Matrix Metalloproteinases Polymorphisms Research Articles

Association of the functionally significant polymorphisms of the MMP9 gene with H. pylori-positive gastric ulcer in the Caucasian population of Central Russia.

Background and purposeThe study analyzed the association of functionally significant polymorphisms of matrix metalloproteinases (MMPs) genes with the development of gastric ulcer (GU) in Caucasians from Central Russia.MethodsThe 781 participants, including 434 patients with GU (196 Helicobacter pylori (H. pylori)-positive and 238 H. pylori-negative) and 347 controls (all H. pylori-negative) were recruited for the study. Ten SNPs of the MMP1 (rs1799750), MMP2 (rs243865), MMP3 (rs679620), MMP8 (rs1940475), and MMP9 (rs3918242, rs3918249, rs3787268, rs17576, rs17577, and rs2250889) genes were considered for association with GU using multiple logistic regression. The SNPs associated with GU and loci linked (r2≥0.8) to them were analyzed in silico for their functional assignments.ResultsThe SNPs of the MMP9 gene were associated with H. pylori-positive GU: alleles C of rs3918249 (OR = 2.02, pperm = 0.008) and A of rs3787268 (OR = 1.60–1.82, pperm ≤ 0.016), and eight haplotypes of all studied MMP9 gene SNPs (OR = 1.85–2.04, pperm ≤ 0.016) increased risk for H. pylori-positive GU. None of the analyzed SNPs was independently associated with GU and H. pylori-negative GU. Two haplotypes of the MMP9 gene (contributed by rs3918242, rs3918249, rs17576, and rs3787268) increased risk for GU (OR = 1.62–1.65, pperm ≤ 0.006). Six loci of the MMP9 gene, which are associated with H. pylori-positive GU, and 65 SNPs linked to them manifest significant epigenetic effects, have pronounced eQTL (17 genes) and sQTL (6 genes) values.ConclusionSNPs of the MMP9 were associated with H. pylori-positive GU but not with H. pylori-negative GU in Caucasians of Central Russia.

Correlation between matrix metalloproteinase-2 polymorphisms and first and recurrent atherosclerotic ischemic stroke events: a case-control study.

ObjectiveTo determine the associations between matrix metalloproteinase-2 (MMP-2, encoded by the MMP2 gene) 1306C/T and 735C/T polymorphisms and first and recurrent ischemic stroke in a Chinese population.MethodsPatients with first and recurrent ischemic stroke were included. Serum MMP-2 was measured, and MMP2 1306C/T and 735C/T polymorphisms were detected. The associations between MMP2 1306C/T and 735C/T polymorphisms and first and recurrent ischemic stroke were analyzed.ResultsSerum MMP-2 in patients with first and recurrent ischemic stroke was significantly higher compared with controls, and patients with recurrent ischemic stroke had higher MMP-2 than those with first ischemic stroke. The frequency of the CC genotype and C allele of MMP2 735C/T was highest in patients with recurrent ischemic stroke, followed by patients with first ischemic stroke, and controls. Conversely, the genotype and allele of MMP2 1306C/T did not significantly differ between groups. The CC genotype of MMP2 735C/T was independently associated with first and recurrent ischemic stroke (odds ratios = 1.45 and 1.64, respectively), as was the C allele of MMP2 735C/T (odds ratios = 1.68 and 1.77, respectively).ConclusionsThe CC genotype and C allele of MMP2 735C/T were associated with first and recurrent ischemic stroke in a Chinese population.

Association between MMP-2 gene polymorphism and cataract susceptibility: A protocol for systematic review and meta-analysis.

Background:Matrix metalloproteinase-2 (MMP-2) polymorphisms have been considered as risk factors of cataracts, but the results still remain controversial. In this study, we have performed a systematic meta-analysis to evaluate the association between MMP-2 polymorphisms and cataract risks.Methods:Published literature was retrieved from Wanfang, Chinese Biomedical Literature Database, Chinese National Knowledge Infrastructure, Chongqing VIP Chinese Science and Technology Periodical Database, PubMed, Embase, and Web of Science databases. The case–control studies that explored the association between MMP-2 polymorphisms and cataract risks were included. Pooled odds ratio (OR) and 95% confidence interval (CI) were calculated using random- or fixed-effects model.Results:This study could provide high-quality and evidence-based medical evidence for the correlation between MMP-2 polymorphisms and cataract risksConclusion:The study could provide updated evidence for the evaluation of the relationship between MMP-2 polymorphism and cataract risk.Ethics and dissemination:The private information from individuals will not be published. This systematic review also will not involve endangering participant rights. Ethical approval is not available. The results may be published in a peer-reviewed journal or disseminated in relevant conferences.OSF Registration Number:DOI 10.17605/OSF.IO/KU9NE.

Single nucleotide polymorphisms in matrix metalloproteinase 2 (MMP2) enhance BRAFV600E mutation-mediated oncogenicity and invasiveness of papillary thyroid cancer cells.

Thyroid cancer is a common endocrine neoplasm. Despite its good prognosis, it can lead to significant morbidity and mortality due to metastasis and recurrence. However, the factors involved in metastasis are not well studied. Therefore, we selected matrix metalloproteinases 2 (MMP2) and determined whether it has any role in thyroid cancer. We sequenced the exons of MMP2 in 211 samples including 16 multi-nodular goiters and 195 differentiated thyroid cancers. We identified four non-synonymous single nucleotide polymorphisms (SNPs) of the MMP2 gene in 3.06% (6/195) thyroid cancers. Of the four tumors harboring MMP2 SNPs, three (75%) concomitantly had BRAFV600E. Hence, we speculated that the MMP2 SNPs may cooperate with BRAFV600E in promoting tumor aggressiveness. Overexpression of two MMP2 SNPs (P38L and T458I) exhibited markedly enhanced gelatinase activity with an intact dimerization and induced strong cortactin foci formation in HEK293T cells. Stable expression of the two MMP2 SNPs in BRAFV600E positive BCPAP cells dramatically enhanced cell proliferation, colony formation, and focus formation. Analysis of the morphology of MMP2 SNP bearing BCPAPV600E cells exhibited highly invasive phenotypes characterized by a high rate of wound healing and enhanced cell invasion compared with parental BCPAPV600E cells bearing vector. We also determined that BCPAPV600E cells stably transfected with MMP2 SNPs were highly sensitive to the treatment of BRAF inhibitor, PLX4720. Our study demonstrates that MMP2 SNPs could cooperate with BRAFV600E to promote oncogenicity, migration, and invasiveness of PTC cells. These results suggest that a subset of papillary thyroid cancer with this genetic makeup may benefit from BRAF-mediated therapeutic interventions.

The association between genetic polymorphisms in matrix metalloproteinases and caries experience.

The variation in the caries susceptibility while environmental factors are similar indicates that the effect of individual factors such as genetics on caries process and tooth development should be revealed. The aim of this study was to evaluate the association between genetic polymorphisms in MMP13 (rs2252070) and MMP20 (rs1784418) with caries experience. A cross-sectional study was conducted on 200 subjects aged 6 to 14 years. Demographic data, data on oral health habits were obtained through the statements of guardian of the individuals, caries data was collected by clinical examination. Unstimulated whole saliva was collected to extract the genomic DNA. Genotyping of the selected polymorphisms was carried out by real-time PCR. Allele and genotype frequencies were compared between different subgroups considering caries experience. Data were analyzed using SPSS 16.0 by chi-square test and logistic regression analysis. Allele distribution of MMP13 was different between caries-affected and caries-free subjects. MMP13 A allele increased the caries risk (p=0.005, OR=1.84, 95% CI 1.20-2.82). Allele and genotype distribution of the polymorphism in MMP20 were not associated with caries experience (p>0.05). It is concluded that the genetic variation in MMP13 was associated with the caries experience in selected subjects in Turkey. The knowledge regarding association between the MMP genes and caries experience, might benefit the clinical practice, improving caries-preventive and caries-therapeutic approaches.

High Prevalence of MMP9 −1562C/T Gene Polymorphism in an Iranian Population of Neuromyelitis Optica, A Pilot Study

Expression of matrix metalloproteinases correlates to blood-brain barrier disruption in Neuromyelitis Optica disease (NMO). Matrix metalloproteinase-9 (MMP9) −1562C/T polymorphism which influences the transcriptional activity of this gene is considered to play a role in some neuroinflammatory diseases. In the present study, the possible association of MMP9 –1562C/T polymorphism in Iranian NMO patients is studied.Association of the mentioned gene polymorphism of MMP9 with NMO susceptibility was evaluated via genotyping of DNA extraction from the blood samples of unrelated Iranian subjects referred to AlZahra Hospital, Isfahan, Iran during 2017 to 2019.Frequency distribution of MMP9 genotypes has a significant relationship with NMO disease; in such a way that CT + TT genotypes was more seen in NMO patients.Altogether, Since the MMP9 is one of the potential target molecules for future alternative treatment, the result of this study should be taken into account for further research. However, more studies should carry out to confirm our results in larger populations and reveal the convoluted role of MMP9 in Devic's disease.

How matrix metalloproteinase (MMP)-9 (rs3918242) polymorphism affects MMP-9 serum concentration and associates with autism spectrum disorders: A case-control study in Iranian population

The aim of this project was to evaluate the relationship of matrix metalloproteinase-9 (MMP-9) genetic variation and its serum concentration with autism spectrum disorder (ASD). One hundred ASD and 120 controls were enrolled in this study. Genomic DNA was extracted from blood and MMP-9 polymorphism was determined by polymerase chain reaction restriction fragment length polymorphism and serum levels were measured by enzyme-linked immunosorbent assay. The frequencies of CC, CT, and TT genotypes were 72%, 26%, and 2% in controls and 31%, 57%, and 12% in ASD, respectively. The frequencies of C and T alleles in ASD were 59.5% and 40.5%, and controls were 86% and 14%, respectively. There is a significant increase in serum MMP-9 levels in ASD as compared to controls. We have also shown that TT genotype is significantly associated with increase serum MMP-9 levels in patients (TT, CT, and CC serum levels were 91.77 ± 10.53, 70.66 ± 7.21, and 38.66 ± 5.52 and in controls were 55.55 ± 11.39, 42.66 ± 7.85, and 30.55 ± 6.34 ng/ml, respectively). It is concluded that there is a significant association between rs3918242 MMP-9 polymorphism and its serum concentration with autism. We also suggest that TT genotype is associated with increased MMP9 expression and may be a risk factor for ASD.

Genetic Association between MMP9 and Choroidal Neovascularization in Age-Related Macular Degeneration

PurposeTo evaluate the first association specific to exudative age-related macular degeneration (AMD) located near the matrix metalloproteinase 9 (MMP9) gene.DesignGenetic association study.ParticipantsOne thousand seven hundred twelve patients with AMD (672 nonexudative, 1040 exudative) of predominantly northern European descent seeking treatment at the University of Iowa Hospitals and Clinics.MethodsWe reanalyzed the International AMD Genetics Consortium (IAMDGC) data to validate the association of polymorphisms near MMP9 with exudative AMD and to identify additional associated single nucleotide polymorphisms (SNPs), especially MMP9 coding sequence SNPs. We genotyped a cohort of 1712 AMD patients from Iowa with 3 SNPs identified with our analysis of the IAMDGC cohort using commercially available real-time quantitative polymerase chain reaction (PCR) assays. Firth regression was used to measure the association between MMP9 SNP genotypes and exudative AMD in our cohort of patients from Iowa. In addition, we developed a PCR-based assay to genotype the Iowa cohort at a short tandem repeat polymorphism (STRP) at the MMP9 locus.Main Outcome MeasuresOdds ratios and P values for exudative compared with nonexudative AMD patients in the Iowa cohort for MMP9 SNPs (rs4810482, rs17576, and rs17577) and STRP.ResultsWe identified 3 SNPs in the MMP9 locus (rs4810482, rs17576, and rs17577) that are highly associated with exudative AMD in patient cohorts of the IAMDGC. These MMP9 SNPs also are associated with exudative AMD in the cohort of 1712 AMD patients from Iowa (rs4810482: odds ratio [OR], 0.82; P = 0.010; rs17576: OR, 0.86; P = 0.046; and rs17577: OR, 0.80; P = 0.041). We also genotyped the cohort of AMD patients from Iowa at rs142450006, another MMP9 polymorphism that previously was associated with exudative AMD. We detected a 4bp STRP, (TTTC)n, at the rs142450006 locus that is highly polymorphic and associated significantly with exudative AMD (OR, 0.78; P = 0.016).ConclusionsThis study independently confirms and expands an association between the MMP9 locus and exudative AMD, further implicating a role for extracellular matrix abnormalities in choroidal neovascularization.

The role of gene-gene and gene-environment interactions of polymorphic locuses of <i>MMPs</i> in the formation of hypertension in women

Objective . To study the role of gene-gene and gene-environment interactions of polymorphisms of matrix metalloproteinases with obesity and smoking in the formation of hypertension (HTN) in women. Design and methods . The study included genotyping data for seven polymorphic loci of MMPs — rs3025058, rs11568818, rs1320632, rs11225395, rs652438, rs243865 and rs17577 in 375 patients with HTN and 209 women in the controls. Genetic and environmental interactions involved in the HTN formation were detected using the Multifactor Dimensionality Reduction (MDR) method in Model-Based-MDR modification (MB-MDR vers. 2.6). The results were visualized in the MDR vers. 3.0.2 (http://sourceforge.net/projects/mdr). Results . Eight models of genegene interactions associated with the HTN formation in women (p perm ≤ 0,05) have been identified which are based on SNPs rs652438 MMP12 , rs1320632 MMP8 , rs3025058 MMP3 and rs11568818 MMP7 . Eight models of interactions of locuses of MMPs with obesity and smoking (p perm < 0,002) were identified. Most of models include the polymorphic locus rs243865 MMP2 . For the identified models, combinations of high (β = 0,76–2,06) and low (β = –0,37 — –1,23) risk of developing HTN were established. Conclusions . Our findings suggest that the polymorphic variants of MMPs and environmental factors have a synergistic effect in the formation of susceptibility to HTN.

Association of MMP-9 polymorphisms with diabetic nephropathy risk: A protocol for systematic review and meta-analysis.

Background:Diabetic nephropathy (DN) is a multifactorial disease with gene–environment interaction resulting in progressive renal function damage. Multiple studies have assessed the association between matrix metalloproteinase-9 (MMP-9) gene promoter polymorphism and DN susceptibility. However, the results are inconclusive. In the present study, we will conduct a meta-analysis to further examine this relationship more precisely.Methods:Electronic databases (Pubmed, Web of Science, Embase, Google Scholar, Wanfang, China Biological Medicine and China National Knowledge Infrastructure) will be used to search clinical case–control studies about MMP-9 polymorphism and DN published until 18 August 2020. The language will be restricted to Chinese and English. Two reviewers will take charge of completing the selection of study, the extraction of data as well as the assessment of study quality independently. The Newcastle-Ottawa Scale will be used to evaluate the study quality. We will evaluate the association under 5 genetic models. Fixed-effects or random-effects models will be used to calculate the effect sizes of odds ratio and 95% confidence intervals. Afterwards, subgroup analysis will be conducted in terms of the ethnicity and genotyping method. Additionally, sensitivity analysis will be performed via sequentially omitting each of the included studies one at a time. The funnel plots, Egger regression test, and Begg rank correlation test will be used to test the potential publication bias. All the statistical analyses will be performed using Review Manager 5.3 and Stata 12.0.Results:This protocol reported according to the Preferred Reporting ltems for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) statement. This study will provide a better understanding of the association between MMP-9 polymorphisms and DN risk.Conclusion:Publishing this protocol will minimize the potential bias related to data mining, thus contributing to generation of reliable evidence.OSF registration number:DOI 10.17605/OSF.IO/H5FS4

Matrix Metalloproteinases in Age-Related Macular Degeneration (AMD).

Age-related macular degeneration (AMD) is a complex, multifactorial and progressive retinal disease affecting millions of people worldwide. In developed countries, it is the leading cause of vision loss and legal blindness among the elderly. Although the pathogenesis of AMD is still barely understood, recent studies have reported that disorders in the regulation of the extracellular matrix (ECM) play an important role in its etiopathogenesis. The dynamic metabolism of the ECM is closely regulated by matrix metalloproteinases (MMPs) and the tissue inhibitors of metalloproteinases (TIMPs). The present review focuses on the crucial processes that occur at the level of the Bruch’s membrane, with special emphasis on MMPs, TIMPs, and the polymorphisms associated with increased susceptibility to AMD development. A systematic literature search was performed, covering the years 1990–2020, using the following keywords: AMD, extracellular matrix, Bruch’s membrane, MMPs, TIMPs, and MMPs polymorphisms in AMD. In both early and advanced AMD, the pathological dynamic changes of ECM structural components are caused by the dysfunction of specific regulators and by the influence of other regulatory systems connected with both genetic and environmental factors. Better insight into the pathological role of MMP/TIMP complexes may lead to the development of new strategies for AMD treatment and prevention.

MMP-9-C1562T polymorphism and susceptibility to chronic obstructive pulmonary disease: A meta-analysis.

Background:To comprehensively evaluate the association between the polymorphism of matrix metalloproteinase-9 (MMP-9)-C1562T (rs3918242) and susceptibility to chronic obstructive pulmonary disease (COPD) in middle-aged and elderly patients through Meta-analysis.Methods:PubMed, EMBASE, CNKI, Wanfang, VIP, and other databases were searched by computer in the inception to August 2019 to collect all the case-control studies that met the inclusion criteria in this literature. Meta-analysis was performed using Stata 15.0, including the OR value calculations of the association between the merged MMP-9-C1562T polymorphism and the COPD susceptibility. Subgroup analysis, sensitivity analysis, and publication bias test were also performed. A total of 13 literature were included in this Meta-analysis with a total of 2512 cases and 2716 controls.Results:The results have shown that the OR of MMP-9-C1562T T allele to C allele was 0.35 (95% confidence interval [CI]: 0.23–0.52, P < .01). The subgroup analysis of ethnicity result showed that the merged OR of MMP-9-C1562T T allele to C allele was 0.24 (95% CI: 0.17–0.34, P < .01) in Caucasian while the merged OR was 0.62 (95% CI: 0.22–1.70, P > .05) in Asian. However, there were no statistically significant models in the dominant, recessive, homozygote and heterozygote genetic models.Conclusion:The MMP-9-C1562T polymorphism was associated with the susceptibility to middle-aged and elderly COPD patients. Compared with T allele, C allele increased the risk of disease, especially in Caucasian, but not found in Asian.

Association Study between Functional Polymorphisms of MMP9 Gene Promoter and Multiple Sclerosis Susceptibility in an Iranian Population

Matrix metalloproteinase-9 (MMP-9) polymorphisms, C-1562 T and -90 (CA) n repeats, which influence transcriptional activity of this gene, are proposed to play a role in MS susceptibility and its development. In the present study, the possible association of MMP-9 polymorphisms in Iranian MS patients is studied. Association of MMP-9 mentioned gene polymorphisms with MS susceptibility was evaluated in unrelated Iranian subjects referred to Al-Zahra Hospital, Isfahan, Iran during 2014 to 2017. -1562 T allele of MMP-9 was associated with increased MS risk. However, we found no overall significant effect of -90 (CA)n repeat on MS susceptibility. For as much as MMP-9 molecule is a potential target for MS therapy, to determine whether any of MMP-9 polymorphisms influence MS susceptibility in Iranian MS patients or not, concerning the significant influence of T allele on MS susceptibility and the non-significant association regarding CA repeats, further research is needed before proposing any definite conclusion.

Matrix Metalloproteinases as Biomarkers of Atherosclerotic Plaque Instability.

Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases responsible for tissue remodeling and degradation of extracellular matrix (ECM) proteins. MMPs may modulate various cellular and signaling pathways in atherosclerosis responsible for progression and rupture of atherosclerotic plaques. The effect of MMPs polymorphisms and the expression of MMPs in both the atherosclerotic plaque and plasma was shown. They are independent predictors of atherosclerotic plaque instability in stable coronary heart disease (CHD) patients. Increased levels of MMPs in patients with advanced cardiovascular disease (CAD) and acute coronary syndrome (ACS) was associated with future risk of cardiovascular events. These data confirm that MMPs may be biomarkers in plaque instability as they target in potential drug therapies for atherosclerosis. They provide important prognostic information, independent of traditional risk factors, and may turn out to be useful in improving risk stratification.

Matrix metalloproteinases (MMPs) family gene polymorphisms and the risk of multiple sclerosis: systematic review and meta-analysis

BackgroundSeveral studies have reported the association between polymorphisms in Matrix metalloproteinases (MMPs) gene family and risk of Multiple sclerosis (MS). However, the results have been inconsistent and inconclusive. To resolve this issue, here we performed a systematic review and meta-analysis of the MMP-91562 C/T (rs3918242), MMP-3 (− 1612 5A/6A), and MMP-2 (− 1306 C/T) polymorphisms and susceptibility to MS.MethodsWe conducted a comprehensive systematic search in the major electronic database, including Scopus and PubMed to look up for relevant studies published before December 2019 that surveyed the association between the MMP-91562 C/T (rs3918242), MMP-3 (− 1612 5A/6A), and MMP-2 (− 1306 C/T) polymorphisms and susceptibility to MS. The level of association between the polymorphisms and susceptibility to MS in the polled analysis was determined by calculating the odds ratio (OR) and the corresponding 95% confidence interval (CI).ResultsWe found 15 studies containing 2430 MS subjects and 2304 controls. A statistically significant association was observed in the all five comparisons of the MMP-91562 C/T polymorphism and MS risk as follows: dominant model (OR = 1.62, 95% CI = 1.03–2.53, P = 0.03), recessive model (OR = 2.69, 95% CI = 1.68–4.29, P < 0.001), allelic model (OR = 1.51, 95% CI = 1–2.28, P = 0.04), TT vs. CC model (OR = 3.20, 95% CI = 1.87–5.46, P < 0.001), and CT vs. CC model (OR = 1.53, 95% CI = 1.02–2.28, P = 0.04).ConclusionsOur meta-analysis revealed significant association of MMP-9 (− 1562 C/T) Single-nucleotide polymorphism (SNP) with MS susceptibility that increased the disease risk.

Association of matrix metalloproteinase-9 polymorphism with severity of Guillain-Barré syndrome

Guillain-Barré syndrome (GBS) is an immune-mediated neurological disorder with a multifaceted nature. Infectious agents and immune-response genetic host factors may contribute to the development of GBS. The matrix metalloproteinase-9 (MMP-9), an enzyme is upregulated by pro-inflammatory cytokines and might play an important role in the pathogenesis of GBS. This study investigated the association of a single nucleotide polymorphism (−1562C/T, rs3918242) in the MMP9 gene with the susceptibility and severity of GBS in Bangladesh. The allele and genotype distributions of the MMP9 polymorphism were not significantly different between 303 patients with GBS and 303 healthy controls. Serum concentrations of MMP-9 were significantly elevated in patients with GBS compared to healthy controls (P ≤.0001). No significant association of MMP-9 (−1562C/T) polymorphism was observed with disease prognosis. The frequencies of the MMP9–1562 CT genotype and T allele (P = .01, OR = 2.28, 95% CI = 1.22–4.22; Pc = 0.03 and P = .012, OR = 2.0, 95% CI = 1.14–3.38; Pc = 0.024, respectively) were significantly increased in patients with severe form of GBS, indicates the MMP9 polymorphism plays a role in the disease severity of GBS.

Association of matrix metalloproteinases 3 and 9 single nucleotide polymorphisms with breast cancer risk: A case-control study.

Two single nucleotide polymorphisms (SNPs) of matrix metalloproteinase (MMPs) 3 and 9 are functionally implicated in the progression of various types of cancer, including breast cancer (BC). However, the roles of these SNPs remain controversial. In addition, they also vary between one population and another. Therefore, the present study aimed to investigate the possible association between MMP3-1171 5A/6A and MMP9-1562 CT SNPs and the risk of BC among Egyptians, and to elucidate the alteration of MMP3 and MMP9 gene expression in patients with BC. The present case-control study enrolled 162 patients with BC and 146 control subjects. Restriction fragment length polymorphism-PCR was performed for analysis of the selected SNPs, gene expression of MMP3 and MMP9 was also assessed in 50 patients and 50 control subjects by reverse transcription-quantitative PCR. The frequencies of 5A/6A genotype and 5A allele of MMP3 were significantly higher in patients with BC compared with in healthy subjects. On the other hand, the distributions of MMP9 genotypes and alleles were not significantly different among patients and healthy subjects. Compared with healthy subjects, the expression levels of the two genes were found to be upregulated in patients with BC. Therefore, the present study indicated that MMP3-1171 5A/6A SNP, not MMP9-1562 C>T SNP may be a risk factor for developing BC among Egyptian females.

A protective polymorphism in MMP16, improved blood gas levels, and chronic obstructive pulmonary diseases: Family and two population-based studies.

The aberrant expression of matrix metalloproteinases (MMPs) is known to contribute to the pathogenesis of airway remodeling and alveolar disruption in chronic obstructive pulmonary disease (COPD). In the discovery stage, 11 COPD from five families were subjected to whole-genome sequencing, and 21 common polymorphisms in MMPs and TIMPs were identified. These polymorphisms were genotyped in two subsequent verification studies. Of these polymorphisms, c.2392G>A (rs2664370T>C) and c.4158C>A (rs2664369T>G) in MMP16 remained significantly different. Functionally, we found that MMP16 expression was significantly increased in peripheral blood monocytes (PBMCs) from COPD and in cigarette smoke extract-treated 16HBE cells compared with controls. This was also shown by bioinformatics analysis. COPD carrying rs2664370CC showed decreased levels of MMP16 in the plasma and in PBMCs compared with those carrying CT and TT. Treatment with hsa-miR-576-5p mimics led to a greater reduction in luciferase reporter activity in cells transfected with rs2664370CC. Moreover, blood levels of base excess, PCO2 , and PO2 in COPD with rs2664370CC were significantly lower than those with rs2664370CT+TT. Taken together, these results demonstrate that the rs2664370T>C polymorphism in MMP16 protects against the risk of COPD, likely by favoring interaction with hsa-miR-576-5p, leading to reduced MMP16 expression and improved blood gas levels.

Matrix metalloproteinase family gene polymorphisms and lung cancer susceptibility: an updated meta-analysis.

BackgroundMany studies have investigated the association between matrix metalloproteinase polymorphisms and lung cancer susceptibility. However, the results are still controversial. To clarify these associations, we conducted a meta-analysis.MethodsA systematic search of studies was conducted in PubMed, Embase, and China National Knowledge Infrastructure. Overall and subgroup analysis stratified by ethnicity was conducted. OR with 95% CI was used to assess the strength of the association. Furthermore, false-positive report probability (FPRP) tests were also performed for associations obtained in this meta-analysis.ResultsTwenty-four studies, including 10,099 cases and 9,395 controls, were analyzed. Nine polymorphisms were reported. For MMP1 -1607 1G/2G and MMP7 -181 A/G, increased lung cancer risk was found in Asians. For MMP2 -1306 C/T and MMP2 -735 C/T, decreased lung cancer risk was found in both “diverse populations” and Asians. For MMP9 -1562, C/T decreased lung cancer risk was found in both “diverse populations” and Caucasians. For MMP13 -77A/G, the A/G genotype decreased lung cancer risk in Asians. However, only associations between MMP1 -1607 1G/2G, MMP2 -1306 C/T, MMP2 -735 C/T, and MMP7 -181 A/G and lung cancer risk were considered noteworthy according to FPRP tests. There was no association between MMP3 -1171 5A/6A, MMP9 R279Q, and MMP12 -82A/G and lung cancer risk.ConclusionsOur meta-analysis suggested that MMP1 -1607 1G/2G and MMP7 -181 A/G were risk factors for lung cancer, while MMP2 -1306 C/T, MMP2 -735 C/T, MMP9 -1562 C/T, and MMP13 -77A/G might be protective factors. However, results for MMP9 -1562 C/T and MMP13 -77A/G should be interpreted with caution due to the probability of false-positive reports.

Associations Between Polymorphisms of Endothelial Nitric Oxide Synthase, Matrix Metalloproteinase 3, Angiotensinogen, and Angiotensin II Type 1 Receptor and Risk of Restenosis After Percutaneous Coronary Intervention: A Meta-analysis

PurposePrevious studies have reported controversial results regarding the risk of restenosis with polymorphisms of endothelial nitric oxide synthase (eNOS), matrix metalloproteinase 3 (MMP-3), angiotensinogen (AGT), and angiotensin II type 1 receptor (AT1R) after percutaneous coronary intervention (PCI). This study aimed to summarize the association between these polymorphisms and risk of restenosis after PCI. MethodsWe searched the electronic databases of PubMed, Embase, Cochrane's Library, and ClinicalTrials.gov for studies on the association of eNOS, MMP-3, AGT, and AT1R polymorphisms with restenosis. FindingsA total of 17 studies (7781 patients) were analyzed, including 5 studies on eNOS G298A (n = 912), 5 studies on MMP3 5A/6A (n = 4519), 6 studies on AGT M235T (n = 1801), and 7 studies on AT1R A1166C (n = 2477). For the G298A variant of the eNOS gene, the allele odds ratio (OR) was 1.685 (95% CI, 1.269–2.338; P < 0.001), the heterozygote OR was 2.144 (95% CI, 1.490–3.085; P < 0.001), the dominant OR was 2.078 (95% CI, 1.462–2.954; P < 0.001), and the overdominant OR was 0.496 (95% CI, 0.348–0.706; P < 0.001). For the 5A/6A variant of the MMP3 gene, the heterozygote OR was 0.839 (95% CI, 0.722–0.975; P = 0.022), the dominant OR was 0.846 (95% CI, 0.733–0.976; P = 0.022), and the overdominant OR was 1.141 (95% CI, 1.001–1.301; P = 0.049). For the M235T variant of the AGT gene, the heterozygote OR was 1.594 (95% CI, 1.179–2.155; P = 0.002), the dominant OR was 1.437 (95% CI, 1.077–1.918; P = 0.014), and the overdominant OR was 0.694 (95% CI, 0.555–0.869; P = 0.001). Positive results were observed in the AT1R gene A1166C polymorphism under 3 models (homozygote OR = 2.009; 95% CI, 1.433–2.816; P < 0.001; recessive OR 1.874; 95% CI, 1.353–2.595; P < 0.001; and dominant OR = 1.350; 95% CI, 1.105–1.649; P = 0.003). ImplicationsThe G298A variant of eNOS, the 5A/6A variant of MMP3, the M235T variant of AGT, and the A1166C variant of A1TR may increase the risk of restenosis after PCI.