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

被引:211
作者
Flores-Villanueva, PO [1 ]
Ruiz-Morales, JA
Song, CH
Flores, LM
Jo, EK
Montaño, M
Barnes, PF
Selman, M
Granados, J
机构
[1] Univ Texas Hlth Ctr, Ctr Biomed Res, Tyler, TX 75708 USA
[2] Chungnam Natl Univ, Coll Med, Dept Microbiol, Taejon 301747, South Korea
[3] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA
[4] Mexican Inst Resp Dis, Mexico City 14080, DF, Mexico
[5] Mexican Natl Inst Med & Nutr Salvador Zubiran, Dept Immunol & Rheumatol, Mexico City 14000, DF, Mexico
关键词
D O I
10.1084/jem.20050126
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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 alpha 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.
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收藏
页码:1649 / 1658
页数:10
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