Dataset Information

Joint effect of MCP-1 genotype GG and MMP-1 genotype 2G/2G increases the likelihood of developing pulmonary tuberculosis in BCG-vaccinated individuals.

ABSTRACT: We previously reported that the -2518 MCP-1 genotype GG increases the likelihood of developing tuberculosis (TB) in non-BCG-vaccinated Mexicans and Koreans. Here, we tested the hypothesis that this genotype, alone or together with the -1607 MMP-1 functional polymorphism, increases the likelihood of developing TB in BCG-vaccinated individuals. We conducted population-based case-control studies of BCG-vaccinated individuals in Mexico and Peru that included 193 TB cases and 243 healthy tuberculin-positive controls from Mexico and 701 TB cases and 796 controls from Peru. We also performed immunohistochemistry (IHC) analysis of lymph nodes from carriers of relevant two-locus genotypes and in vitro studies to determine how these variants may operate to increase the risk of developing active disease. We report that a joint effect between the -2518 MCP-1 genotype GG and the -1607 MMP-1 genotype 2G/2G consistently increases the odds of developing TB 3.59-fold in Mexicans and 3.9-fold in Peruvians. IHC analysis of lymph nodes indicated that carriers of the two-locus genotype MCP-1 GG MMP-1 2G/2G express the highest levels of both MCP-1 and MMP-1. Carriers of these susceptibility genotypes might be at increased risk of developing TB because they produce high levels of MCP-1, which enhances the induction of MMP-1 production by M. tuberculosis-sonicate antigens to higher levels than in carriers of the other two-locus MCP-1 MMP-1 genotypes studied. This notion was supported by in vitro experiments and luciferase based promoter activity assay. MMP-1 may destabilize granuloma formation and promote tissue damage and disease progression early in the infection. Our findings may foster the development of new and personalized therapeutic approaches targeting MCP-1 and/or MMP-1.

SUBMITTER: Ganachari M

PROVIDER: S-EPMC2810343 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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Joint effect of MCP-1 genotype GG and MMP-1 genotype 2G/2G increases the likelihood of developing pulmonary tuberculosis in BCG-vaccinated individuals.

Ganachari Malathesha M Ruiz-Morales Jorge A JA Gomez de la Torre Pretell Juan C JC Dinh Jeffrey J Granados Julio J Flores-Villanueva Pedro O PO

PloS one 20100125 1

We previously reported that the -2518 MCP-1 genotype GG increases the likelihood of developing tuberculosis (TB) in non-BCG-vaccinated Mexicans and Koreans. Here, we tested the hypothesis that this genotype, alone or together with the -1607 MMP-1 functional polymorphism, increases the likelihood of developing TB in BCG-vaccinated individuals. We conducted population-based case-control studies of BCG-vaccinated individuals in Mexico and Peru that included 193 TB cases and 243 healthy tuberculin-p ...[more]

PMID: 20111728

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Project description:BackgroundOsteoarthritis (OA) is a common disease characterized by articular cartilage degeneration and secondary hyperosteogenesis. Genetic factors are associated with the occurrence of OA. While several studies have shown that the matrix metalloproteinase-1- (MMP-1-) 1607 1G/2G (rs1799750) polymorphism may be related to the occurrence and development of OA, there is inconsistency in the literature. To better estimate the relationship between the MMP-1 gene polymorphism and OA, a comprehensive meta-analysis of relevant literature was carried out.ResultsIn total, seven studies comprising 1245 OA patients and 1230 controls were included in this meta-analysis. The combined results revealed no significant association between the MMP-1-1607 1G/2G polymorphism and risk of OA in the five genetic models. However, after Bonferroni correction, the results of subgroup analysis revealed a significant correlation between the MMP-1-1607 1G/2G polymorphism and OA susceptibility in the temporomandibular joint (TMJ) OA subgroup (allelic: 2G vs. 1G: OR = 1.575, 95%CI = 1.259-1.972, P < 0.01; recessive: 2G2G vs. 1G1G+1G2G: OR = 2.411, 95%CI = 1.658-3.504, P < 0.01; and homozygote: 2G2G vs. 1G1G: OR = 2.313, 95%CI = 1.341, 3.991, P = 0.003), the younger subgroup (aged less than 60 years; allelic: 2G vs. 1G: OR = 1.635, 95%CI = 1.354, 1.974, P < 0.01; dominant: 2G1G+2G2G vs. 1G1G: OR = 1.622, 95%CI = 1.158, 2.271, P = 0.005; recessive: 2G2G vs. 1G1G+1G2G: OR = 2.209, 95%CI = 1.718, 2.840, P < 0.01; and homozygote: 2G2G vs. 1G1G: OR = 2.578, 95%CI = 1.798, 3.696, P < 0.01), the larger subgroup (N > 300), and the hospital-based case-control study (HCC) subgroup. The sensitivity analysis suggested that the results of the meta-analysis were stable and reliable. Begg's funnel plot and Egger's test indicated that there was no publication bias in this study.ConclusionOur meta-analysis indicated that although the MMP-1-1607 1G/2G polymorphism was not significantly associated with OA susceptibility among the whole sample, it played a key role in the etiology and development of TMJ OA and OA in people aged less than 60 years.

Project description:OBJECTIVES:To investigate the safety and immunogenicity of a booster BCG vaccination delivered intradermally in healthy, BCG vaccinated subjects and to compare with a previous clinical trial where BCG vaccinated subjects were boosted with a new TB vaccine, MVA85A. DESIGN:Phase I open label observational trial, in the UK. Healthy, HIV-negative, BCG vaccinated adults were recruited and vaccinated with BCG. The primary outcome was safety; the secondary outcome was cellular immune responses to antigen 85, overlapping peptides of antigen 85A and tuberculin purified protein derivative (PPD) detected by ex vivo interferon-gamma (IFN-gamma) ELISpot assay and flow cytometry. RESULTS AND CONCLUSIONS:BCG revaccination (BCG-BCG) was well tolerated, and boosting of pre-existing PPD-specific T cell responses was observed. However, when these results were compared with data from a previous clinical trial, where BCG was boosted with MVA85A (BCG-MVA85A), MVA85A induced significantly higher levels (>2-fold) of antigen 85-specific CD4+ T cells (both antigen and peptide pool responses) than boosting with BCG, up to 52 weeks post-vaccination (p = 0.009). To identify antigen 85A-specific CD8+ T cells that were not detectable by ex vivo ELISpot and flow cytometry, dendritic cells (DC) were used to amplify CD8+ T cells from PBMC samples. We observed low, but detectable levels of antigen 85A-specific CD8+ T cells producing IFNgamma (1.5% of total CD8 population) in the BCG primed subjects after BCG boosting in 1 (20%) of 5 subjects. In contrast, in BCG-MVA85A vaccinated subjects, high levels of antigen 85A-specific CD8+ T cells (up to 14% total CD8 population) were observed after boosting with MVA85A, in 4 (50%) of 8 subjects evaluated. In conclusion, revaccination with BCG resulted in modest boosting of pre-existing immune responses to PPD and antigen 85, but vaccination with BCG-MVA85A induced a significantly higher response to antigen 85 and generated a higher frequency of antigen 85A-specific CD8+ T cells. TRIAL REGISTRATION:ClinicalTrials.gov NCT00654316 NCT00427830.

Dataset Information

Joint effect of MCP-1 genotype GG and MMP-1 genotype 2G/2G increases the likelihood of developing pulmonary tuberculosis in BCG-vaccinated individuals.

Publications

Joint effect of MCP-1 genotype GG and MMP-1 genotype 2G/2G increases the likelihood of developing pulmonary tuberculosis in BCG-vaccinated individuals.

Similar Datasets

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