A functional promoter polymorphism in monocyte chemoattractant protein–1 is associated with increased susceptibility to pulmonary tuberculosis

• Published in: The Journal of experimental medicine Vol. 202; no. 12; pp. 1649 - 1658
• Main Authors: Flores-Villanueva, Pedro O., Ruiz-Morales, Jorge A., Song, Chang-Hwa, Flores, Ludmila M., Jo, Eun-Kyeong, Montaño, Marta, Barnes, Peter F., Selman, Moises, Granados, Julio
• Format: Journal Article
• Language: English
• Published: United States The Rockefeller University Press 19.12.2005
• Subjects: Adult; Aged; Chemokine CCL2 - blood; Chemokine CCL2 - genetics; Chemokine CCL2 - metabolism; Chemokine CCL4; DNA Primers; Enzyme-Linked Immunosorbent Assay; Epistasis, Genetic; Genetic Predisposition to Disease; Humans; Interleukin-12 - blood; Interleukin-12 - metabolism; Interleukin-12 Subunit p40; Korea; Macrophage Inflammatory Proteins - genetics; Mexico; Middle Aged; Mycobacterium tuberculosis; Nitric Oxide Synthase Type II - genetics; Polymorphism, Single Nucleotide - genetics; Promoter Regions, Genetic - genetics; Protein Subunits - blood; Protein Subunits - metabolism; Tuberculosis, Pulmonary - genetics; Mexico; Korea
• ISSN: 0022-1007; 1540-9538; 1892-1007
• DOI: 10.1084/jem.20050126

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–1α 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.