The -2518A/G Polymorphism in the MCP-1 Gene and Tuberculosis Risk: A Meta-Analysis

Background

The -2518A/G polymorphism in the monocyte chemoattractant protein-1 (MCP-1) gene has been implicated in the susceptibility to tuberculosis (TB), but the results are not conclusive. The aim of this study is to investigate the association between the -2518A/G polymorphism in the MCP-1 gene and the risk of tuberculosis by meta-analysis.

Methods

We searched Pubmed, Embase, CNKI and Wanfang databases, covering all studies until April 29^th, 2011. Statistical analyses were performed using the Revman4.2 and STATA10.0 software.

Results

A total of 5341 cases and 6075 controls in 13 case-control studies were included in the meta-analysis. The results indicated that the GG homozygote carriers had a 67% increased risk of TB compared with the A allele carriers (GG vs. GA+AA: OR = 1.67, 95%CI = 1.25–2.23, P = 0.0006). In the subgroup analysis by ethnicity, significant elevated risks were found in Asians and Latinos, but not in Africans (GG vs. GA+AA: OR = 1.79, 95%CI = 1.19–2.70 and P = 0.005 for Asians; OR = 2.15, 95%CI = 1.32–3.51 and P = 0.002 for Latinos; OR = 1.28, 95%CI = 0.45–3.64 and P = 0.65 for Africans).

Conclusion

This meta-analysis suggested that the -2518A/G polymorphism of MCP-1 gene would be a risk factor for TB in Asians and Latinos, while not in Africans.     

相关个体基因型联合概率分布及在身份鉴定中的应用

从联合父系基因概率出发,得出处在同一代的多个个体的联合基因型概率,讨论两种符合我国国情的家谱图,得到同一家族内第m代独生子女之间的联合基因型概率,相应的方法可用来求多个家族、多代独生子女之间的联合基因型概率．列举了两个案例来说明相关个体的联合基因型概率在身份鉴定中的应用．     

博莱霉素致肺间质成纤维细胞MMP-2/TIMP-1表达失衡

观察博莱霉素对肺间质成纤维细胞中基质金属蛋白酶-2（MMP-2）及组织金属蛋白酶抑制剂-1（TIMP-1）表达的影响,探讨博莱霉素引起肺纤维化的机制。体外培养肺间质成纤维细胞,并向培养基中加入博莱霉素,在作用不同时间后收集样本,采用酶谱图测定细胞培养上清液中MMP-2酶活性、ELISA测定TIMP-1量,免疫组织化学法检测细胞中MMP-2、TIMP-1的原位表达,RT-PCR法检测MMP-2和TIMP-1的mRNA水平。结果发现,博莱霉素在2h、12h促进MMP-2的分泌,24h后无促分泌作用;而2-48h,MMP-2的原位表达及mRNA均不受博莱霉素的影响;博莱霉素从12h开始促进TIMP-1及mRNA的表达,并持续至48h。结果表明博莱霉素可引起肺间质戍纤维细胞MMP-2／TIMP-1表达失衡,并可能参与肺纤维化的发生。     

Rheumatoid Arthritis Increases the Risk of Nontuberculosis Mycobacterial Disease and Active Pulmonary Tuberculosis

Background

Few studies have examined the association of rheumatoid arthritis (RA) with nontuberculosis mycobacterium (NTM) disease and pulmonary tuberculosis (PTB).

Methods

We identified 29 131 patients with RA from the catastrophic illness registry who were diagnosed from 1998–2008; 116 524 patients without RA from inpatient data files were randomly frequency matched according to sex, age, and index year and used as a comparison group. Both groups were followed-up until the end of 2010 to measure the incidence of NTM disease and active PTB. We analyzed the risk of NTM disease and active PTB using the Cox proportional hazards regression models, controlling for sex, age, and Charlson comorbidity index (CCI).

Results

The incidence of NTM disease was 4.22 times greater in the RA group than in the non-RA group (1.91 vs 0.45 per 10,000 person-years). The incidence of PTB was 2.99 times greater in the RA group than in the non-RA group (25.3 vs 8.46 per 10,000 person-years). After adjusting for age, sex, and CCI, the adjusted hazard ratios (HRs) of NTM disease and active PTB for the RA group were 4.17 (95% CI = 2.61–6.65) and 2.87 (95% CI = 2.55–3.23), respectively, compared with the non-RA group. In the first 2 years of follow-up, the RA group yielded corresponding adjusted HRs of 4.98 and 3.39 compared with the non-RA group. The follow-up time-specific RA group to the non-RA group HR of both the NTM disease and active PTB varied.

Conclusion

This study can serve as a reference for clinical physicians to increase awareness regarding the detection of NTM disease and active PTB in RA patients among the any stage of the clinical course even without CCI.     

Promoter polymorphism MMP-1 (-1607 2G/1G) and MMP-3 (-1612 5A/6A) in development of HAND and modulation of pathogenesis of HAND

The pathogenesis of HIV-associated neurocognitive disorder (HAND) is modulated by host genetic susceptibility factors such as Matrix metalloproteinases (MMPs). Promoter polymorphism of MMP-1 and MMP-3 may modify the expression of the gene. Hence, we evaluated the association of MMP-1-16072G/1G and MMP-3-1612 5A/6A polymorphisms with development of HAND and the modulation of pathogenesis of HAND. We enrolled a total of 180 individuals, 50 HIV-infected individuals with HAND, 130 without HAND, and 150 healthy controls. Polymorphism of MMP-1 and MMP-3 were genotyped by PCR-RFLP. MMP-1-1607 2G1G, -16071G/2G-1G/1G genotypes and -1607 1G allele were associated with the development of HAND (OR = 1.64, P = 0.05; OR = 1.45, P = 0.04; OR = 1.69, P = 0.05). MMP-1-16071G1G, MMP-3-16125A5A genotypes increased the risk for the development of HAND (OR = 1.78, P = 0.25; OR = 2.39, P = 0.13). MMP-3-1612 5A5A, -1612 6A/5A-5A/5A genotypes and -1612 5A allele were associated with the reduced risk of HAND (OR = 0.40, P = 0.05; OR = 0.53, P = 0.04; OR = 0.40, P = 0.01). Haplotype 5A1G increased the risk of development of HAND (OR = 1.93, P = 0.05). As observed in advanced HIV disease stage, MMP-1-1607 1G1G genotype enhance the risk for advancement of HIV disease (OR = 1.69, P = 0.89). MMP-3-1612 6A5A genotype showed higher risk for development of HAND in alcohol users (0R = 1.65, P = 0.44). MMP-1 genotype may have an influence on development of HAND whereas MMP3-1612 5A5A genotype may reduce risk for pathogenesis of HAND.     

我国肺结核发病率的发展动向及预测研究

目的:揭示我国肺结核发病率的发展方向,为预防工作的顺利开展提供事前预测工具.方法:本文采用灰色GM(1,1)模型及其改进形式对过去十年我国肺结核发病率的统计数据加以分析处理,得到最优灰色模型,并通过该模型时我国未来几年肺结核发病率情况作出预测.结果:通过该最优模型时我国未来几年肺结核发病率的预测可知,若按照目前这种形势发展下,我国肺结核发病率将逐年升高,且在2013年将突破100/10万人次.结论:肺结核发病率在我国有上升的趋势,若不加以控制,将威胁整个民族的健康,加强基础卫生医疗设施的建设,完善医保体制改革,做到早发现、早治疗仍是我国未来几年控制肺结核的重点工作.     

Functional polymorphism of the MMP-1 promoter (-1607 1G/2G) in potentially malignant and malignant head and neck lesions in an Indian population

Matrix metalloproteinases (MMP) are a family of zinc-dependent proteases that degrade the entire component of the extracellular matrix. Our study explores the association of the MMP1 gene promoter (-1607 1G/2G) polymorphisms in oral submucous fibrosis (OSMF) and head and neck squamous cell carcinoma (HNSCC) in an Indian population. The MMP1single-nucleotide polymorphism (SNP) was genotyped by polymerase chain reaction–restriction fragment length polymorphism analysis in 412 patients with OSMF, 422 with HNSCC and 426 controls. Our results showed that the frequency of 1G/2G or 2G/2G promoter genotypes having the 2G allele is associated with higher enzymatic activity and significantly increases in OSMF (p<0.001) and HNSCC cases (p<0.00). In this study, results concluded that SNPs in the MMP1 promoter region may be associated with susceptibility to OSMF as well as HNSCC in an Indian population and addiction habits such as areca nut chewing and alcohol abuse may enhance the expression of the 2G allele of MMP1 genes in OSMF and HNSCC cases.     

Involvement of Arp2/3 complex in MCP-1-induced chemotaxis

The migrating monocyte shows dynamic actin polymerization in response to MCP-1. We investigated the involvement of the actin-related protein 2 and 3 complex (Arp2/3 complex) during chemotaxis of a human monocyte cell line (THP-1). To clarify whether the Arp2/3 complex directly polymerizes actin in response to MCP-1 stimulation, THP-1 cells were transfected with complementary DNA constructs encoding ScarWA. In ScarWA-transfected cells, neither recruitment of Arp2/3 complex at the leading edge nor actin polymerization was detected. Indeed, migration induced by MCP-1 was almost completely blocked. At the same time, transfection also interfered with the recruitment of integrin beta-1 at the leading edge and reduced affinity binding to fibronectin. Immunoprecipitation with an anti-Arp2 antibody showed that integrin beta-1 and WASP were co-precipitated under the condition of MCP-1 stimulation. These results indicate that interaction between the Arp2/3 complex and WASP stimulates actin polymerization and integrin beta-1-mediated adhesion during MCP-1-induced chemotaxis of THP-1 cells.     

Proteolytic processing and inactivation of CCL2/MCP-1 by meprins

Monocyte chemotactic protein 1 (CCL2/MCP-1) is a small chemokine involved in the recruitment and trafficking of mononuclear immune cells to inflammation sites. Our studies demonstrate that the metalloendopeptidases meprin A (purified from kidney cortex), recombinant meprin α, and recombinant meprin β can all process CCL2/MCP-1. The cleavage sites were determined by amino acid sequencing and mass spectrometry analysis of the generated products, and the biological activity of the products was evaluated by chemotactic migration assay using THP-1 cells. The cleavage sites generated by the meprin isoforms revealed that meprin A and meprin α cleaved the N-terminal domain of mouse CCL2/MCP-1 at the Asn⁶ and Ala⁷ bond, resulting in significant reduction in the chemotactic activity of the cleaved CCL2/MCP-1. Meprin β was unable to cleave the N-terminus of mouse CCL2/MCP-1 but cleaved the C-terminal region between Ser⁷⁴ and Glu⁷⁵. Human CCL2/MCP-1 that lacks the murine C-terminal region was also cleaved by meprin α at the N-terminus resulting in significant loss of CCL2/MCP-1 biological activity, whereas meprin β did not affect the biological activity. These studies suggest that meprin α and meprin β may play important roles in regulating the CCL2/MCP-1 chemokine activity during inflammation.     

Inhibition of MCP-1/CCR2 pathway ameliorates the development of diabetic nephropathy

Monocyte chemoattractant protein (MCP-1) is an important mediator for macrophage recruitment in atherosclerosis and various glomerulonephritis. However, the role of MCP-1 and its receptor CCR2 in the progression of diabetic nephropathy remains unknown. Using a type 1 diabetic nephropathy model that shows noticeable glomerulosclerosis, we examined the role of MCP-1/CCR2 by propagermanium (Pro; CCR2 antagonist) treatment, and confirmed it by transfection of plasmids carrying the 7ND (a mutant of MCP-1) gene. We measured the mesangial matrix expansion, type IV collagen (Col4), transforming growth factor (TGF)-beta1 positive area, and macrophage infiltration in glomeruli after 12 weeks. Mesangial matrix expansion and macrophage infiltration were increased in diabetic mice and inhibited by Pro or 7ND-treatment. Increased glomerular expression of Col4 and TGF-beta1 in diabetic mice was also ameliorated. Thus blocking the MCP-1/CCR2 pathway ameliorated glomerulosclerosis, indicating that the MCP-1/CCR2 pathway plays a crucial role in the progression of diabetic nephropathy.     

Insertion Polymorphism of the CYP2E1 Gene in Patients with Infiltrative Pulmonary Tuberculosis from Bashkortostan

Insertion polymorphism Ins₉₆ of the CYP2E1 promoter region was for the first time studied in three ethnic groups of Bashkortostan. Population-specific features of genotype and allele frequency distributions were observed. The CYP2E1 polymorphism was associated with infiltrative pulmonary tuberculosis in the Bashkortostan population.     

Peptide Fragments and Structural Analogues of Chemokine MCP-1: Synthesis and Effect on the MCP-1-Induced Migration of Mononuclear Cells

Fourteen fragments and structural analogues of chemokine MCP-1 were synthesized using the Fmoc-strategy of solid phase peptide synthesis. The effect of synthesized peptides on the MCP-1-stimulated migration of mononuclear cells was examined. Both in vitro stimulants and inhibitors of the monocyte migration were found among the peptides. A possible participation of the C-terminal part of the MCP-1 molecule in the inhibition of the MCP-1-stimulated cell migration was found for the first time.     

Pro-MMP-9 activation by the MT1-MMP/MMP-2 axis and MMP-3: role of TIMP-2 and plasma membranes

MMP-9 (gelatinase B) is produced in a latent form (pro-MMP-9) that requires activation to achieve catalytic activity. Previously, we showed that MMP-2 (gelatinase A) is an activator of pro-MMP-9 in solution. However, in cultured cells pro-MMP-9 remains in a latent form even in the presence of MMP-2. Since pro-MMP-2 is activated on the cell surface by MT1-MMP in a process that requires TIMP-2, we investigated the role of the MT1-MMP/MMP-2 axis and TIMPs in mediating pro-MMP-9 activation. Full pro-MMP-9 activation was accomplished via a cascade of zymogen activation initiated by MT1-MMP and mediated by MMP-2 in a process that is tightly regulated by TIMPs. We show that TIMP-2 by regulating pro-MMP-2 activation can also act as a positive regulator of pro-MMP-9 activation. Also, activation of pro-MMP-9 by MMP-2 or MMP-3 was more efficient in the presence of purified plasma membrane fractions than activation in a soluble phase or in live cells, suggesting that concentration of pro-MMP-9 in the pericellular space may favor activation and catalytic competence.     

The 4G/4G Genotype of PAI-1 Polymorphism Is Associated with Higher Plasma PAI-1 Concentrations and Mortality in Patients with Severe Sepsis

Objective

Two studies have reported that patients with the 4G/4G genotype of the plasminogen activator inhibitor-1 (PAI-1) genetic polymorphism had higher plasma PAI-1 concentrations and higher risk of death than those with the 4G/5G or 5G/5G genotypes; one study involved 175 children with meningococcal disease, and the other included 88 adult patients with septic shock. Thus, the objective of this study was to determine whether there is an association between carriage of the 4G/4G genotype, plasma PAI-1 concentrations and mortality in a large series of adult septic patients.

Methods

An observational, prospective, multicenter study was carried out in six Spanish Intensive Care Units including severe septic patients. We determined the PAI-1 4G/5G polymorphism and plasma PAI-1 concentrations in all patients. The end-points of the study were 30-day and 6-month mortality.

Results

We included a total of 260 patients, 82 (31.5%) with 4G/4G, 126 (48.5%) with 4G/5G and 52 (20.0%) with 5G/5G genotype. Multivariate logistic regression analysis showed that the 4G/4G genotype was associated with higher mortality at 30 days (Odds Ratio = 1.95; 95% CI = 1.063–3.561; p = 0.03) and at 6 months (Odds Ratio = 2.19; 95% CI = 1.221–3.934; p = 0.01), and that higher plasma PAI-1 concentrations were associated with higher mortality at 30 days (Odds Ratio = 1.01; 95% CI = 1.002–1.022; p = 0.02) at 6 months (Odds Ratio = 1.01; 95% CI = 1.003–1.023; p = 0.01). Multivariate linear regression analysis showed that increased plasma PAI-1 concentrations were associated with the PAI-1 4G/4G genotype (regression coefficient = 4.82; 95% CI = 3.227 to 6.406; p<0.001).

Conclusions

The major findings of our study, to our knowledge the largest series reporting data about 4G/5G polymorphism of the PAI-1 gene, plasma PAI-1 concentrations and mortality in septic patients, were that septic patients with the 4G/4G genotype had higher plasma PAI-1 concentrations and higher risk of death than those with 4G/5G or 5G/5G genotypes.