 74 level III, 7 level IV, 14 level V. and 1 level VI. 49 individuals presented genotype DD, related to high serum levels of ECA, while 18 were II (related with low ECA levels) and 48 DI (allele frequencies of D = 0,635; I = 0,365). For TNF-α promoter polymorphisms (where allele A is associated with high TNF-α level), 59 presented genotype GG, 21 GA, and 8 AA at position -308 (G = 0,790; A = 0,210), while 84 were GG, 3 GA, and 2 AA at position -238 (G = 0,961; A = 0,039). The allele T at position +874 of INF-γ (related to high INF-γ levels) was present in 45 subjects, while for MMP-9 SNP 49 individuals presented genotype CC, 14 CT, and 3 TT (C = 0,848; T = 0,152). In conclusion, we observed a high prevalence of early atherosclerotic lesions (level III) in young adults, with high prevalence of DD genotype, associated with high ECA serum levels.

The MMP1 (−16071G/2G) single nucleotide polymorphism associates with the HAART-related lipodystrophic syndrome

Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are involved in extracellular matrix remodelling and adipocyte differentiation and are inhibited by antiretrovirals. MMPs and TIMPs and their single nucleotide polymorphisms (SNPs) might contribute to the HAART-related lipodystrophic syndrome pathogenesis. Cross-sectional study in a university-based outpatient clinic. Two hundred and sixteen HIV-infected patients on extended HAART were studied. Serum MMPs (1, 2, 3, 8, 9, 10, 13) and TIMPs (1, 2, 4) were measured by ELISA microarrays. MMP1 (-16071G/2G) SNP was also genotyped. Lipodystrophic syndrome was diagnosed by a clinical scale validated by fat dual energy X-ray absorptiometry. Eighty-two patients (38.0%) showed lipodystrophic syndrome, mostly lipoatrophy. The 2G/2G MMP1 SNP genotype was more frequent among lipodystrophic syndrome patients (41.3 vs. 20.5%, odds ratio, 2.73; 95% confidence interval, 1.41-5.29; χ² = 9.62, P = 0.002 for HIV-infected patients with and without lipodystrophic syndrome respectively). Carriers of this genotype had higher serum levels of MMP1 compared with those with the 1G/1G (P = 0.02). Higher MMP1 (P = 0.022) and lower TIMP4 (P = 0.038) serum levels were observed while comparing HIV patients with and without lipodystrophic syndrome. MMP1 2G carriage (P = 0.0008), TIMP4 lower serum levels (P = 0.02), treatment with stavudine (P < 0.0001), treatment with zidovudine (P = 0.006) and absence of hepatitis C virus coinfection (P = 0.002) were associated with lipodystrophic syndrome by logistic regression. MMP1 SNP, which induced increased serum levels of this protein, was associated with lipodystrophic syndrome.

MMP9 polymorphisms and breast cancer risk: a report from the Shanghai Breast Cancer Genetics Study

In addition to tumor invasion and angiogenesis, matrix metalloproteinase (MMP)9 also contributes to carcinogenesis and tumor growth. Genetic variation that may influence MMP9 expression was evaluated among participants of the Shanghai Breast Cancer Genetics Study (SBCGS) for associations with breast cancer susceptibility. In stage 1, 11 MMP9 single nucleotide polymorphisms (SNPs) were genotyped by the Affymetrix Targeted Genotyping System and/or the Affymetrix Genome-Wide Human SNP Array 6.0 among 4,227 SBCGS participants. One SNP was further genotyped using the Sequenom iPLEX MassARRAY platform among an additional 6,270 SBCGS participants. Associations with breast cancer risk were evaluated by odds ratios (OR) and 95% confidence intervals (CI) from logistic regression models that included adjustment for age, education, and genotyping stage when appropriate. In Stage 1, rare allele homozygotes for a promoter SNP (rs3918241) or a non-synonymous SNP (rs2274756, R668Q) tended to occur more frequently among breast cancer cases (P value = 0.116 and 0.056, respectively). Given their high linkage disequilibrium (D' = 1.0, r (2) = 0.97), one (rs3918241) was selected for additional analysis. An association with breast cancer risk was not supported by additional Stage 2 genotyping. In combined analysis, no elevated risk of breast cancer among homozygotes was found (OR: 1.2, 95% CI: 0.8-1.8). Common genetic variation in MMP9 was not found to be significantly associated with breast cancer susceptibility among participants of the Shanghai Breast Cancer Genetics Study.

Intrinsic genetic characteristics determine tumor-modifying capacity of fibroblasts: matrix metalloproteinase-3 5A/5A genotype enhances breast cancer cell invasion

BackgroundStromal fibroblasts can contribute to tumor invasion through the release of matrix metalloproteinases (MMPs). Population studies have suggested that single nucleotide polymorphisms (SNPs) in MMP genes influence levels of expression and may be associated with breast cancer risk and with disease progression. This study directly examined the impact of MMP SNP genotype on the ability of host fibroblasts to promote tumor cell invasion.MethodsPrimary breast fibroblasts were isolated from patients with (n = 13) or without (n = 19) breast cancer, and their ability to promote breast cancer cell invasion was measured in in vitro invasion assays. Fibroblast invasion-promoting capacity (IPC) was analyzed in relation to donor type (tumor or non-tumor patient), MMP-1, MMP-3, and MMP-9 SNP genotype and MMP activity using independent samples t test and analysis of variance. All statistical tests were two-sided.ResultsTumor-derived fibroblasts promoted higher levels of invasion than normal fibroblasts (p = 0.041). When IPC was related to genotype, higher levels of IPC were generated by tumor fibroblasts with the high-expressing MMP-3 5A/5A genotype compared with the 5A/6A and 6A/6A genotypes (p = 0.05 and 0.07, respectively), and this was associated with enhanced MMP-3 release. The functional importance of MMP-3 was demonstrated by enhanced invasion in the presence of recombinant MMP-3, whereas reduction occurred in the presence of a specific MMP-3 inhibitor. An inverse relationship was demonstrated between fibroblast IPC and the high-expressing MMP-1 genotype (p = 0.031), but no relationship was seen with MMP-9 SNP status. In contrast, normal fibroblasts showed no variation in IPC in relation to MMP genotype, with MMP-3 5A/5A fibroblasts exhibiting significantly lower levels of IPC than their tumor-derived counterparts (p = 0.04).ConclusionThis study has shown that tumor-derived fibroblasts exhibit higher levels of IPC than normal fibroblasts and that the MMP-3 5A/5A genotype contributes to this through enhanced MMP-3 release. Despite a high-expressing genotype, normal fibroblasts do not exhibit higher IPC or enhanced MMP release. This suggests that more complex changes occur in tumor-derived fibroblasts, enabling full expression of the MMP SNP genotype and these possibly are epigenetic in nature. The results do suggest that, in women with breast cancer, a high-expressing MMP-3 genotype may promote tumor progression more effectively.

The collagenase-1 (MMP-1) gene promoter polymorphism - 1607/2G is associated with favourable prognosis in patients with colorectal cancer

Matrix metalloproteinase (MMP) overexpression has been implicated in the pathogenesis of colorectal carcinoma (CRC). Accumulating evidence suggests that MMP promoter single nucleotide polymorphisms (SNPs) effecting gene transcription are associated with enhanced susceptibility for the development of malignant disease, increased tumour invasiveness and poor patient survival. The aim of the current investigation was to determine whether such associations exist in a large CRC patient/control study population. Using an allelic discrimination real-time polymerase chain reaction, polymorphisms in the MMP-1, MMP-2 and MMP-3 gene promoters (−1607, −1306, and −1612 bp, respectively) were assessed in normal blood mononuclear cells from patients with CRC (n=503) and control subjects (n=471). Genotypes corresponding to each MMP SNP were correlated with tumour characteristics and clinical outcome. The frequency of each genotype was not statistically different between patients and control subjects and no significant differences were noted between the genotypes and tumour characteristics for the three MMP SNPs. CRC patients with the 2G/2G genotype for the MMP-1 SNP had significantly better 5-year survival compared to patients with a 1G allele (P<0.05). Our results demonstrate that CRC patients with a 2G/2G genotype in the MMP-1 gene promoter SNP have a favourable prognosis. Although our results were unexpected, given that this genotype is associated with enhanced MMP-1 transcriptional activity, they are consistent with recent data highlighting the anti-tumorigenic properties of MMPs.