MMP-9 Polymorphisms Research Articles

Gender-specific effects of MMP-2 and MMP-9 gene variants and the risk of aneurysmal subarachnoid haemorrhage

Matrix metalloproteinases (MMPs), a family of zinc-dependent proteases, have been linked with the pathogenesis of intracranial aneurysm (IA) formation and rupture. Patients with IA have elevated serum levels of MMP-2 and MMP-9 gene expression has been shown to be increased in aneurysm tissue. In this study, we have evaluated the association between MMP gene variants and aneurysmal subarachnoid hemorrhage (aSAH). The rs243865 in MMP-2 and rs17576 in MMP-9 genes were genotyped using Taqman allelic discrimination assay. Upon gender stratification, the presence of G allele of MMP-9 gene exon variant was found to increase the risk of aSAH by 1.4 fold (p = 0.032), in men. The GG genotype also showed a trend towards association with the risk of aSAH (OR: 1.785, CI: 0.971–3.283, p = 0.062) in men, after adjusting for the vascular risk factors. In women, no association was observed. The MMP-2 gene variants were not associated with aSAH in both genders. Further functional studies are required to describe the exact basis of the association between MMP-9 polymorphism and intracranial aneurysm in men.

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.

Correlations of MMP-2 and MMP-9 gene polymorphisms with the risk of hepatopulmonary syndrome in cirrhotic patients: A case-control study

Hepatopulmonary syndrome (HPS) increases the mortality of patients who suffered from liver cirrhosis, especially patients plagued by severe hypoxemia. Gene polymorphisms are reported to be related to the risk of HPS in cirrhotic patients. Thus, our study aims to elucidate the correlation between MMP-2 and MMP-9 gene polymorphisms and HPS in cirrhotic patients. A total of 152 cirrhotic patients suffering from HPS as well as another 152 cirrhotic patients without HPS were recruited. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was performed for MMP-2 and MMP-9 gene polymorphisms and logistic regression analysis for the relationship between clinicopathological features and HPS occurrence in cirrhotic patients. There were significant differences in genotype and allele frequency of MMP-2 rs243865 and MMP-9 rs3918242 polymorphisms between the HPS and control groups. CC/CT genotype and C allele of MMP-2 rs243865 polymorphism as well as CC/TT genotype and T allele of MMP-9 rs3918242 polymorphism increased the risk of HPS in cirrhotic patients. Genotypes of rs243865 and rs3918242 polymorphisms had remarkable correlations with spider nevi, clubbed fingers (toes), transaminase elevation, portal vein width, esophageal varices, Child-Pugh classification and partial pressure of arterial oxygen (PaO2). Logistic regression analysis showed that rs243865 and rs3918242 polymorphisms, spider nevi, clubbed fingers (toes), esophageal varices, and Child-Pugh classification were closely associated with the occurrence of HPS in cirrhotic patients. Our findings demonstrate that MMP-2 rs243865 polymorphism and MMP-9 rs3918242 polymorphism can increase the risk of HPS occurrence in cirrhotic patients, which provides a potential target for prevention of HPS in cirrhotic patients.

Association of zinc level and polymorphism in MMP-7 gene with prostate cancer in Polish population.

IntroductionProstate cancer is one of the most commonly diagnosed malignancies among men in Western populations. Evidence reported in the literature suggests that zinc may be related to prostate cancer. In this study we evaluated the association of serum zinc levels and polymorphisms in genes encoding zinc-dependent proteins with prostate cancer in Poland.MethodsThe study group consisted of 197 men affected with prostate cancer and 197 healthy men. Serum zinc levels were measured and 5 single nucleotide polymorphisms in MMP-1, MMP-2, MMP-7, MMP-13, MT2A genes were genotyped.ResultsThe mean serum zinc level was higher in prostate cancer patients than in healthy controls (898.9±12.01 μg/l vs. 856.6±13.05 μg/l, p<0.01). When compared in quartiles a significant association of higher zinc concentration with the incidence of prostate cancer was observed. The highest OR (OR = 4.41, 95%CI 2.07–9.37, p<0.01) was observed in 3rd quartile (>853.0–973.9 μg/l). Among five analyzed genetic variants, rs11568818 in MMP-7 appeared to be correlated with 2-fold increased prostate cancer risk (OR = 2.39, 95% CI = 1.19–4.82, p = 0.015).ConclusionOur results suggest a significant correlation of higher serum zinc levels with the diagnosis of prostate cancer. The polymorphism rs11568818 in MMP-7 gene was also associated with an increased prostate cancer risk in Poland.

Impact of MMP2, MMP9 and TIMP2 Gene Polymorphisms on Allograft Rejection in Pediatric Renal Transplant Recipients

Impact of MMP2, MMP9 and TIMP2 Gene Polymorphisms on Allograft Rejection in Pediatric Renal Transplant Recipients

POLYMORPHISM OF SOME GENES IN PATIENTS WITH CHRONIC ENDOMETRITIS

Chronic inflammation of the endometrium is one of the causes of infertility and impaired menstrual function. The issues of the diagnosis and treatment of this disease are often discussed, but remains too unclear. In connection with this, the study of the role of genetic polymorphism in patients with chronic endometritis is topical. The occurrence of polymorphisms in promoter sites of VEGF, ApoE, ESR1, PPARGC1A, MMP9, eNOS genes in patients with chronic endometritis and in practically healthy women were studied. As primers, the DNA portion of the VEGF genes rs2010963 (G634C), ApoE rs429358 (Cys130Arg), ESR1 2228480 (Thr594Thr), PPARGC1A 8192678 (Gly482Ser), MMP9 17576 (Gln279Arg), and eNOS 1799983 (Glu298Asp) were used. To study the polymorphic variants of genes investigated, a real-time polymerase chain reaction was used, the material was sampled by smear extraction from the mucous membrane of the oropharynx. In the analysis, the percentage of homozygotes and heterozygotes, the prevalence of the normal and pathological (minor) allele were counted. Based on the results obtained, it can be assumed that in patients with chronic endometritis polymorphism of genes responsible for angiogenesis, oxidative processes in the body and metabolism is more common. In particular, there was noted a statistically significant predominance of polymorphism in the promoter sites of the eNOS and ESR1 genes in patients with chronic endometritis, which may be indicative of negative genetic associations with impaired fertility; at the same time, the issues of the presence of genetic polymorphism of the genes MMP9, VEGF and ApoE and a lower frequency of somatic and gynecological pathology in a group of practically healthy women require further study.

Collagenase-1 (-1607 1G/2G), Gelatinase-A (-1306 C/T), Stromelysin-1 (-1171 5A/6A) functional promoter polymorphisms in risk prediction of type 2 diabetic nephropathy

Type 2 Diabetic Nephropathy (DN) is a common multifactorial disorder. Degradation of glomerular basement membrane (GBM) by matrix metalloproteases (MMPs) is a key event in the progression of renal disease. A functional polymorphism at position -1607 1G/2G, -1306 C/T and -1171 5A/6A has been shown to alter the transcriptional activity of MMP-1, MMP-2, and MMP-3 respectively, and also associated with several diseases contributing to inter-individual differences in susceptibility to type 2 DN. The study population consisted of 310 type 2 DN patients and 310 healthy controls. Genotypes of MMP-1, 2 and 3 were determined by PCR-RFLP assay. Gene interactions, Linkage disequilibrium, and haplotype analysis were carried out by MDR analysis and Haploview software respectively. The promoter binding sites of MMP genes were determined by using Alibaba 2.1 and the gene-gene interactions of MMPs were analyzed by GeneMania. The individuals carrying 2G allele of -1607, C allele of -1306 and 5A/6A genotype of -1171 were associated with type 2 DN susceptibility and progression from stage 1 to stage 5. 2G-5A haplotypes of MMP-1 (-1607 1G/2G) and MMP-3 (-1171 5A/6A) gene polymorphisms were found to be significantly predominant in the disease group. MDR analysis revealed a strong interaction between the genes under study. 2G allele of MMP-1, C allele of MMP-2 and 5A/6A genotype of MMP-3 were associated with susceptibility and disease progression of type 2 DN and might be used as potential markers for risk prediction and prognosis of type 2 DN.

Risk Factor Assessment in a Greek Cohort of Patients With Large Abdominal Aortic Aneurysms.

Environmental and genetic risk factors contribute to the etiology of abdominal aortic aneurysms (AAAs). Matrix metalloproteinases (MMPs) have been associated with the pathophysiology of AAAs. A prospective, nonrandomized case-control study was undertaken to investigate the risk factors for large AAAs (≥5.5 cm) among 175 male Greek AAA patients and to compare the results with a cohort of 166 male controls free from any aortic dilatation, as confirmed by ultrasonography from an existing AAA screening program in the same region. We also assessed the potential association between 2 functional single nucleotide polymorphisms in the genes MMP9 (-1561C/T; rs3918242) and MMP13 (-77A/G; rs2252070), and the presence of large AAAs. Multiple logistic regression analysis revealed AAA family history ( P = .028), hypercholesterolemia ( P < .001), and current smoking ( P < .001) as AAA risk factors. Statistical difference was reached in genotype ( P = .047) and allele ( P = .037) frequencies for rs2252070, but the results did not remain significant after correction for multiple testing. No significant differences in genotype or allele frequencies for rs3918242 were detected. In summary, AAA family history, hypercholesterolemia, and current smoking were found to be risk factors for large AAAs.

14P MMP-2 1306 C/T promoter polymorphism and smoking: A possible role as risk factors in lung cancer

Background: Lung cancer is the leading cause of cancer death in both gender accounting for 15% of deaths among young people (0–49 years), 30% among adults (50–69 years) and 27% among those over seventy. Matrix metalloproteases (MMPs) are a large family of proteins consisting of at least 26 human MMPs. They are zincdependent endopeptidases that cleave components of the extracellular matrix (ECM) and basement membrane and has been reported that play an important role in several steps of cancer development. Many studies have shown that a nucleotide polymorphism (–1306C3T) in the MMP2 promoter in addition to smoking and age are major risk factors for the onset of lung cancer. The aim of this study was to examine the association of MMP-2 polymorphism and smoke as a risk for cancer in 71 Italians lung cancer patients. Methods: Seventy-one patients (56 men and 15 women) aged between 44 and 84 years with adeno or squamous carcinoma in inoperable stage IIIA/IIIB/IV were enrolled in this study; information about clinical and histopathological data and smoking habits were collected through the clinical charts; genotyping was performed using direct DNA sequencing. Results: 44/71 patients (62%) had the CC genotype, 15/71 (21%) patients had CT genotype and 12/71 (16%) had TT genotype. About smoking 47/71 (66%) patients were smokers, 5/71 (7%) patients had never smoked and 19/71 (26%) of them were ex-smokers and had stopped for at least 3 years. In subgroup of smokers patients, the overall average number of years of smoke was 44, the average number of smoked cigarettes was 25 and the number of pack-year 48; the smoker group was divided into heavy smokers smoking from 50 to 60 cigarettes/day, a group of heavy smokers smoking from 11 to 49 cigarettes/day and light smokers smoking from 2 to 10 cigarettes/day. A higher allelic frequency of CC genotype and stage IV disease in the heavy and mean smoking group were observed compared to light smokers (p < 0.001 and p < 0.0001 respectively) while the TT genotype was much more frequent in stage III and in subgroup of light smokers (p < 0.05). Conclusions: These preliminary results suggest a significant association between the mmp2-1306c/t polymorphism and smoke that could represent a significant risk factors of developing lung cancer. Legal entity responsible for the study: IRCCS Istituto Tumori Giovanni Paolo II Funding: Has not received any funding Disclosure: All authors have declared no conflicts of interest.

Association of matrix metalloprotease 1, 3, and 12 polymorphisms with rheumatic heart disease in a Chinese Han population

BackgroundRheumatic heart disease (RHD) is an autoimmune disease triggered by acute rheumatic fever (ARF). Matrix metalloproteinases (MMPs) play an important role in the modulation of immune responses. The purpose of this study was to evaluate the association of MMP1, 3, and 12 promoter polymorphisms with RHD in a Han population in Southern China since the 3 genes are localized on the same chromosome and have a combined effect.MethodsDNA samples were obtained from 90 adult patients with RHD and 90 control subjects. Polymorphisms in MMP1 (rs1799750), MMP3 (rs3025058), and MMP12 (rs2276109) were genotyped by direct sequencing. Differences in genotype and allele frequencies of these polymorphisms were compared between the cases and the controls using Unconditional logistic regression models and Chi-squared test.ResultsThe 2G/2G genotype of rs1799750 in MMP1 was associated with a significantly higher risk of RHD when compared with the 1G/1G genotype (OR = 3.227; 95% CI:1.118–9.31; p = 0.03). The frequency of allele 2G was higher in patients with RHD compared to the controls (69.4% vs. 58.9%; p = 0.048) No significant differences in genotype and allele frequencies of rs3025058 in MMP3 and rs2276109 in MMP12 were found between the patients with RHD and the controls (p > 0.05).ConclusionsOur results suggest that rs1799750 in MMP1 might be a risk factor for RHD in a Han population in Southern China, and individuals carrying the 2G/2G genotype are likely more susceptible to RHD. In contrast, rs3025058 in MMP3 and rs2276109 in MMP12 might not contribute to the risk of developing RHD in this population. Further studies with larger samples and other ethnic populations are required to confirm these findings.

Significance of MMP-9 expression and MMP-9 polymorphism in prostate cancer.

The aim of the study was to assess the expression of the MMP-9 gene and -1562 C/T polymorphism in MMP-9 gene promoter in relation to clinicopathological parameters in predicting the clinical outcome of prostate cancer patients. A total of 82 patients with histopathologically diagnosed prostate cancer were enrolled in the study. MMP-9 gene expression was assessed by reverse transcription-PCR method. MMP-9 (-1562 C/T) polymorphism variants were determined by the polymerase chain reaction-based restriction fragment length polymorphism method. MMP-9 expression and MMP-9 -1562 polymorphism variants in relation to disease pathological stage (P = 0.006; P <0.0001, respectively), as well as to prognostic group (P = 0.019; P <0.0001, respectively), were statistically significant. Only MMP-9 -1562 polymorphism variants in relation to tumor differentiation grade (P = 0.044) were found to be statistically significant. Positive MMP-9 gene expression was associated with 5-year survival rate of prostate cancer patients with pathological stage III (P = 0.036) and for the patients in prognostic group III (P = 0.012). Patients with tumor differentiation grade G2 and with the identified CC variant had a significantly longer survival time than patients with the identified TT variant (P = 0.007). MMP-9 gene expression and MMP-9 -1562 polymorphism variants were associated with prostate cancer pathological stage and prognostic group. MMP-9 -1562 polymorphism CC variant was associated with prostate cancer tumor differentiation grade. Five-year survival analysis showed the relationship between MMP-9 gene expression and pathological stage III, as well as prognostic group III, whereas MMP-9 -1562 polymorphism variants, with tumor differentiation grade G2.

Association of Maternal and Fetal Single-Nucleotide Polymorphisms in Metalloproteinase (MMP1, MMP2, MMP3, and MMP9) Genes with Preeclampsia.

Background Metalloproteinases (MMPs) play a pivotal role during the process of trophoblast invasion and placentation. The appearance of five functional single-nucleotide polymorphisms (SNP) in the genes of the metalloproteinases most commonly implicated in the implantation process may influence the development of preeclampsia. Methods Blood samples were collected from 86 mothers and 86 children after preeclampsia and 85 mothers and 85 children with uncomplicated pregnancies. The distribution of genotypes for −1607 1G/2G MMP1, −735 C/T MMP2, −1306 C/T MMP2, −1171 5A/6A MMP3, and −1562C/T MMP9 polymorphisms was determined by RFLP-PCR. Results The occurrence of 1G/1G MMP1 or 5A/5A MMP3 genotype in the mother or 1G/1G MMP1 or 5A/6A MMP3 genotype in the child is associated with preeclampsia development. Moreover, simultaneous maternal and fetal 1G/1G homozygosity increases the risk of preeclampsia development 2.39-fold and the set of maternal 5A/5A and fetal 5A/6A MMP3 genotypes by over 4.5 times. No association between the carriage of studied MMP2 or MMP9 polymorphisms and the predisposition to preeclampsia was found. Conclusion The maternal 1G/1G MMP1 and 5A/5A MMP3 and fetal 1G/1G MMP1 and 5A/6A MMP3 gene polymorphisms may be strong genetic markers of preeclampsia, occurring either individually or together.

Association of exudative age-related macular degeneration with matrix metalloproteinases-2 (-1306 C/T) rs243865 gene polymorphism.

Purpose:Age-related macular degeneration (AMD) is a disease of the macula that significantly affects eyesight and leads to irreversible central vision loss. Recent studies have demonstrated that angiogenesis is the most important mechanism of AMD development. It is associated with extracellular remodeling involving different proteolytic systems, among them matrix metalloproteinases (MMPs), which play an essential role in the etiopathogenesis of AMD. The main objective of the present study was to determine the relationship between exudative AMD and MMP-2 (-1306 C/T) rs243865 polymorphism.Methods:The study enrolled 267 patients with exudative AMD and 318 controls. DNA was extracted from peripheral venous blood leukocytes by commercial kits. Genotyping of MMP-2 (-1306 C/T) rs243865 was carried out using real-time polymerase chain reaction method.Results:The analysis of MMP-2 (-1306 C/T) polymorphism did not reveal any differences in the distribution of CC, CT, and TT genotypes between the exudative AMD and control groups: 58.8%, 31.5% and 9.7% vs. 59.75%, 33.96% and 6.29%, respectively, P = 0.287). When the study population was subdivided into age groups, MMP-2 (-1306 C/T) rs243865 CT genotype showed 5.7-fold increased the risk of exudative AMD development compared to CC and TT genotypes together in younger (<65 years) males group (P = 0.05).Conclusion:MMP-2 (-1306 C/T) polymorphism is associated with exudative AMD development in younger males.

Association of Matrix Metalloproteinase-7 Genotypes with the Risk of Bladder Cancer.

The breakage of matrix metalloproteinases (MMPs) has been reported to be one of the mechanisms required for tumor invasion, and the expression of MMP-7 in serum is correlated with poor prognosis of urinary bladder cancer patients. However, the role of the MMP-7 genotypes has been seldom examined among bladder cancer patients. Therefore, this study aimed at examining the promoter polymorphic MMP-7 genotypes A-181G and C-153T among Taiwanese bladder cancer patients and evaluate the contribution of the genotypic variants of MMP-7 to bladder cancer risk in Taiwan. Three hundred and seventy-five bladder cancer patients and the same number of gender- and age-matched healthy controls were genotyped for A-181G and C-153T in the promoter of MMP-7 via polymerase chain reaction-restriction fragment length polymorphism methodology. The frequencies of AA, AG and GG at A-181G of the promoter of MMP-7 were 89.1, 8.8 and 2.1% in the bladder cancer patient group and 87.5, 10.9 and 1.6% in the matched healthy control group, respectively (p for trend=0.5475). There was no polymorphic genotype for MMP-7 C-153T among the Taiwanese population. The comparisons in allelic frequency distribution also support the findings that the G allele may not be the determinant allele for bladder cancer in Taiwan. In addition, the results showed that there is no significant association of the bladder risk with the MMP-7 A-181G genotype, even after adjustment for the possible confounding factors. Furthermore, there is no interaction of the genotypes of MMP-7 with age, gender, smoking and alcohol consumption on bladder cancer risk. The results of this study suggest that the two MMP-7 polymorphisms, - A-181G and C-153T, do not play a major role in determining personal susceptibility to bladder cancer in Taiwan.

Association of MMP-1, 9, 12 and TIMP-1 gene polymorphisms in Malaysian male hypertensive subjects

Background: Matrix Metalloproteinases (MMPs) plays an important role in hypertensive vascular stiffness, remodeling and dysfunction. Several studies have been reported the imbalanced MMP: TIMP (tissue inhibitors of metalloproteinase-1) ratio in hypertensive subjects, indicating the depressed systematic degradation of collagenase in etiology of hypertension. The main objective of this study was to determine the candidate gene polymorphisms involved in extracellular matrix metabolism among Malaysian male subject with Essential Hypertension (EH). Methods: A total of 133 newly diagnosed EH subjects and 129 unrelated healthy individuals were included in this study. The genomic DNA was extracted and the genotyping was done by PCR-RFLP method. Result: The demographic characteristic of the subjects such as age, body mass index, systolic blood pressure, diastolic blood pressure, low-density lipoprotein, triglyceride and cholesterol were shown to be significantly different (p?0.05) in case subjects when compared to controls. The allelic distribution of TIMP-1 372 T/C gene polymorphism was significantly associated with hypertension (p?0.05). While, MMP-1: rs1799750, MMP-9: rs3918242 and rs17576 and MMP-12: rs2276109 polymorphisms did not differ significantly (p?0.05). Conclusion: Hence, the rs4898 polymorphism of TIMP-1 may be considered as a possible genetic biomarker and a risk factor predictor for EH among Malaysian male subjects.

Association of Smoking and XPG, CYP1A1, OGG1, ERCC5, ERCC1, MMP2, and MMP9 Gene Polymorphisms with the early detection and occurrence of Laryngeal Squamous Carcinoma.

A total of 200 smoking-related laryngeal carcinoma patients with pathology confirmation from the Eye and ENT Hospital and 190 high-risk smokers were included in a survey. All of the participants had a smoking index greater than 400 (cigarettes/day*year.) We obtained data on clinical and baseline characteristics, and peripheral blood was obtained and subjected to DNA extraction to analyse the correlation between smoking and the occurrence of laryngeal carcinoma. We selected candidate genes and SNP fragments that were found to be closely associated with smoking-related tumours in preliminary studies. The selected candidate genes were XPG, CYP1A1, OGG1, ERCC5, ERCC1, MMP2, and MMP9. We then performed SNP sequencing using Sequenom SNP detection technology. Target genes and single nucleotide polymorphism (SNP) fragments were evaluated to analyse the correlation between genotype or allele and smoking-related laryngeal carcinoma and to identify susceptibility genes related to laryngeal carcinoma. The results included four main findings: (1) The smoking index differed significantly between laryngeal cancer patients and control subjects (P=0.0035). The risk of laryngeal cancer was increased among individuals with a smoking index greater than 600 cigarettes/day*year (P=0.03). (2) The smoking index was significantly correlated with the T, N and clinical stages (P<0.05). (3) The polymorphisms CYP1A1-rs1048943, rs4646421, and rs4646422 and MMP9-rs17577 were significantly associated with laryngeal squamous carcinoma (P<0.05). (4) After stratifying the subjects by smoking degree, the GT genotype of ERCC1-rs2298881 was associated with a significantly greater risk of laryngeal carcinoma among heavy smokers (P=0.04). The results suggest that smoking plays an important role in the occurrence and development of laryngeal squamous carcinoma; CYP1A1 and MMP9 might be susceptibility gene SNPs for smoking-related laryngeal carcinoma, and ERCC1 might play an important role in heavy smokers. The results of this study might help identify an early marker for the detection and prevention of laryngeal carcinoma.

MMP-3 (-1171 5A/6A; Lys45Glu) variants affect serum levels of matrix metalloproteinase (MMP)-3 and correlate with severity of COPD: A study of MMP-3, MMP-7 and MMP-12 in a Tunisian population.

The present study aimed to examine the role of matrix metalloproteinase (MMP)-3 [(-1171) 5A/6A; Lys45Glu (A/G)], MMP-7 [(-181) A/G] and MMP-12 [(-82) A/G; Asn357Ser (A/G)] variants in the development and severity of chronic obstructive pulmonary disease (COPD) in Tunisians. Plethysmography was performed in all participants to measure forced expiratory volume in 1s (FEV1), forced vital capacity (FVC) and FEV1/FVC parameters. Genotyping of MMP-3, MMP-7 and MMP-12 polymorphisms was carried out in 138 patients with COPD and 216 healthy controls using a polymerase chain reaction-restriction fragment length polymorphism. Serum levels of MMPs and cytokines (interleukin-6, tumor necrosis factor-α) were determined by an enzyme-linked immunosorbent assay. No significant correlations were observed between genetic variations in MMP-3, MMP-7 and MMP-12 and the risk of development of COPD. Additionally, no impact of MMP-7 (-181) A/G and MMP-12 [(-82) A/G; Asn357Ser (A/G)] polymorphisms was observed on the respective protein levels and clinical parameters of the disease. Interestingly, both MMP-3 (-1171) 5A/6A and Lys45Glu (A/G) variants were associated with respiratory function, as well as with serum levels of MMP-3 in COPD patients. A relationship was found between the (-1171) 6A and 45Glu (G) alleles of the MMP-3 gene and enhanced airflow limitation among COPD patients. Additionally, carriers of the 6A6A and 45 GG genotypes present higher MMP-3 levels than noncarriers. MMP-3 (-1171) 5A/6A and Lys45Glu (A/G) polymorphisms were associated with the decline of lung function among COPD patients. These results could be linked to the upregulation of MMP-3 in serum from COPD patients carrying the (-1171) 6A and 45G homozygous genotypes.

Multiple sites of vascular dilation or aneurysmal disease and matrix metalloproteinase genetic variants in patients with abdominal aortic aneurysm

ObjectiveThe objective of this study was to assess whether functional genetic polymorphisms of matrix metalloproteinases (MMPs) 1, 3, 9, and 12 are associated with arterial enlargements or aneurysms of the thoracic aorta or popliteal arteries in patients with abdominal aortic aneurysm (AAA). MethodsThe associations between MMP1 (−1607 G in/del, rs1799750), MMP3 (−1171 A in/del rs35068180), MMP9 (13-26 CA repeats around −90, rs2234681, rs917576, rs917577), and MMP12 (G/T missense variation, rs652438) polymorphisms and enlargements or aneurysms of the thoracic aorta and popliteal arteries were tested in 169 consecutive AAA patients. ResultsThoracic aorta enlargement or aneurysm (TE/A; maximum diameter, >35 mm) was detected in 34 patients (20.1% prevalence). MMP9 rs2234681 microsatellite was the only genetic determinant of TE/A in AAA patients (P = .003), followed by hypercholesterolemia and antiplatelet use. Carriers of both alleles with ≥22 CA repeats had a 5.9 (95% confidence interval, 1.9-18.6; P < .0001) increased odds of TE/A, and a score considering all three variables showed 98% negative predictive value and 30% positive predictive value for thoracic aortic aneurysm detection. Eighty-two popliteal artery enlargements or aneurysms (diameter >10 mm) occurred in 55 patients (33.1% prevalence). Carriers of MMP12 rs652438 C allele showed an 18% (P = .006) increased diameter in popliteal arteries and a 2.8 (95% confidence interval, 1.3-6; P = .008) increased odds of popliteal artery enlargement or aneurysm compared with TT genotype. ConclusionsAmong patients with AAA, carriers of homozygous ≥22 CA repeats in MMP9 rs12234681 and of C allele in MMP12 rs652438 have a substantial risk of carrying thoracic and popliteal enlargements, respectively.

Rapid Mobilization Reveals a Highly Engraftable Hematopoietic Stem Cell

Hematopoietic stem cell transplantation is a potential curative therapy for malignant and nonmalignant diseases. Improving the efficiency of stem cell collection and the quality of the cells acquired can broaden the donor pool and improve patient outcomes. We developed a rapid stem cell mobilization regimen utilizing a unique CXCR2 agonist, GROβ, and the CXCR4 antagonist AMD3100. A single injection of both agents resulted in stem cell mobilization peaking within 15min that was equivalent in magnitude to a standard multi-day regimen of granulocyte colony-stimulating factor (G-CSF). Mechanistic studies determined that rapid mobilization results from synergistic signaling on neutrophils, resulting in enhanced MMP-9 release, and unexpectedly revealed genetic polymorphisms in MMP-9 that alter activity. This mobilization regimen results in preferential trafficking of stem cells that demonstrate a higher engraftment efficiency than those mobilized by G-CSF. Our studies suggest a potential new strategy for the rapid collection of an improved hematopoietic graft.

The Association of Single-Nucleotide Polymorphisms in the MMP-9 Gene with Normal Tension Glaucoma and Primary Open-Angle Glaucoma

ABSTRACTPurpose: To evaluate the association of matrix metalloproteinases (MMP)-9 gene polymorphisms with normal tension glaucoma (NTG) and primary open-angle glaucoma (POAG) in the South Korean population.Materials and Methods: A total of 700 South Korean subjects were recruited: 146 patients with NTG, 174 patients with POAG, and 380 healthy adults. Five single-nucleotide polymorphisms (SNPs; rs3918429, rs2274755, rs3787268, rs3918261, and rs3918270) of MMP-9 were analyzed in all subjects. The association with each disease was tested using an allelic χ2 test and p values were corrected by permutation tests with 100 000 permutations.Results: Among the five SNPs, rs2274755 showed a significant association with NTG (p = 0.021). The T allele of rs2274755 had an allelic odds ratio of 1.67 (95% confidence interval, 1.12–2.50). The association remained significant after correction using permutation tests (p = 0.039). It was also significant in an association analysis for genotype frequency (p = 0.011). The SNP was predicted to be found within a splicing site and a conserved region. No SNPs analyzed were significantly associated with POAG (p > 0.05).Conclusions: The rs2274755 SNP in the MMP-9 gene was significantly associated with NTG. This supports a possible role of the MMP-9 gene in NTG pathogenesis.