Next Article in Journal
Exploring the Continuum of Hypertrophic Cardiomyopathy—From DNA to Clinical Expression
Previous Article in Journal
Different Patterns of HIV-1 Replication in MACROPHAGES is Led by Co-Receptor Usage
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Association between P2X7 Polymorphisms and Susceptibility to Tuberculosis: An Updated Meta-Analysis of Case-Control Studies

1
Genetics of Non-communicable Disease Research Center, Zahedan University of Medical Sciences, Zahedan 9816743463, Iran
2
Department of Genetics, School of Medicine, Zahedan University of Medical Sciences, Zahedan 9816743463, Iran
3
Children and Adolescent Health Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan 9816743111, Iran
4
Department of Clinical Biochemistry, Iranshahr University of Medical Sciences, Iranshahr 9916643535, Iran
5
Infectious Diseases and Tropical Medicine Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan 9816743111, Iran
6
Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Sciences, Zahedan 9816743175, Iran
*
Author to whom correspondence should be addressed.
Medicina 2019, 55(6), 298; https://doi.org/10.3390/medicina55060298
Submission received: 21 February 2019 / Revised: 25 April 2019 / Accepted: 18 June 2019 / Published: 21 June 2019

Abstract

:
Background and Objectives: Several studies inspected the impact of P2X7 polymorphisms on individual susceptibility to tuberculosis (TB), but the findings are still controversial and inconclusive. To achieve a more precise estimation, we conducted a meta-analysis of all eligible studies on the association between P2X7 polymorphisms and TB risk. Materials and Methods: Relevant studies were identified by searching the PubMed, Web of Science, Scopus and Google scholar databases up to November 2018. Twenty-four full-text articles were included in our meta-analysis. The strength of association between P2X7 polymorphisms and TB risk was evaluated by odds ratios (ORs) and 95% confidence intervals (95% CIs) under five genetic models. Results: The findings of this meta-analysis revealed that the rs3751143 variant significantly increased the risk of TB in heterozygous codominant (OR = 1.44, 95%CI = 1.17–1.78, p = 0.0006, AC vs. AA), homozygous codominant (OR = 1.87, 95% CI = 1.40–2.49, p = 0.0004, CC vs. AA), dominant (OR = 1.50, 95% CI = 1.22–1.85, p = 0.0002, AC + CC vs. AA), recessive (OR = 1.61, 95% CI = 1.25–2.07, p = 0.001, CC vs. AC + AA), and allele (OR = 1.41, 95% CI = 1.19–1.67, p < 0.0001, C vs. A) genetic models. Stratified analysis showed that rs3751143 increased the risk of pulmonary tuberculosis (PTB) and extrapulmonary tuberculosis (EPTB) in all genetic models. Furthermore, the rs3751143 increased risk of TB in the Asian population. The findings did not support an association between the rs2393799, rs1718119, rs208294, rs7958311, and rs2230911 polymorphisms of P2X7 and TB risk. Conclusions: The findings of this meta-analysis suggest that P2X7 rs3751143 polymorphism may play a role in susceptibility to TB in the Asian population. More well-designed studies are required to elucidate the exact role of P2X7 polymorphisms on TB development.

1. Introduction

Tuberculosis (TB) is a chronic infectious disease caused by the bacillus Mycobacterium tuberculosis (MTB). It remains a serious public global health problem. According to the World Health Organization (WHO) report, there were an estimated 10.4 million new cases of TB worldwide and approximately 1.3 million deaths in 2016 [1]. Approximately one-third of the general population is currently infected with Mtb, and nearly 5–10% of these infected individuals will progress to active TB [2,3]. Mounting evidence has proposed that host genetic factors play an important role in determining inter-individual difference in susceptibility to TB [4,5,6].
The human P2X7 gene is mapped to chromosome 12 (12q24.31). It encodes cell-surface nucleotide receptors called P2X7 receptor (P2X7R) [7]. The P2X7R, a ligand-gated cation channel, is highly expressed on macrophages and other immune cells [8]. Activation of P2X7R by extracellular adenosine triphosphate (eATP) causes immediate opening of a cation selective channel, permitting the influx of Ca2+ and Na+ and the efflux of K+ [9]. In M. tuberculosis infection, activation of the P2X7R promotes a range of signaling cascades leading to the apoptosis of MTB-infected macrophages [10,11].
The P2X7R gene is indeed polymorphic. The precise correlation between the P2X7 polymorphisms and susceptibility to TB is not completely documented. Several single nucleotide polymorphisms (SNPs) have been revealed that affect the function of this receptor which cause P2X7R loss-of-function (LOF) or gain-of-function (GOF) [8]. Many studies have inspected the association between P2X7 polymorphisms and risk of tuberculosis in various populations, but the findings were inconsistent [12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35]. So we conducted an updated meta-analysis of all available eligible case-control studies published to date, focusing on the association between P2X7 polymorphisms and tuberculosis risk.

2. Methods

2.1. Literature Search

The PubMed, Web of Science, Scopus, and Google scholar databases for all potentially eligible research articles up to November 2018 on the relationship between P2X7 polymorphisms and TB risk were searched. The search key words used were “P2X7 or P2X7R” and “tuberculosis” and “polymorphism or variant”. Figure 1 shows the process of recognizing eligible studies. The inclusion criteria were as follows: case-control studies focusing on the association between P2X7 polymorphisms and TB risk; the frequencies distribution of alleles and genotypes in patients and controls can be extracted. The exclusion criteria were studies that are not associated with P2X7 polymorphisms and TB risk; overlapping data, conference papers, reviews, meta-analyses; no sufficient data reported.

2.2. Data Extraction

Two investigators independently inspected and evaluated the articles for eligibility according to inclusion and exclusion criteria. The following data were recorded from the selected studies such as the first author’s name, publication year, ethnicity, genotyping methods, genotype and allelic profile, as well as the source of controls.

2.3. Statistical Analysis

The chi-square test was used to check whether genotypes within the controls conformed to the Hardy-Weinberg equilibrium (HWE). We calculated the pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) to assess the association between the P2X7 polymorphisms and TB susceptibility. The significance of the pooled OR was determined by the Z-test, and a p-value less than 0.05 was considered significant. Heterogeneity between the studies was estimated by Q statistic and the I2 test. p < 0.10 designated significant heterogeneity. If heterogeneity did not exist, a fixed-effects model was used to calculate the pooled ORs; otherwise, a random-effects model was utilized.
Publication bias was inspected with the funnel plot and an asymmetric plot suggests a possible publication bias. Funnel plot asymmetry was further measured using Egger’s linear regression test. p value < 0.05 was considered a significant publication bias. Sensitivity analysis was done by neglecting each study in turn to assess the quality and consistency of the results. All statistical analyses were executed using STATA v14.1 software (College Station, TX, USA).

3. Results

3.1. Study Characteristics

Through a comprehensive literature search and selection based on the inclusion criteria, 59 relevant case-control studies from 24 selected articles [12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35] were included in the pooled analysis. There were 30 studies with 5247 cases and 7614 controls on rs3751143 (1513A > C), 19 studies with 3235 cases and 4685 controls on rs2393799 (−762 C > T), 3 studies with 2185 cases and 2107 controls on rs1718119 (Thr348Ala), 3 studies with 1994 cases and 2037 controls on rs208294 (His155Tyr), 2 studies with 2000 cases and 2006 controls on rs7958311, 2 studies with 1853 cases and 1797 controls on rs2230911 included into meta-analysis. The main characteristics of included studies are shown in Table 1.

3.2. Main Analysis Results

The Forest plots were applied to show meta-analysis results for each genetic model. Overall, the rs3751143 variant significantly increased the risk of TB in heterozygous codominant (OR = 1.44, 95% CI = 1.17–1.78, p = 0.0006, AC vs. AA), homozygous codominant (OR = 1.87, 95% CI = 1.40–2.49, p = 0.0004, CC vs. AA), dominant (OR = 1.50, 95% CI = 1.22–1.85, p = 0.0002, AC + CC vs. AA), recessive (OR = 1.61, 95% CI = 1.25–2.07, p = 0.001, CC vs. AC + AA), and allele (OR = 1.41, 95% CI = 1.19–1.67, p < 0.0001, C vs. A) genetic models (Table 2 and Figure 2).
No significant association was found between P2X7 rs2393799, rs1718119, rs208294, rs7958311, and rs2230911 polymorphisms and TB risk (Table 2).

3.3. Subgroup Analysis Results

Stratified analysis was achieved (Table 3). The findings proposed that rs3751143 polymorphism increased the risk of pulmonary tuberculosis (PTB) and extrapulmonary tuberculosis (EPTB) in all genetic models. Besides, this polymorphism only contributes to the risk of TB in the Asian population, but not in the Caucasian population (Table 3). The rs2393799 polymorphism was not associated with the risk of TB in the Asian population (Table 3).

3.4. Heterogeneity and Publication Bias

In our study, relatively obvious heterogeneities existed under all five genetic models for rs3751143 and rs2393799 (Table 2). For rs1718119, heterogeneities were not observed under all genetic models. For rs208294, heterogeneities were not observed under heterozygous codominant and recessive genetic models. For rs7958311, heterogeneities were not observed under heterozygous codominant and for rs2230911 variant, heterogeneities were not observed under heterozygous codominant and dominant models.
Begg’s tests were done with funnel plot to assess publication bias. Publication bias was found for rs3751143 under five genetic models (Table 2 and Figure 3).
The Begg’s tests indicated no evidence of publication bias for rs2393799, rs1718119, and rs208294 (Table 2) under all genetic models.

3.5. Sensitivity Analysis

To better inspect the impact of individual study on the pooled OR, we performed sensitivity analysis through deleting each study one by one. Outcomes indicated that ORs were not statistically influenced in all genetic models for rs3751143 (Figure 4), as well as for rs2393799, showing that our results are stable and reliable.

4. Discussion

Mounting evidence proposed that host genetic factors are implicated in tuberculosis susceptibility [4,6]. The P2X7R is highly expressed on macrophages and other immune cells [8]. It is a key molecule in the clearance of MTB in macrophages by adenosine triphosphate (ATP)-induced apoptosis of macrophage [8,10]. P2X7 is polymorphic and several studies investigated the impact of P2X7 polymorphisms on predisposition to TB [12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35]. But these studies failed to reach a consistent conclusion. Therefore, to provide a comprehensive and reliable conclusion, we conducted the present meta- analysis to increase the statistical power of the association. Our findings suggest the P2X7 rs3751143 (Glu498Ala) polymorphism significantly increased the risk of overall TB. Stratified analysis of this polymorphism significantly increased the risk of PTB and EPTB. Also, the rs3751143 polymorphism increased the risk of TB in the Asian population. Findings did not support an association between rs2393799 (−762 C > T), rs1718119 (Thr348Ala), rs208294 (His155Tyr), rs7958311 (Arg270His), and rs2230911(Thr357Ser) polymorphisms and TB risk.
Ge et al. [36] performed a meta-analysis (n = 10) on the association between P2X7 rs3751143 polymorphism and PTB risk and found that this variant significantly increased the risk of PTB. Another meta-analysis (n = 11) performed by Alshammari et al. [37] showed no significant association between rs3751143 polymorphism and risk of TB. Stratified analysis revealed an association between this variant and the risk of TB in the Asian population. The results of a meta-analysis of 8 studies indicated that rs3751143 polymorphism significantly increased the risk of EPTB [38]. Another meta-analysis of 9 studies conducted by Wu et al. [39] revealed that rs3751143 significantly increased the risk of TB. A meta-analysis published by Yi et al. [40] on the association between rs2393799 (−762 C > T) polymorphism and TB susceptibility indicated that this variant is associated with TB risk. Our meta-analysis has more advantages than previous meta-analyses. We included a higher number of relevant published studies. Besides, we evaluated 6 polymorphisms in this meta-analysis.
Several polymorphisms have been described that cause P2X7R loss-of-function (LOF) or gain-of-function (GOF) [8]. The common polymorphism of P2X7 is rs3751143 (A1513C; Glu498Ala) polymorphism located in exon 13, accountable for LOF. This polymorphism affects the sensitivity of P2X7R to ATP and may contribute to increased susceptibility to MTB infection in humans [13,14,41]. The findings of the present meta-analysis support an association between rs3751143 polymorphism and the risk of TB. Another LOF polymorphism is rs2393799 (−762 C > T), which is located in the promoter of P2X7 and decrease the expression of P2X7R. The relationship between the rs2393799 polymorphism and susceptibility to TB is still debated [12,13,14,17,18,19,21,23,27,28,29,31,32,33,34], and pooled analysis of all available data did not support an association between this variant and susceptibility to TB. The rs208294 (489 C > T; His155Tyr) is GOF polymorphism. This polymorphism increases the affinity of P2X7R to ATP [42]. Limited studies investigated the impact of this polymorphism on TB susceptibility [14,30,34]. Pooled analysis revealed no evidence of association between this variant and TB risk.
Up until now, only 3 studies investigated the association between rs1718119 (1068 G > A; Thr348Ala) polymorphism and TB risk [30,31,34]. Our findings did not support an association between this polymorphism and TB risk.
Porphyromonas gingivalis, a bacterial carcinogen, plays a key role in cancer development by inhibiting apoptosis through several mechanisms. It has been shown that this bacterium secretes an anti-apoptotic enzyme nucleoside diphosphate kinase (NDK) which cleaves ATP and prevents proapoptotic P2X7 receptor activation, consequently modulating ATP/P2X7-signaling pathway [43]. It has been proposed that MTB secrete NDK, which act as a Rho-GTPase-activating protein (Rho-GAP), and covert Guanosine triphosphate (GTP)-bound active form to guanosine diphosphate (GDP)-bound inactive form, eventually facilitating its pathogenesis [44].
Some limitations of our meta-analysis should be acknowledged. Firstly, heterogeneity between studies was evident, which might distort the conclusion of this meta-analysis. Heterogeneity may be partly arising in the differences of ethnicities. Secondly, the sample sizes for some polymorphisms were small. Therefore, the results of this meta-analysis should be interpreted with caution.
Despite these limitations, however, there are still some advantages to having done this meta-analysis. First, this meta-analysis involved more studies than the previous meta-analyses, so the statistical power of our study is higher than the published meta-analysis. Second, we evaluated six polymorphisms of P2X7.

5. Conclusions

Overall, our meta-analysis proposed that P2X7 rs3751143 polymorphism may serve as a risk factor for TB in the Asian population. However, further well-designed studies with large sample sizes are necessary to confirm our findings.

Author Contributions

M.T., designed the study. H.S. and A.M.-R. searched the literatures and extracted the data. M.H. performed the statistical analyses. M.T. and M.H. wrote the manuscript. All authors read and approved the manuscript.

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest, financial or otherwise.

References

  1. WHO. Global Tuberculosis Report; WHO: Geneva, Switzerland, 2017. [Google Scholar]
  2. Trebucq, A.; Schwoebel, V. Numbers of tuberculosis cases: Dreams and reality. Int. J. Tuberc. Lung Dis. 2016, 20, 1288–1292. [Google Scholar] [CrossRef] [PubMed]
  3. Zumla, A.; Raviglione, M.; Hafner, R.; von Reyn, C.F. Tuberculosis. N. Engl. J. Med. 2013, 368, 745–755. [Google Scholar] [CrossRef] [PubMed]
  4. Naderi, M.; Hashemi, M.; Ansari, H. Macrophage migration inhibitory factor −173 G > C polymorphism and risk of tuberculosis: A meta-analysis. EXCLI J. 2017, 16, 313–320. [Google Scholar] [PubMed]
  5. Naderi, M.; Hashemi, M.; Mirshekari, H.; Bahari, G.; Taheri, M. Toll-like Receptor 1 Polymorphisms Increased the Risk of Pulmonary Tuberculosis in an Iranian Population Sample. Biomed. Environ. Sci. 2016, 29, 825–828. [Google Scholar] [PubMed]
  6. Qiu, Y.; Cao, S.; Gou, C.; Yue, Y.; Jiang, S.; Ma, T.; Xue, X. Associations of tumor necrosis factor-alpha polymorphisms with the risk of tuberculosis: A meta-analysis. Scand. J. Immunol. 2018, e12719. [Google Scholar] [CrossRef] [PubMed]
  7. Ralevic, V.; Burnstock, G. Receptors for purines and pyrimidines. Pharmacol. Rev. 1998, 50, 413–492. [Google Scholar] [PubMed]
  8. Miller, C.M.; Boulter, N.R.; Fuller, S.J.; Zakrzewski, A.M.; Lees, M.P.; Saunders, B.M.; Wiley, J.S.; Smith, N.C. The role of the P2X7 receptor in infectious diseases. PLoS Pathog. 2011, 7, e1002212. [Google Scholar] [CrossRef] [PubMed]
  9. Khakh, B.S.; North, R.A. P2X receptors as cell-surface ATP sensors in health and disease. Nature 2006, 442, 527–532. [Google Scholar] [CrossRef]
  10. Placido, R.; Auricchio, G.; Falzoni, S.; Battistini, L.; Colizzi, V.; Brunetti, E.; Di Virgilio, F.; Mancino, G. P2X7 purinergic receptors and extracellular ATP mediate apoptosis of human monocytes/macrophages infected with Mycobacterium tuberculosis reducing the intracellular bacterial viability. Cell. Immunol. 2006, 244, 10–18. [Google Scholar] [CrossRef]
  11. Fairbairn, I.P.; Stober, C.B.; Kumararatne, D.S.; Lammas, D.A. ATP-mediated killing of intracellular mycobacteria by macrophages is a P2X7-dependent process inducing bacterial death by phagosome-lysosome fusion. J. Immunol. 2001, 167, 3300–3307. [Google Scholar] [CrossRef]
  12. Amiri, A.; Sabooteh, T.; Ahmadi, S.A.Y.; Azargoon, A.; Shahsavar, F. Association of P2X7 gene common polymorphisms with pulmonary tuberculosis in Lur population of Iran. Egypt. J. Med Hum. Genet. 2018, 19, 231–234. [Google Scholar] [CrossRef]
  13. Ben-Selma, W.; Ben-Kahla, I.; Boukadida, J.; Harizi, H. Contribution of the P2X7 1513A/C loss-of-function polymorphism to extrapulmonary tuberculosis susceptibility in Tunisian populations. FEMS Immunol. Med. Microbiol. 2011, 63, 65–72. [Google Scholar] [CrossRef] [PubMed]
  14. Chaudhary, A.; Singh, J.P.; Sehajpal, P.K.; Sarin, B.C. P2X7 receptor polymorphisms and susceptibility to tuberculosis in a North Indian Punjabi population. Int. J. Tuberc. Lung Dis. 2018, 22, 884–889. [Google Scholar] [CrossRef] [PubMed]
  15. De, R.; Kundu, J.K. Tuberculosis risk in P2X7 1513A/C polymorphism of the tribes of Jhargram, West Bengal. Int. J. Zool. Stud. 2017, 2, 189–193. [Google Scholar]
  16. Fernando, S.L.; Saunders, B.M.; Sluyter, R.; Skarratt, K.K.; Goldberg, H.; Marks, G.B.; Wiley, J.S.; Britton, W.J. A polymorphism in the P2X7 gene increases susceptibility to extrapulmonary tuberculosis. Am. J. Respir. Crit. Care Med. 2007, 175, 360–366. [Google Scholar] [CrossRef]
  17. Li, C.M.; Campbell, S.J.; Kumararatne, D.S.; Bellamy, R.; Ruwende, C.; McAdam, K.P.; Hill, A.V.; Lammas, D.A. Association of a polymorphism in the P2X7 gene with tuberculosis in a Gambian population. J. Infect. Dis. 2002, 186, 1458–1462. [Google Scholar] [CrossRef]
  18. Mokrousov, I.; Sapozhnikova, N.; Narvskaya, O. Mycobacterium tuberculosis co-existence with humans: Making an imprint on the macrophage P2X7 receptor gene? J. Med. Microbiol. 2008, 57, 581–584. [Google Scholar] [CrossRef]
  19. Nino-Moreno, P.; Portales-Perez, D.; Hernandez-Castro, B.; Portales-Cervantes, L.; Flores-Meraz, V.; Baranda, L.; Gómez-Gómez, A.; Acuña-Alonzo, V.; Granados, J.; González-Amaro, R. P2X7 and NRAMP1/SLC11 A1 gene polymorphisms in Mexican mestizo patients with pulmonary tuberculosis. Clin. Exp. Immunol. 2007, 148, 469–477. [Google Scholar] [CrossRef]
  20. Ozdemir, F.A.; Erol, D.; Konar, V.; Yuce, H.; Kara Senli, E.; Bulut, F.; Deveci, F. Lack of association of 1513 A/C polymorphism in P2X7 gene with susceptibility to pulmonary and extrapulmonary tuberculosis. Tuberkuloz ve toraks 2014, 62, 7–11. [Google Scholar] [CrossRef]
  21. Sambasivan, V.; Murthy, K.J.; Reddy, R.; Vijayalakshimi, V.; Hasan, Q. P2X7 gene polymorphisms and risk assessment for pulmonary tuberculosis in Asian Indians. Dis. Markers 2010, 28, 43–48. [Google Scholar] [CrossRef]
  22. Sharma, S.; Kumar, V.; Khosla, R.; Kajal, N.; Sarin, B.; Sehajpal, P. Association of P2X7 receptor +1513 (A-->C) polymorphism with tuberculosis in a Punjabi population. Int. J. Tuberc. Lung Dis. 2010, 14, 1159–1163. [Google Scholar] [PubMed]
  23. Singla, N.; Gupta, D.; Joshi, A.; Batra, N.; Singh, J. Genetic polymorphisms in the P2X7 gene and its association with susceptibility to tuberculosis. Int. J. Tuberc. Lung Dis. 2012, 16, 224–229. [Google Scholar] [CrossRef] [PubMed]
  24. De Lima, D.S.; Ogusku, M.M.; Sadahiro, A.; Pontillo, A. Inflammasome genetics contributes to the development and control of active pulmonary tuberculosis. Infect. Genet. Evol. 2016, 41, 240–244. [Google Scholar] [CrossRef] [PubMed]
  25. Taype, C.A.; Shamsuzzaman, S.; Accinelli, R.A.; Espinoza, J.R.; Shaw, M.A. Genetic susceptibility to different clinical forms of tuberculosis in the Peruvian population. Infect. Genet. Evol. 2010, 10, 495–504. [Google Scholar] [CrossRef] [PubMed]
  26. Tekin, D.; Kayaalti, Z.; Dalgic, N.; Cakir, E.; Soylemezoglu, T.; Kutlubay, B.I.; Kilic, B.A. Polymorphism in the P2X7 gene increases susceptibility to extrapulmonary tuberculosis in Turkish children. Pediatr. Infect. Dis. J. 2010, 29, 779–782. [Google Scholar] [CrossRef]
  27. Velayati, A.A.; Farnia, P.; Farahbod, A.M.; Karahrudi, M.A.; Derakhshaninezhad, Z.; Kazampour, M.; Sheikhghomi, S.; Saeif, S. Association of receptors, purinergic P2X7 and tumor necrosis factor-alpha gene polymorphisms in susceptibility to tuberculosis among Iranian patients. Arch. Clin. Infect. Dis. 2013. [Google Scholar] [CrossRef]
  28. Wu, J.; Lu, L.; Zhang, L.; Ding, Y.; Wu, F.; Zuo, W.; Zhang, W. Single Nucleotide Polymorphisms in P2X7 Gene Are Associated with Serum Immunoglobulin G Responses to Mycobacterium tuberculosis in Tuberculosis Patients. Dis. Markers 2015, 2015, 671272. [Google Scholar] [CrossRef] [PubMed]
  29. Xiao, J.; Sun, L.; Jiao, W.; Li, Z.; Zhao, S.; Li, H.; Jin, J.; Jiao, A.; Guo, Y.; Jiang, Z.; et al. Lack of association between polymorphisms in the P2X7 gene and tuberculosis in a Chinese Han population. FEMS Immunol. Med. Microbiol. 2009, 55, 107–111. [Google Scholar] [CrossRef]
  30. Zheng, X.; Li, T.; Chen, Y.; Pan, H.; Zhang, Z.; Dai, Y.; Wang, J. Genetic polymorphisms of the P2X7 gene associated with susceptibility to and prognosis of pulmonary tuberculosis. Infect. Genet. Evol. 2017, 53, 24–29. [Google Scholar] [CrossRef]
  31. Bahari, G.; Hashemi, M.; Taheri, M.; Naderi, M.; Moazeni-Roodi, A.; Kouhpayeh, H.R.; Eskandari-Nasab, E. Association of P2X7 gene polymorphisms with susceptibility to pulmonary tuberculosis in Zahedan, Southeast Iran. Genet. Mol. Res. GMR 2013, 12, 160–166. [Google Scholar] [CrossRef]
  32. Shamsi, M.; Zolfaghari, M.R.; Farnia, P. Association of IFN-gamma and P2X7 Receptor Gene Polymorphisms in Susceptibility to Tuberculosis among Iranian Patients. Acta Microbiol. Immunol. Hung. 2016, 63, 93–101. [Google Scholar] [CrossRef] [PubMed]
  33. Songane, M.; Kleinnijenhuis, J.; Alisjahbana, B.; Sahiratmadja, E.; Parwati, I.; Oosting, M.; Plantinga, T.S.; Joosten, L.A.; Netea, M.G.; Ottenhoff, T.H.; et al. Polymorphisms in autophagy genes and susceptibility to tuberculosis. PLoS ONE 2012, 7, e41618. [Google Scholar] [CrossRef] [PubMed]
  34. Zhou, Y.; Tan, C.Y.; Mo, Z.J.; Gao, Q.L.; He, D.; Li, J.; Huang, R.F.; Li, Y.B.; Guo, C.F.; Guo, Q.; et al. P2X7 receptor in spinal tuberculosis: Gene polymorphisms and protein levels in Chinese Han population. Infect. Genet. Evol. 2018, 57, 138–144. [Google Scholar] [CrossRef]
  35. Zhu, X.; Guo, W.; Ren, G.; He, X.; Hu, Q.; Zhang, Y.; Kang, L.; Yuan, D.; Jin, T. P2X7R Gene Polymorphisms are Associated with Increased Risk of Pulmonary Tuberculosis in the Tibetan Chinese Population. Am. J. Trop. Med. Hyg. 2016, 95, 1016–1020. [Google Scholar] [CrossRef] [PubMed]
  36. Ge, H.B.; Chen, S. A meta-analysis of P2X7 gene-1513A/C polymorphism and pulmonary tuberculosis susceptibility. Hum. Immunol. 2016, 77, 126–130. [Google Scholar] [CrossRef]
  37. Alshammari, E.M.; Mandal, R.K.; Wahid, M.; Dar, S.A.; Jawed, A.; Areeshi, M.Y.; Khan, S.; Khan, M.E.A.; Panda, A.K.; Haque, S. Genetic association study of P2X7 A1513C (rs 3751143) polymorphism and susceptibility to pulmonary tuberculosis: A meta-analysis based on the findings of 11 case-control studies. Asian Pac. J. Trop. Med. 2016, 9, 1150–1157. [Google Scholar] [CrossRef] [PubMed]
  38. Areeshi, M.Y.; Mandal, R.K.; Dar, S.; Wahid, M.; Khan, M.E.; Panda, A.K.; Jawed, A.; Haque, S. P2X7 1513 A>C Polymorphism Confers Increased Risk of Extrapulmonary Tuberculosis: A Meta-analysis of Case-Control Studies. Curr. Genom. 2015, 17, 450–458. [Google Scholar] [CrossRef]
  39. Wu, G.; Zhao, M.; Gu, X.; Yao, Y.; Liu, H.; Song, Y. The effect of P2X7 receptor 1513 polymorphism on susceptibility to tuberculosis: A meta-analysis. Infect. Genet. Evol. 2014, 24, 82–91. [Google Scholar] [CrossRef]
  40. Yi, L.; Cheng, D.; Shi, H.; Huo, X.; Zhang, K.; Zhen, G. A meta-analysis of P2X7 gene-762T/C polymorphism and pulmonary tuberculosis susceptibility. PLoS ONE 2014, 9, e96359. [Google Scholar] [CrossRef]
  41. Wesselius, A.; Bours, M.J.; Arts, I.C.; Theunisz, E.H.; Geusens, P.; Dagnelie, P.C. The P2X7 loss-of-function Glu496Ala polymorphism affects ex vivo cytokine release and protects against the cytotoxic effects of high ATP-levels. BMC Immunol. 2012, 13, 64. [Google Scholar] [CrossRef]
  42. Cabrini, G.; Falzoni, S.; Forchap, S.L.; Pellegatti, P.; Balboni, A.; Agostini, P.; Cuneo, A.; Castoldi, G.; Baricordi, O.R.; Di Virgilio, F. A His-155 to Tyr polymorphism confers gain-of-function to the human P2X7 receptor of human leukemic lymphocytes. J. Immunol. 2005, 175, 82–89. [Google Scholar] [CrossRef] [PubMed]
  43. Karpinski, T.M. Role of Oral Microbiota in Cancer Development. Microorganisms 2019, 7, 20. [Google Scholar] [CrossRef] [PubMed]
  44. Chopra, P.; Koduri, H.; Singh, R.; Koul, A.; Ghildiyal, M.; Sharma, K.; Tyagi, A.K.; Singh, Y. Nucleoside diphosphate kinase of Mycobacterium tuberculosis acts as GTPase-activating protein for Rho-GTPases. FEBS Lett. 2004, 571, 212–216. [Google Scholar] [CrossRef] [PubMed]
Figure 1. Flow chart illustrates the detailed study selection process of this meta-analysis.
Figure 1. Flow chart illustrates the detailed study selection process of this meta-analysis.
Medicina 55 00298 g001
Figure 2. The forest plot for association between P2X7 rs3751143 polymorphism and tuberculosis risk under allelic genetic model (C vs. A).
Figure 2. The forest plot for association between P2X7 rs3751143 polymorphism and tuberculosis risk under allelic genetic model (C vs. A).
Medicina 55 00298 g002
Figure 3. The funnel plot for the test of publication bias. The funnel plot for rs3751143 polymorphism under allele genetic model (C vs. A).
Figure 3. The funnel plot for the test of publication bias. The funnel plot for rs3751143 polymorphism under allele genetic model (C vs. A).
Medicina 55 00298 g003
Figure 4. Sensitivity analyses for studies on P2X7 rs3751143 polymorphism and the risk of tuberculosis for C vs. A.
Figure 4. Sensitivity analyses for studies on P2X7 rs3751143 polymorphism and the risk of tuberculosis for C vs. A.
Medicina 55 00298 g004
Table 1. Characteristics of all studies included in the meta-analysis.
Table 1. Characteristics of all studies included in the meta-analysis.
First AuthorYearCountryEthnicityTBSource of ControlGenotyping MethodCase/ControlCasesControlsHWE (p)
rs3751143 A > C AAACCCACAAACCCAC
Amiri2018IranAsianPTBPBPCR-RFLP100/10076213173274058213862<0.001
Ben-Selma2011TunisiaAfricanPTBHBPCR-RFLP168/15013034429442104406248520.395
Ben-Selma2011TunisiaAfricanEPTBHBPCR-RFLP55/1501923136149104406248520.395
Chaudhary2018IndiaAsianPTBPBARMS-PCR145/247637391999114195113771170.315
Chaudhary2018IndiaAsianEPTBPBARMS-PCR100/2474242161267414195113771170.315
De2017IndiaAsianPTBPBPCR-RFLP56/6026181270423621393270.978
Fernando2007Southeast AsiaAsianPTBPBTaqMan56/167341758527105557265690.952
Fernando2007Southeast AsiaAsianEPTBPBTaqMan30/16791743525105557265690.952
Fernando2007AustraliaCaucasianPTBPBTaqMan49/10228210772164344162420.845
Fernando2007AustraliaCaucasianEPTBPBTaqMan50/10218284643664344162420.845
Li2002GambiaAfricanPTBHBPCR-RFLP325/29726158658070256374549450.057
Mokrousov2008RussiaCaucasianPTBHBPCR-RFLP188/1261205992997796273219330.511
Nino-Moreno2007MéxicoMixedPTBHBPCR-RFLP94/110533381394970382178420.215
Ozdemir2014TurkeyAsianPTBPBPCR-RFLP71/16044189106367663212151050.176
Ozdemir2014TurkeyAsianEPTBPBPCR-RFLP89/16047348128507663212151050.176
Sambasivan2010IndiaAsianPTBHBPCR-RFLP156/1008955122337971218163370.002
Shamsi2016IranAsianPTBHBPCR-RFLP100/100336611326883161182180.817
Sharma2010IndiaAsianPTBPBT-ARMS-PCR181/17710275427983126483300540.515
Sharma2010IndiaAsianEPTBPBT-ARMS-PCR23/17781322917126483300540.515
Singla2012IndiaAsianPTBPBPCR-RFLP286/39216211212436136258123116391450.420
Singla2012IndiaAsianEPTBPBPCR-RFLP71/3924522411230258123116391450.420
Souza de Lima2016BrazilSouth AmericanPTBHBTaqMan288/287170952343514118489144571170.450
Taype2010PeruCaucasianPTBHBPCR-RFLP498/51335213016834162347149178431830.838
Taype2010PeruCaucasianEPTBHBPCR-RFLP121/5138237220141347149178431830.838
Tekin2010TurkeyCaucasianEPTBHBPCR-RFLP74/1923928710642141465328560.595
Velayati2013IranAsianPTBHBPCR- RFLP79/5042352119393712186140.981
Wu2015ChinaAsianPTBPBPCR-RFLP103/873349211159151279129450.075
Xiao2009ChinaAsianPTBHBPCR-RFLP41/38421182602222111944561207<0.001
Xiao2009ChinaAsianEPTBHBPCR-RFLP55/38430196793122111944561207<0.001
Zheng2017ChinaAsianPTBPBTaqMan1595/15219725517224956959005447723446980.655
rs2393799
C > T
CCCTTTCTCCCTTTCT
Amiri2018IranAsianPTBPBPCR-RFLP100/100888410496495110397<0.001
Bahari2013IranAsianPTBPBARMS-PCR150/150715425196104104406248520.395
Ben-Selma2011TunisiaAfricanPTBHBARMS-PCR168/15016579589247145185792210.130
Ben-Selma2011TunisiaAfricanEPTBHBARMS-PCR55/150415362387145185792210.130
Chaudhary2018IndiaAsianPTBPBARMS-PCR145/24762671619199101111353131810.614
Chaudhary2018IndiaAsianEPTBPBARMS-PCR100/2474448813664101111353131810.614
Li2002GambiaAfricanPTBHBPCR-RFLP323/34723118182164482441401632284660.111
Mokrousov2008RussiaCaucasianPTBHBARMS190/127868717259121654616176780.093
Nino-Moreno2007MéxicoMixedPTBHBARMS92/1108325248136154451741460.275
Sambasivan2010IndiaAsianPTBHBPCR-RFLP156/100388830164148154936791210.801
Shamsi2016IranAsianPTBHBPCR-RFLP100/100199010199693110595<0.001
Singla2012IndiaAsianPTBPBARMS286/39214311528401171231143186051790.485
Singla2012IndiaAsianEPTBPBARMS71/3924025610537231143186051790.485
Songane2012IndonesiaAsianPTBPBMassARRAY842/844181413248775909177412255766922<0.001
Velayati2013IranAsianPTBHBARMS79/5010672877134705347<0.001
Wu2015ChinaAsianPTBPBPCR-RFLP103/873547211178993048481260.202
Xiao2009ChinaAsianPTBHBARMS38/384231145719208135415512170.009
Xiao2009ChinaAsianEPTBHBARMS58/384401269224208135415512170.009
Zhou2018ChinaAsainEPTBHBMass Spectrometry179/324817721239119122143593872610.137
rs1718119
G > A
GGAGAAGAGGAGAAGA
Bahari2013IranAsianPTBPBT-ARMS-PCR150/150637215198102666915201990.622
Zheng2017ChinaAsianPTBPBTaqMan1568/145410904403826205169784175923735350.087
Zhu2016ChinaAsianPTBHBMassARRAY467/50337291483599412892913930.222
rs208294
G > A
GGAGAAGAGGAGAAGA
Chaudhary2018IndiaAsianMixedPBPCR-RFLP245/246561474225923149143542412510.011
Zheng2017ChinaAsianPTBPBTaqMan1570/146759773224119261214578679210183510990.642
Zhou2018ChinaAsianEPTBHBMass
Spectrometry
179/324228077124234701451092853630.099
rs7958311
G > A
GGAGAAGAGGAGAAGA
Zheng2017ChinaAsianPTBPBTaqMan1533/150340279733416011465396775332156714390.199
Zhu2016ChinaAsianPTBHBMassARRAY467/5031142151384434911372621045364700.300
rs2230911
C > G
CCCGGGCGCCCGGGCG
Souza de Lima2016BrazilSouth AmericanPTBHBTaqMan288/28817095234351411938964751010.245
Zheng2017ChinaAsianPTBPBTaqMan1565/150910294825425405909974674524615570.274
List of abbreviations: PTB: Pulmonary Tuberculosis; TB: Tuberculosis; EPTB: Extrapulmonary Tuberculosis; PCR-RFLP: PCR-Restriction fragment length polymorphism; ARMS-PCR: Amplification-refractory mutation system-PCR; TaqMan: probes used in quantitative PCR; T-ARMS-PCR: Multiplex Tetra-Primer Amplification Refractory Mutation System-PCR; MassARRAY: Non-fluorescent detection platform utilizing mass spectrometry to accurately measure PCR-derived amplicons.
Table 2. The pooled ORs and 95% CIs for the association between P2X7 polymorphisms and tuberculosis susceptibility.
Table 2. The pooled ORs and 95% CIs for the association between P2X7 polymorphisms and tuberculosis susceptibility.
PolymorphismNo.Genetic ModelAssociation TestHeterogeneityPublication Bias Tests
OR (95%CI)ZPχ2I2 (%)PEgger’s Test
p-Value
Begg’s Test
p-Value
rs375114330AC vs. AA 1.44 (1.17–1.78)3.420.0006158.8681.70.0000.0160.016
CC vs. AA1.87 (1.40–2.49)4.260.000461.7954.70.0000.0020.047
AC + CC vs. AA1.50 (1.22–1.85)3.780.0002178.8583.80.0000.0070.018
CC vs. AC + AA1.61 (1.25–2.07)3.650.00150.7944.90.0050.0060.051
C vs. A1.41 (1.19–1.67)3.97<0.0001173.4183.30.0000.0060.066
rs239379919CT v CC1.00 (0.83–1.20)0.010.98932.3444.30.0200.4600.753
TT vs. CC0.99 (0.68–1.44)0.040.96573.5575.50.0000.9350.510
CT + TT vs. CC0.97 (0.77–1.23)0.220.82558.4169.20.0000.5570.649
TT vs. CT + CC0.99 (0.74–1.32)0.080.93871.3474.80.0000.9620.680
T vs. C0.98 (0.83–1.17)0.200.84495.1581.10.0000.6570.763
rs17181193AG vs. GG0.99 (0.86–1.13)0.160.881.1300.570.3080.602
AA vs. GG0.70 (0.49–0.99)1.990.053.56440.170.1360.117
AG + AA vs. GG0.96 (0.84–1.09)0.680.502.22100.330.3120.602
AA vs. AG + GG0.70 (0.49–1.00)1.980.053.24380.200.1410.117
G vs. A0.93 (0.83–1.04)1.240.213.49430.170.2420.602
rs2082943AG vs. GG1.03 (0.93–1.23)0.890.373.77470.150.6940.602
AA vs. GG1.18 (0.69–2.02)0.610.548.99780.0100.9000.602
AG + AA vs. GG1.16 (0.80–1.68)0.760.456.50690.040.7510.602
AA vs. AG + GG1.08 (0.78–1.49)0.470.645.60640.060.9040.602
A vs. G1.09 (0.85–1.40)0.700.498.82770.010.8600.602
rs79583112AG vs. GG1.01 (0.87–1.17)0.090.930.0200.88
AA vs. GG1.23 (0.77–1.95)0.870.385.15810.02
AG + AA vs. GG0.81 (0.50–1.31)0.870.388.09880.004
AA vs. AG + GG1.24 (0.76–2.01)0.870.388.09880.004
A vs. G1.11 (0.88–1.40)0.870.385.18810.02
rs22309112CG vs. CC1.03 (0.90–1.19)0.420.670.9500.33
GG vs. CC2.10 (0.58–7.66)1.130.266.65850.010
CG + GG vs. CC1.01 (0.88–1.16)0.130.890.2800.60
GG vs. CG + CC2.03 (0.60–6.94)1.130.266.12840.01
G vs. C1.22 (0.83–1.80)1.030.306.09840.01
List of Abbreviations: OR: Odds Ratio; CI: Confidence interval Z: Z-score; P: Probability; χ2: χ2 test; I2: I2 value.
Table 3. Stratified analysis of P2X7 polymorphisms and tuberculosis risk.
Table 3. Stratified analysis of P2X7 polymorphisms and tuberculosis risk.
ParametersNo.AC vs. AACC vs. AAAC + CC vs. AACC vs. AC + AAC vs. A
OR (95% CI)POR (95%CI)POR (95%CI)POR (95%CI)POR (95%CI)P
rs3751143
Tuberculosis
PTB211.35 (1.05–1.74)0.0201.50 (1.10–2.04)0.0101.39 (1.09–1.78)0.0091.34 (1.04–1.73)0.0201.31 (1.09–1.58)0.004
EPTB91.68 (1.17–2.42)0.0052.62 (1.19–5.78)0.0201.84 (1.21–2.79)0.0042.05 (1.07–3.93)0.0301.67 (1.16–2.42)0.006
Ethnicities
Asian191.48 (1.09–2.00)0.0101.70 (1.17–2.48)0.0061.53 (1.13–2.06)0.0061.47 (1.07–2.00)0.0201.57 (1.22–2.02)0.0005
Caucasian61.47 (0.99–2.17)0.051.56 (0.70 − 3.51)0.281.49 (0.98–2.26)0.061.36 (0.70–2.66)0.371.37 (0.96–1.97)0.09
African31.45 (0.66–3.19)0.362.16 (0.33–13.95)0.421.60 (0.62–4.13)0.331.89 (0.41–8.81)0.421.56 (0.62–3.94)0.35
rs2393799 CT vs. CCTT vs. CCCT + TT vs. CCTT vs. CT + CCC vs. T
Asian140.92 (0.74–1.14)0.440.87 (0.54–1.41)0.580.86 (0.66–1.14)0.300.92 (0.61–1.40)0.700.98 (0.83–1.17)0.84

Share and Cite

MDPI and ACS Style

Taheri, M.; Sarani, H.; Moazeni-Roodi, A.; Naderi, M.; Hashemi, M. Association between P2X7 Polymorphisms and Susceptibility to Tuberculosis: An Updated Meta-Analysis of Case-Control Studies. Medicina 2019, 55, 298. https://doi.org/10.3390/medicina55060298

AMA Style

Taheri M, Sarani H, Moazeni-Roodi A, Naderi M, Hashemi M. Association between P2X7 Polymorphisms and Susceptibility to Tuberculosis: An Updated Meta-Analysis of Case-Control Studies. Medicina. 2019; 55(6):298. https://doi.org/10.3390/medicina55060298

Chicago/Turabian Style

Taheri, Mohsen, Hosna Sarani, Abdolkarim Moazeni-Roodi, Mohammad Naderi, and Mohammad Hashemi. 2019. "Association between P2X7 Polymorphisms and Susceptibility to Tuberculosis: An Updated Meta-Analysis of Case-Control Studies" Medicina 55, no. 6: 298. https://doi.org/10.3390/medicina55060298

Article Metrics

Back to TopTop