P2X7 and NRAMP1/SLC11 A1 gene polymorphisms in Mexican mestizo patients with pulmonary tuberculosis

Abstract

SummaryTuberculosis remains one of the most important infectious diseases worldwide. Several studies have suggested that genetic factors may affect susceptibility to tuberculosis, but the specific genes involved have not yet been fully characterized. NRAMP1/SLC11 A1 and P2X7 genes have been linked to increased risk for tuberculosis in some African and Asiatic populations. To explore the potential role of these genes in the susceptibility to pulmonary tuberculosis in a Mexican mestizo population, we evaluated the association of D543N and 3Ј-UTR polymorphisms in NRAMP1/SLC11 A1 and -762 and A1513C polymorphisms in P2X7 genes with the risk for tuberculosis. Polymerase chain reaction (PCR) amplification of genomic DNA followed by restriction fragment length polymorphism analysis, and allelic-specific PCR was employed. We found no significant differences in allelic frequency in NRAMP1/SLC11 A1 gene polymorphisms in 94 patients with tuberculosis compared to 100 healthy contacts. Similarly, no significant association of the P2X7-762 gene polymorphism with tuberculosis was detected. In contrast, the P2X7 A1513C polymorphism was associated significantly with tuberculosis (P = 0·02, odds ratio = 5·28, 95% CI, 0·99-37·69), an association that had not been reported previously. However, when the function of P2X7 was assessed by an l-selectin loss assay, we did not find significant differences in patients compared to healthy contacts or between PPD + and PPD -control individuals. This study further supports the complex role of P2X7 gene in host regulation of Mycobacterium tuberculosis infection, and demonstrates that different associations of gene polymorphisms and tuberculosis are found in distinct racial populations.

P2X7 receptors regulate multiple types of membrane trafficking responses and non-classical secretion pathways

“…Given the ability of various P2Y family receptors to regulate Ca 2+ and lipid signaling, it seems likely that P2X7 and various P2Y receptors act cooperatively to mediate the actions of extracellular ATP on killing of internalized mycobacteria or chlamydia. Such an interaction between P2X7R and another P2 receptor subtype(s) could explain the disparate associations of particular P2X7R polymorphisms with altered progression of tubercular phenotypes within different subgroups of human populations or mouse models [64,[68][69][70][71][72][73][74][75].…”

Cell signaling via the P2X7 nucleotide receptor: linkage to ROS production, gene transcription, and receptor trafficking

“…Investigations evaluating the significance of P2X 7 polymorphisms and overall protein expression levels support the idea that cells need to correctly respond to extracellular ATP via P2X 7 for the mediation of several functions, including neurotransmission, mycobacterial killing, and appropriate cell death. Genetic analyses have linked P2X 7 polymorphisms to Mycobacterium tuberculosis (TB) infection and bipolar affective disorder [13,14,28,29]. The P2X 7 A1513C polymorphism, which results in mutation of Glu496 to Ala, has been associated with TB in two different population groups [13,14], and one report has shown that a SNP located in the promoter at position −762 is protective against the bacterium [28].…”

“…There are two P2 receptor subfamilies, the seven-transmembrane spanning P2Y G-protein-coupled receptors and the double membrane spanning P2X cation channels. There are at least eight P2Y family members (P2Y 1-2 , P2Y 4 , P2Y 6 , P2Y [11][12][13][14] ) and seven P2X receptors (P2X 1-7 ) [8,9]. All of the P2X receptors contain a short (<35 amino acids) intracellular N-terminal region, a large extracellular nucleotide-binding domain, and an intracellular C-terminus.…”

“…Given that animal and human genetic studies support the concept that P2X 7 is a major immune modulator and may be an effective therapeutic target [11][12][13][14][27][28][29], in this report, we will discuss several key events associated with P2X 7 signaling and trafficking, with an emphasis on their role in mediating/regulating the immune responses of monocytic cells. Specifically, we will provide evidence that P2X 7 stimulation in macrophages promotes ROS production via the extracellular-regulated kinases-1 and 2 (ERK1/2) and the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex, and that ligand binding to P2X 7 results in activation of the transcription factor cyclic-AMP response element-binding protein (CREB) and the expression of key components of the transcription factor activating protein-1 (AP-1) complex.…”

“…The stimulation of P2X receptors, in particular P2X 7 , has been implicated as a key process in a variety of inflammatory conditions, including sepsis, arthritis, extrapulmonary tuberculosis, granuloma formation, and Alzheimer's disease [10][11][12][13][14][15][16]. P2X 7 is unique among the other P2X receptors in that it requires high concentrations (millimolar) of ATP, such as those observed at sites of inflammation, to be activated.…”