A functional promoter polymorphism in monocyte chemoattractant protein-1 is associated with increased susceptibility to pulmonary tuberculosis.
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.
Flores-Villanueva
Pedro O
PO
Center for Biomedical Research, University of Texas Health Center at Tyler, Tyler, TX 75708, USA. pedro.flores@UTHCT.edu
Ruiz-Morales
Jorge A
JA
Song
Chang-Hwa
CH
Flores
Ludmila M
LM
Jo
Eun-Kyeong
EK
Montaño
Marta
M
Barnes
Peter F
PF
Selman
Moises
M
Granados
Julio
J
D000328:Adult; D000368:Aged; D018932:Chemokine CCL2 / Q000097:blood / Q000235:genetics* / Q000378:metabolism*; D054407:Chemokine CCL4; D017931:DNA Primers; D004797:Enzyme-Linked Immunosorbent Assay; D004843:Epistasis, Genetic; D020022:Genetic Predisposition to Disease; D006801:Humans; D018664:Interleukin-12 / Q000097:blood / Q000378:metabolism*; D053762:Interleukin-12 Subunit p40; D007723:Korea; D019402:Macrophage Inflammatory Proteins / Q000235:genetics; D008800:Mexico; D008875:Middle Aged; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D021122:Protein Subunits / Q000097:blood / Q000378:metabolism*; D014397:Tuberculosis, Pulmonary / Q000235:genetics*
C111835:CCL2 protein, human; D018932:Chemokine CCL2; D054407:Chemokine CCL4; D017931:DNA Primers; D053762:Interleukin-12 Subunit p40; D019402:Macrophage Inflammatory Proteins; D021122:Protein Subunits; D018664:Interleukin-12; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II