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¹ Center for Biomedical Research, University of Texas Health Center at Tyler, Tyler, TX 75708
² Department of Microbiology, College of Medicine, Chungnam National University, Daejeon 301-747, South Korea
³ Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02115
⁴ Mexican Institute of Respiratory Diseases, Mexico D.F. 14080, Mexico
⁵ Department of Immunology and Rheumatology, Mexican National Institute of Medicine and Nutrition "Salvador Zubiran," Mexico D.F. 14000, Mexico

CORRESPONDENCE Pedro O. Flores-Villanueva: pedro.flores{at}UTHCT.edu

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–1 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.

Abbreviations used: ANOVA, analysis of variance; BCG, Bacillus Calmette-Guerin; BMI, body mass index; CI, confidence interval; MCP-1, monocyte chemoattractant protein–1; MIP-1, macrophage inflammatory protein–1; NOS2A, nitric oxide synthase 2A; OR, odds ratio; RANTES, regulated on activation, normal T cell expressed and secreted; SNP, single nucleotide polymorphism.

P.O. Flores-Villanueva and J.A. Ruiz-Morales contributed equally to this work.

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