1. A functional promoter polymorphism in monocyte chemoattractant protein-1 is associated with increased susceptibility to pulmonary tuberculosis.
- Author
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Flores-Villanueva PO, Ruiz-Morales JA, Song CH, Flores LM, Jo EK, Montaño M, Barnes PF, Selman M, and Granados J
- Subjects
- Adult, Aged, Chemokine CCL2 blood, Chemokine CCL4, DNA Primers, Enzyme-Linked Immunosorbent Assay, Humans, Interleukin-12 blood, Interleukin-12 Subunit p40, Korea, Macrophage Inflammatory Proteins genetics, Mexico, Middle Aged, Nitric Oxide Synthase Type II genetics, Polymorphism, Single Nucleotide genetics, Promoter Regions, Genetic genetics, Protein Subunits blood, Chemokine CCL2 genetics, Chemokine CCL2 metabolism, Epistasis, Genetic, Genetic Predisposition to Disease, Interleukin-12 metabolism, Protein Subunits metabolism, Tuberculosis, Pulmonary genetics
- Abstract
We examined the distribution of single nucleotide polymorphisms (SNPs) in nitric oxide synthase 2A, monocyte chemoattractant protein-1 (MCP-1), regulated on activation, normal T cell expressed and secreted, and macrophage inflammatory protein-1alpha genes in tuberculosis patients and healthy controls from Mexico. The odds of developing tuberculosis were 2.3- and 5.4-fold higher in carriers of MCP-1 genotypes AG and GG than in homozygous AA. Cases of homozygous GG had the highest plasma levels of MCP-1 and the lowest plasma levels of IL-12p40, and these values were negatively correlated. Furthermore, stimulation of monocytes from healthy carriers of the genotype GG with Mycobacterium tuberculosis antigens yielded higher MCP-1 and lower IL-12p40 concentrations than parallel experiments with monocytes from homozygous AA. Addition of anti-MCP-1 increased IL-12p40 levels in cultures of M. tuberculosis-stimulated monocytes from homozygous GG, and addition of exogenous MCP-1 reduced IL-12p40 production by M. tuberculosis-stimulated monocytes from homozygous AA. Furthermore, we could replicate our results in Korean subjects, in whom the odds of developing tuberculosis were 2.8- and 6.9-fold higher in carriers of MCP-1 genotypes AG and GG than in homozygous AA. Our findings suggest that persons bearing the MCP-1 genotype GG produce high concentrations of MCP-1, which inhibits production of IL-12p40 in response to M. tuberculosis and increases the likelihood that M. tuberculosis infection will progress to active pulmonary tuberculosis.
- Published
- 2005
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