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

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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.

Authors: Ganachari, M  Ruiz-Morales, JA  Gomez de la Torre Pretell, JC  Dinh, J  Granados, J  Flores-Villanueva, PO 
Citation: Ganachari M, etal., PLoS One. 2010 Jan 25;5(1):e8881.
RGD ID: 4891439
Pubmed: PMID:20111728   (View Abstract at PubMed)
PMCID: PMC2810343   (View Article at PubMed Central)
DOI: DOI:10.1371/journal.pone.0008881   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
pulmonary tuberculosis susceptibilityIAGP 4891439DNA:polymorphism: :-2518A>G (human)RGD 
pulmonary tuberculosis susceptibilityISOCCL2 (Homo sapiens)4891439; 4891439DNA:polymorphism: :-2518A>G (human)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Ccl2  (C-C motif chemokine ligand 2)

Genes (Mus musculus)
Ccl2  (C-C motif chemokine ligand 2)

Genes (Homo sapiens)
CCL2  (C-C motif chemokine ligand 2)

Objects referenced in this article
Gene CCL13 C-C motif chemokine ligand 13 Homo sapiens

Additional Information