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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 10  |  Issue : 3  |  Page : 243-254

Ethnicity based comprehensive evaluation of polymorphism in interferon-gamma gene and its association with pulmonary and extra-pulmonary tuberculosis risk: An updated trial sequential meta-analysis


Department of Zoology and DS Kothari Central Facility for Interdisciplinary Research, Miranda House, University of Delhi, Delhi, India

Date of Submission08-May-2021
Date of Decision17-Jun-2021
Date of Acceptance20-Jun-2021
Date of Web Publication03-Sep-2021

Correspondence Address:
Sadhna Sharma
Department of Zoology, Miranda House, University of Delhi, Delhi - 110 007
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijmy.ijmy_108_21

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  Abstract 


Background: Host genetic background plays an important role in susceptibility to intracellular infectious pathogens like Mycobacterium tuberculosis (Mtb). Cellular immune response activation is vital for protection to these pathogens. Interferon-gamma (IFN-γ) plays a crucial role in this activation and preventing the intracellular growth of Mtb. A mutation in the IFN-γ gene, therefore, may lead to increased susceptibility to tuberculosis (TB) that may vary in different ethnic groups and its consequence also varies in pulmonary and extra-pulmonary TB (EPTB). Several IFN-γ gene polymorphisms are investigated for susceptibility to TB, but their associations are not always consistent as its impact may vary from one ethnicity to the other as well as with the type of TB. Hence, we performed a meta-analysis to overcome this problem. The present study involves comprehensive meta-analysis of + 874T/A polymorphism in the IFN-γ gene based on type of TB within five different ethnic groups to show its association with increased susceptibility to TB. Methods: Using PubMed and Google Scholar databases, a total of 50 case-control studies were retrieved having 8152 cases and 9755 controls in this meta-analysis. Thirty-eight studies of + 874T/A polymorphism of IFN-γ gene were correlated for Pooled odds ratios with 95% confidence intervals. The polymorphism was analyzed for six genetic models for five major ethnic groups accounting for heterogeneity among studies. Moreover, the sub-group analysis was based on the type of TB within each ethnic group. Trial sequential analysis was also performed for all the sub-groups to estimate the statistical consistency. Results: IFN-γ +874 T/A polymorphism analysis clearly confirmed the increased association of + 874AA genotype with increased TB risk. This polymorphism also showed significant association in East Asian, European, American, and African ethnic groups whereas no such association was found in Asians. Patients with pulmonary TB (PTB) confirmed the association in East Asians, Africans, and Americans, whereas patients with EPTB showed association in Asian and East Asian populations only. Conclusions: This study reaffirms the association of IFN-γ+874 T/A polymorphism with TB risk. It specifically confirms that IFN-γ+874 T/A polymorphism increases the susceptibility of pulmonary infection in Africans and Americans, while the East Asian population is more susceptible to both, pulmonary and EPTB.

Keywords: Ethnicity, gene polymorphism, interferon gamma, meta-analysis, pulmonary tuberculosis and extra-pulmonary tuberculosis, tuberculosis


How to cite this article:
Priyanka, Sharma M, Sharma S. Ethnicity based comprehensive evaluation of polymorphism in interferon-gamma gene and its association with pulmonary and extra-pulmonary tuberculosis risk: An updated trial sequential meta-analysis. Int J Mycobacteriol 2021;10:243-54

How to cite this URL:
Priyanka, Sharma M, Sharma S. Ethnicity based comprehensive evaluation of polymorphism in interferon-gamma gene and its association with pulmonary and extra-pulmonary tuberculosis risk: An updated trial sequential meta-analysis. Int J Mycobacteriol [serial online] 2021 [cited 2021 Dec 8];10:243-54. Available from: https://www.ijmyco.org/text.asp?2021/10/3/243/325486




  Introduction Top


Tuberculosis (TB) is an infectious disease caused by a slow-growing filamentous gram-positive bacterium, Mycobacterium tuberculosis (Mtb). The infection occurs through aerosols from diseased individuals via sneezing, coughing, talking, etc., and reaches lung alveoli.[1] This evokes an inflammatory response leading to immune cell accumulation primarily macrophages which phagocytize Mtb. Eighty-five percent (85%) TB cases are of pulmonary infection called pulmonary TB (PTB) but Mtb can infect several organs by migrating to regional lymph nodes causing Extra-pulmonary TB (EPTB).[2] Mtb can persist in dormant form within the host for years without causing any symptoms of disease. This condition is known as latent TB and such individuals have 10%–15% higher risk of progression from infection to active TB in the host lifetime.[3] According to WHO 2019 global TB report, TB is still one of the top 10 causes of death worldwide and the leading cause of death from a single infectious agent. Globally 10 million people fell ill with TB in 2018, but the TB burden is comparatively falling globally at about 2% per year but that is not fast enough (WHO, 2020).

Several factors influence the host-pathogen interaction in the development of TB. A major role in this is being played by the host genetic factors.[4] The other nongenetic factors such as malnutrition, HIV infection, diabetes, smoking, and alcohol abuse also increases the risk of developing TB disease.[5],[6] The complex immune defense against Mtb infection involves interaction between macrophages and CD4 T-lymphocytes. The ensuing cytokine production of interferon-gamma (IFN-γ), tumor necrosis factor-α, and Interleukin-12 is involved in protection against intracellular Mtb infection.[7] IFN-γ is the most decisive cytokine in humans regarding its role in susceptibility to TB which is produced by activated T-cells and natural killer (NK) cells to eliminate Mtb via both innate and adaptive immunity.[8] IFN-γ is a pro-inflammatory and regulatory cytokine. It enhances the expression of MHC complex proteins on the cell surface, thereby increasing the antigen presentation and promotes the differentiation of CD4 T-lymphocytes to TH1 sub-population.[9] In most of TB patients, the production of IFN-γ is found to be low, while after anti-TB treatment their levels are increased.[10] There are various polymorphisms within the host genes that increase the risk of TB by producing a low level of cytokines.[11],[12]

IFN-γ gene is present on chromosome 12q15 in humans which is about 5.4 Kb in length and composed of 4 exons and 3 introns.[13] It is a highly conserved gene and plays an important role in susceptibility to TB. Mutation in the IFN-γ gene in humans leads to increased susceptibility to pathogenic as well as nonpathogenic mycobacterial species.[14] The IFN-γ +874T/A polymorphism is located in the first intron at 874 base pairs downstream from the translation start site. This polymorphism is globally studied among numerous infectious diseases including TB and also in other noninfectious diseases.[15],[16],[17] Various other polymorphisms are also found within the IFN-γ gene at different positions like +2109 A/G[18],[19] +3234C/T in the third intron and variable number of CA repeats showing polymorphism at 875 base pairs in the first intron of the IFN-γ gene[20],[21],[22] but only a limited number of studies are available which could not describe the adequate effect of the polymorphism with that of the TB susceptibility or severity. Within IFN-γ gene, +874T/A (rs2430561) is the most significant and most studied single nucleotide polymorphism (SNP) located in intron-1 which directly alters the level of IFN-γ production by blocking the site of transcription factor NF-kB. This leads to varied gene expression and cytokine secretion. The AA genotype of IFN-γ +874T/A lowers the cytokine production in TB patients.[11] IFN-γ acts through the IFN-γ receptor and genetic defects in IFN-γ receptors or lack of its expression on target cells also result in increased susceptibility to TB and even dissemination of infection after vaccination with Bacillus Calmette-Guerin strain. Genetic variations specific to ethnicity both in IFN-γ gene and IFN-γ receptor 1 gene has been found to greatly influence the immunity of the host to TB.[11],[22],[23],[24] Accordingly, studies were reported showing the association of +874 T/A polymorphism in IFN-γ in various ethnic populations with TB and other diseases. However, studies on population with different ethnic group show variability in their genetic diversity. To overcome the problem of conflicting results in the association of IFN-γ polymorphism with TB in ethnicity-specific variations among population of different regions, we performed a meta-analysis by grouping the population of different ethnic groups altogether from the studies performed in different regions of the world. The analysis was also done by further categorizing these ethnic groups based on pulmonary or extra-pulmonary infection. Moreover, the trial sequential analysis (TSA) was also performed to nullify the statistical errors and to get an estimation of the statistical consistency of our meta-analysis data. This strengthened the postulated genetic association of genetic variant (+874T/A) in the IFN-γ gene with TB susceptibility. This study provides consistent results showing the association of regional ethnicity-specific genetic variability of IFN-γ gene with PTB and EPTB susceptibility.

The present meta-analysis aims to answer the question that does +874T/A polymorphism leads to susceptibility and severity of only PTB or does it affect the EPTB also and does this susceptibility to PTB and EPTB has any concordance with the ethnicity. This updated meta-analysis study reconciles all the studies published for a particular polymorphic region in the IFN-γ gene to ascertain the role played by this polymorphism in TB susceptibility.


  Methods Top


Study design

This meta-analysis study was conducted to investigate the association between the risk of TB and the +874T/A (rs2430561) (Variation in the IFNG expression regulatory regions) gene polymorphism within the IFN-γ gene. Using the databases, the relevant articles were searched that were evaluating the correlation between the TB risk and the IFN-γ gene polymorphisms. The selected case-control studies were compiled altogether for determining the Pooled Odd Ratios (ORs) and 95% Confidence Intervals (CIs) using all the six genetic models namely, dominant model (AA vs. AT + TT), recessive model (TT vs. AT + AA), over-dominant model (AT vs. AA + TT), additive homozygous model (TT vs. AA), additive heterozygous model (AT vs. AA) and the allelic model (A vs. T). Meta-analysis heterogeneity was assessed to determine the degree of dissimilarity in the results of individual studies on the basis of which the fixed or random-effects model is selected.

Along with the overall analysis, we narrowed down our study based on ethnicity. The ethnicity-based samples were further sub-categorized into two categories: 1) cases with PTB infection and 2) cases with EPTB infection. This stratified subgroup analysis was done to improve the impact of this meta-analysis.

Search strategy

A comprehensive search was made in PubMed and Google Scholar to extract all the potentially relevant articles evaluating the correlation between the TB risk and the relevant IFN-γ gene polymorphisms. The search was made using the keywords “IFN-γ,” “polymorphism or mutation” and “tuberculosis.” The titles and abstracts were analyzed and only the relevant case-control studies about +874T/A IFN-γ gene polymorphism and tuberculosis risk correlation and having the required data were finally selected. The major data collected from the case-control studies was the sample size, ethnicity, type of TB in patients (PTB or EPTB), genotype frequency, ORs and 95% CI and any other relevant information.

Data extraction

A total of 189 (2002–2018) articles were searched from Pubmed and Google Scholar databases, using the keywords in December 2019 as described in the search strategy. Most of the articles were found common among these two databases, so duplicate records were removed. After analyzing the titles and abstracts, 71 articles were rejected because they were related to other cytokines, discussing polymorphism about other diseases, or focusing on interferon-gamma receptor. Meta-analysis studies and review articles were also excluded. Thirty-eight studies that examined the association of IFN-γ gene polymorphism with TB were finally included as shown in [Figure S1]. The flow chart was prepared using PRISMA recommendations.[25] From each article, the following data were extracted: Name of the first author, year of publication, ethnicity, type of TB patients, number of controls and patients, genotype distribution among cases and controls for +874T/A IFN-gene polymorphisms, and conclusion from each study in the form of association (A) or no association (NA) with the polymorphism.



Overall, 50 case-control studies were retrieved having 8152 cases and 9755 controls. The cases were patients either having PTB or EPTB including Spinal TB and Genital TB, while the controls were the healthy population.

Statistical analysis

The strength of association between IFN-γ gene polymorphism and TB risk was assessed by OR with the corresponding 95% CI. All the genetic models were used to evaluate the Pooled OR using both the random-effects as well as the fixed effects models depending upon the heterogeneity analysis. Heterogeneity among studies was assessed by I2 (inconsistency) based Q statistic, with statistical significance. I2 value is independent of the number of studies included in the meta-analysis, but it actually quantifies the effect of heterogeneity.[26] The random-effects model assesses the variance between the studies as well as the sampling errors within the studies whereas the fixed effects model assesses only the intra-study sampling errors.[27] The significance of the Pooled OR was determined by the Chi-square test which describes the association of a polymorphic genotype with TB susceptibility where P < 0.05 was considered as statistically significant. Sensitivity analysis was also performed by sequentially excluding individual study to check the stability of the result and no particular study was found to affect the overall result. Publication bias was examined via Begg's funnel plot and Egger's test. Egger's regression test evaluates the asymmetry in the funnel plot via OR's natural logarithmic scale. HWE was tested by Pearson Chi-square test.[28] The meta-analysis was performed using Comprehensive Meta-analysis software Version 3 (https://www.meta-analysis.com/).

Stratified analysis

This meta-analysis groups the population of different ethnic groups altogether from the studies performed in different regions of the world. All the case-control studies included in quantitative synthesis from different regions of the world is grouped altogether in five different ethnic groups as follows:

  1. ASIANS (12 studies)-Includes population of 3 Asian countries namely, India,[8] Pakistan (1) and Iran (3)
  2. EAST ASIANS-(10 studies)-Includes population of 4 countries, namely, China (7), South Korea (1), Taiwan (1), and Hong Kong (1)
  3. EUROPEANS (6 studies)-Includes population of 4 countries, namely, Turkey (3), Italy (1), Spain (1), and Croatia (1)
  4. AMERICANS (10 studies)-Includes population of 4 countries, namely, Brazil (4), USA (3), Canada (1), and Venezuela (1)
  5. AFRICANS (8 studies)-Includes population of countries, namely, South Africa (2), West Africa (1), USA (study performed in the USA on African group) (1), Tunisia (1), Brazil (1), Malawi (1), and Egypt (1).


Furthermore, these ethnicity-based groups are categorized into groups based on the type of TB as 1) PTB group and 2) EPTB group. In the subgroup of PTB cases, 7 studies were from Asian and American ethnic groups, 5 from European and African groups; and 8 studies belong to East Asian ethnic group. On the other hand, the Asian group includes 6 case-control studies with EPTB cases, East Asians and Africans include 3 studies each, 4 belong to American ethnic group while a single study under European EPTB subgroup.

Trial sequential analysis

As per the Cochrane handbook for systematic reviews of interventions, all the eligible trials must be included in a good meta-analysis. It is known that there are always chances of biasness or errors (systematic or random) while performing a meta-analysis, so it cannot be considered acceptable evidence. Therefore, to minimize these errors, statistical analysis software has been used, that is, TSA tool from Copenhagen Trial Unit, Centre for Clinical Intervention Research, Denmark. The use of this tool minimized the random errors and increased the sturdiness of the conclusion of this study. TSA adjusts the threshold of statistical significance and power to make a robust conclusion and also estimates the required information size (RIS). The confirmation of a robust conclusion is made when the TSA monitoring boundary crosses the cumulative Z-curve before the RIS is reached. This proves that robust evidence has been found and confirms no requirement of further trials. In the opposite case, the requirement of further trials becomes necessary to reach a conclusion.[26],[29],[30],[31] To perform TSA, the TSA software version 0.9.5.10 Beta was used developed by Copenhagen Trial Unit, a clinical intervention research unit in Copenhagen, Denmark (https://ctu.dk/tsa). For the analysis, the two-sided boundary was selected for hypothesis testing with 5% type 1 error using the O'Brien-Fleming alpha spending function and the O'Brien-Fleming beta spending function was adopted for constructing futility monitoring boundaries for type 2 error with 80% power. Finally, assuming 15% of plausible relative risk reduction (RRR) and correcting heterogeneity based on variance in the model, the RIS was calculated.


  Results Top


Publication bias

Begg's funnel plot and Egger's regression test were used to appraise the biasness among the included studies. Begg's funnel plot shows a symmetric inverted structure as shown in [Figure S2], while Egger's regression intercept and its P values (>0.05) for all the models do not show publication bias [Table S1]. In the stratified group of ethnicity, PTB and EPTB cases of different ethnic groups also do not have any significant biasness (except for the dominant model of Africans and homozygous models for East Asians PTB and EPTB groups). This indicates that the publication biasness of the literature does not affect this meta-analysis study.



Heterogeneity test

The heterogeneity was assessed for all the genetic models using Q-test and I2 statistics on the basis of which the selection of model for ORs calculations were done. Adequate amount of heterogeneity was detected in many of the models of all the three subgroups so we opted random-effects model for OR statistics and fixed effects model for the remaining (with no or negligible heterogeneity) [Table S1].

Minor allele frequency and Hardy Weinberg Equilibrium

The Minor allele frequency (MAF) for the five major population groups across the world was checked and compared from the 1000 Genomes Browser which was found to be 0.7198. Whereas, MAF in our analysis comes to be 0.3205 for cases and 0.369 for controls which is lower as compared to the browser [Table 1]. This confirms that “A” allele is more frequently present in the patients with IFN-γ +874 T/A polymorphism. Then we observed that all the studies, except for few studies, were in Hardy Weinberg Equilibrium (HWE) which was tested through χ2 test. This informed us that the genotype frequencies observed in the controls of included studies in different ethnic groups were in agreement with HWE except for the European population.
Table 1: Minor allele frequency and Hardy-Weinberg equilibrium data in the five included ethnic groups for interferon- Gamma +874 T/A polymorphism

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Sensitivity analysis

Sensitivity analysis was carried out by removing one study at a time to evaluate the effect of each study on the pooled OR and the analysis confirmed that it was not significantly affected by any of the individual studies. This validated the statistically robustness of the results from this meta-analysis as well as the stability of the meta-analysis.

Overall analysis

We included 38 studies having different ethnicity with the patients of pulmonary and EPTB. Overall 50 case-control studies with the association of IFN-γ +874 T/A polymorphism and TB in 8152 cases and 9755 controls were included in this meta-analysis. Children infected with TB were also considered in two of the included studies.[23],[32] A study by Moran et al. was performed on African–American, Hispanic, and Caucasian population so we analyzed these groups separately.[33] Out of these 50 studies, 29 studies showed that AA genotype was responsible for TB risk and 21 studies showed no such correlation. As significant heterogeneity was found between the studies so random-effects model was selected for forest plot and OR analysis for all the six models. A significant association in terms of increased risk was observed between IFN-γ +874 T/A polymorphism and TB in overall analysis through dominant model (OR = 1.383 [1.168–1.637], P = 0.00); homozygous model (OR = 1.644 [1.326–2.04], P = 0.00) and heterozygous model (OR = 1.4 (1.214–1.614], P = 0.00) whereas TT and AT genotypes along with A allele were shown to have reduced risk for TB through recessive model (OR = 0.718 (0.610–0.845], P = 0.00); over-dominant model (OR = 0.839 [0.731–0.862], P = 0.012); and the allelic model (OR = 0.736 [0.655–0.827], P = 0.00) for random-effects model [Table S1]. The forest plot clearly represented the increased risk in patients with AA genotype through the dominant model [Figure 1] and the protective effect of TT genotype through the recessive model [Figure 2].
Figure 1: Forest plot for overall meta-analysis showing the association of tuberculosis risk with interferon-gamma +874 T/A polymorphism through random effects dominant model (AA vs. AT + TT) confirming the role of AA genotype in tuberculosis susceptibility. The horizontal line on the forest plot represents 95% confidence interval and the small vertical lines crossing this horizontal line represent odds ratio. The red bars represent relative weight given to each study and the yellow row illustrates Pooled odds ratio with 95% confidence interval. *Studies with extra-pulmonary tuberculosis cases from the same study. 1 = Afro-American; 2 and 3 = American population from the same study

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Figure 2: Forest plot for overall meta-analysis showing the protective effect of TT genotype of interferon-gamma +874 T/A polymorphism in tuberculosis through random effects recessive model (TT vs. AT + AA). The horizontal line on the forest plot represents 95% confidence interval and the small vertical lines crossing this horizontal line represents odds ratio. The red bars represent relative weight given to each study and the yellow row illustrates Pooled odds ratio with 95% confidence interval. *Studies with extra-pulmonary tuberculosis cases from the same study. 1 = Afro-American; 2 and 3 = American population from the same study

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Ethicity-based analysis

These case-control studies were further stratified into five subgroups on the basis of ethnicity. No significant association was found between the IFN-γ +874 T/A polymorphism and TB in Asian group with 1988 cases and 1863 controls. However, in East Asians ethnic group having 2506 cases and 2824 controls, a significant correlation was observed in all the genetic models. Due to the presence of heterogeneity in dominant, heterozygous and allelic models, random effects model was considered while the fixed effects model was considered for the rest [Table S2]. For dominant (OR = 1.578 [1.066–2.336], P = 0.023); homozygous (OR = 1.863 [1.430–2.429], P = 0.00); heterozygous (OR = 1.453 [1.141–1.851], P = 0.002) and allelic model (OR = 1.576 [1.057–2.350], P = 0.026) an increased risk for TB was concluded. On the other hand, a protective role of TT and AT genotypes were also inferred through recessive (OR = 0.684 [0.557–0.840], P = 0.00) and over-dominant models (OR = 0.817 [0.722–0.924], P = 0.001). This data reconfirmed that the IFN-γ +874 T/A polymorphism increases the risk of TB in East Asian population.



The meta-analysis on European group of population with 840 cases and 948 controls also had concordance between IFN-γ polymorphism with susceptibility to TB in dominant (OR = 1.350 [1.084–1.681], P = 0.007); homozygous (OR = 1.368 [1.019–1.837], P = 0.037) and the allelic models (OR = 1.367 [1.019–1.837], P = 0.037) using the fixed effects model. On the other hand, recessive, over-dominant and heterozygous models did not get any significant result. The 1554 cases and 1667 controls of American ethnic group also had a positive correlation with TB susceptibility according to this study. Heterogeneity was seen in dominant, heterozygous and allelic models, so the analysis was done using random effects model for these models. The OR data for dominant (OR = 1.571 [1.160–2.127], P = 0.03); homozygous (OR = 2.082 [1.568–2.764], P = 0.00); heterozygous (OR = 1.439 [1.049–1.975], P = 0.024) and for allelic model (OR = 1.480 [1.208–1.814], P = 0.00) clearly signified that IFN-γ +874 T/A polymorphism in American population increases the severity to TB disease. Similar to East Asian population, Americans also show a reduced risk in TT and AT genotypes as inferred through recessive (OR = 0.578 [0.443–0.754], P = 0.00) and over-dominant models (OR = 0.800 [0.675–0.948], P = 0.01). Significant concordance was seen in African ethnic group having 2681 cases and 2471 controls. The dominant model (OR = 1.338 [1.112–1.609], P = 0.002); homozygous (OR = 1.340 [1.057–1.704], P = 0.017); heterozygous (OR = 1.271 [1.124–1.438], P = 0.00) and the allelic model (OR = 1.120 [1.10–1.324], P = 0.00) favoured the increased risk association. The over-dominant model (OR = 0.822 [0.696–0.972], P = 0.022) showed reduced risk for TB in Africans while no significant protective role of TT was observed. The dominant model was selected for forest plot using random effects model [Figure 3].
Figure 3: Forest plot for meta-analysis showing the risk of tuberculosis in five different ethnic groups with interferon-gamma +874 T/A polymorphism through dominant model (AA vs. AT + TT). (a) Asians; (b) East Asians; (c) Europeans; (d) Americans; and (e) Africans. The horizontal line on the forest plot represents 95% confidence interval and the small vertical lines crossing this horizontal line represents odds ratio. The red bars represent relative weight given to each study and the yellow row illustrates Pooled odds ratio with 95% confidence interval. Significant association was found between AA Genotype of +874 T/A polymorphism and tuberculosis in all ethnic groups except Asian

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Analysis based on the type of tuberculosis (pulmonary tuberculosis and extra-pulmonary tuberculosis)

The five ethnic groups namely Asians, East Asians, Europeans, Americans and Africans were further categorized on the basis of type of TB patients within each group.

Pulmonary tuberculosis group

East Asians PTB group (1511 cases and 2007 controls) proved a significant agreement between IFN-γ +874T/A polymorphism and TB susceptibility through dominant (OR = 1.294 [1.08–1.513). P =0.001); heterozygous (OR = 1.295 [1.1–1.526], P = 0.002) and allelic models (OR = 1.244 [1.088–1.423], P = 0.001). Over-dominant model (OR = 0.796 [0.677–0.936], P = 0.006) showed reduced risk whereas no significant association was observed in recessive and homozygous models. Almost negligible heterogeneity was seen so fixed effects model was used for OR analysis. The cases with PTB in American ethnic group (1149 cases and 1222 controls) also showed positive correlation by dominant (OR = 1.501 [1.067–2.113], P = 0.02) and allelic models (OR = 1.425 [1.143–1.776], P = 0.002) using random effects model and homozygous model (OR = 1.998 [1.449–2.755], P = 0.00) using fixed effects model. Recessive model (OR = 0.598 [0.443–0.807], P = 0.001) through fixed effects model confirmed the protective role of TT genotype. Similarly, the PTB African group (1237 cases and 1215 controls) proved increased PTB risk through dominant (OR = 1.292 [1.085–1.539], P = 0.004); heterozygous (OR = 1.324 [1.103–1.589], P = 0.003) and allelic models (OR = 1.169 [1.019–1.341], P = 0.026) in the absence of heterogeneity. Over-dominant model (OR = 0.779 [0.655–0.926], P = 0.005) showed reduced risk. No significant conclusion was made through recessive and homozygous models [Table S3]. The forest plot showed that Asian and European PTB cases had no significant association [Figure 4].
Figure 4: Forest plot for meta-analysis showing pulmonary tuberculosis risk in different ethnic groups with interferon-gamma +874 T/A polymorphism through allelic model (A allele vs. T allele). (a) Asians; (b) East Asians; (c) Europeans; (d) Americans; and (e) Africans. The horizontal line on the forest plot represents 95% confidence interval and the small vertical lines crossing this horizontal line represents odds ratio. The red bars represent relative weight given to each study and the yellow row illustrates Pooled odds ratio with 95% confidence interval. Significant association was found between +874 T/A polymorphism (AA genotype) and pulmonary tuberculosis in all ethnic groups except Asian and European

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Extra-pulmonary tuberculosis group

A significant association of IFN-γ polymorphism was proved in Asian patients with EPTB (814 cases and 1007 controls) through dominant (OR = 1.523 [1.209–1.920], P = 0.00) and heterozygous models (OR = 1.453 [1.140–1.854], P = 0.003) with no heterogeneity and through homozygous (OR = 1.786 [1.013–3.146], P = 0.045) and allelic models (OR = 1.385 [1.084–1.769], P = 0.009) with significant heterogeneity. Homogeneity was observed in East Asians EPTB cases group (609 cases and 925 controls) and a positive association between the severity of TB and IFN-γ +874T/A polymorphism was observed through dominant (OR = 2.529 [1.940–3.298], P = 0.00); heterozygous (OR = 2.333 [1.758–3.095], P = 0.00) and the allelic models (OR = 2.07 [1.701–2.519], P = 0.00). Recessive model confirmed reduced EPTB risk of TT in East Asian population (OR = 0.483 [0.337–0.692], P = 0.00) whereas no significance was found in over-dominant and homozygous models. European population had only a single study with EPTB cases. IFN-γ +874T/A polymorphism in African EPTB cases (343 cases and 442 controls) were found to be associated with disease susceptibility in fixed effects model of heterozygous model with OR = 2.165 [1.365–3.434], P = 0.001. No significant association was found in American EPTB cases [Table S4]. The forest plot in [Figure 5] depicts significant association in Asians, East Asians and Africans.
Figure 5: Forest plot for meta-analysis showing extra-pulmonary tuberculosis risk in different ethnic groups with interferon-gamma + 874 T/A polymorphism through heterozygous model (AA vs. AT). (a) Asians; (b) East Asians; (c) Americans; and (d) Africans. The horizontal line on the forest plot represents 95% confidence interval and the small vertical lines crossing this horizontal line represents odds ratio. The red bars represent relative weight given to each study and the yellow row illustrates Pooled odds ratio with 95% confidence interval. Significant association was found between + 874 T/A polymorphism (AA Genotype) and extra-pulmonary tuberculosis in Asians, East Asians and Africans

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Trial sequential analysis

TSA was used to look into the relevance of IFN-γ +874T/A gene polymorphism with PTB and EPTB susceptibility in each ethnicity-based sub-groups. TSA was performed using the data of the dominant model for all the groups and sub-groups as an example which conclude that RIS for overall analysis was 11798. RIS for five ethnic groups were found to be 7569, 11,934, 6976, 17737, and 17540 for Asians, East Asians, Europeans, Americans, and Africans. Sub-group of each ethnic group with PTB patients have RIS 8947, 3007, 11585, 6803, and 8885 for Asians, East Asians, Europeans, Americans, and Africans, respectively. On the other hand, The RIS were 6548 and 6524 for Asian EPTB patients and East Asians EPTB patients, respectively. Before reaching RIS, the cumulative Z-curve and the TSA monitoring boundary intersects in the overall study [Figure 6]a and in the East Asian sub-group with PTB patients [Figure 6]b. This confers sufficient cumulative evidence for the association of AA polymorphism and PTB risk in East Asian PTB Patients and therefore no necessity of further trials. This is also true for the overall significant association of IFN-γ +874 T/A polymorphism with PTB risk. However, TSA analysis of all other ethnic groups suggested that there is a necessity of further relevant trials without which cumulative evidence is not sufficient.
Figure 6: (a) Trial sequential analysis of interferon-gamma +874T/A gene polymorphism in all the included studies. (b) trial sequential analysis of pulmonary tuberculosis cases in East Asian population. The required information size was calculated using two-sided α =0.05, β =0.20, relative risk reduction = 15% using the data of dominant model which was found to be 117,98 and 3007 for overall analysis and East Asian pulmonary tuberculosis group respectively. The cumulative Z-curve is represented by the solid blue line. The cumulative Z-curve crosses the trial sequential analysis monitoring boundary before reaching the required information size indicating sufficient cumulative evidences

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  Discussion Top


The active protein of IFN-γ is a homo-dimer which triggers a cellular response to viral and microbial infections by binding to the interferon-gamma receptor. Any alteration in this gene or its receptor increases the susceptibility to viral, bacterial, and parasitic infections and to several autoimmune diseases. In earlier studies, we have seen that the production of the cytokine IFN-γ is pivotal in determining the effectiveness of the immune response to M. TB.[34],[35] Its significance was spotlighted in mice and humans with defects in IFN-γ and IFN-γ receptor, which resulted in profound deficiencies in response to M. tuberculosis.[36] It has long been known that IFN-γ is produced not only by CD4+ and CD8+ T cells but also by gdT cells, NK cells and NK T cells, even alveolar epithelial cells, thereby permitting rapid response in the absence of specific T-cell recognition of pathogens.[37] However, there are also reports of low levels of IFN-γ in broncho-alveolar lavage fluid as compared to peripheral blood[38] and the effect of anti-tubercular treatment on IFN-γ levels in both drug-sensitive and drug-resistant TB.[39],[40] Its importance is further shown by comparability of Tuberculin Skin Test and QuantiFERON-TB Gold In-Tube (QFT-GIT) Test in the diagnosis of TB because IFN-γ participates in the production of the results in both the tests.[41] It has been shown in a number of studies that polymorphism in the cytokine genes especially SNPs in promoter or coding regions can alter cytokine expression.[14],[42],[43],[44] Such changes in cytokine levels can affect the homeostasis of the immune response against infectious diseases including TB.[45] Therefore, genetic polymorphisms in IFN-γ have been biologically plausible candidate markers associated with individual's susceptibility to infectious diseases. There are many polymorphisms in IFN-γ genes which have been studied in association with TB risk but with inconsistent results. This inconsistency may be due to small sample size and therefore inadequate statistical power which could be overcome by a good meta-analysis. Meta-analysis studies combine a number of relevant studies, therefore, increasing the sample size to come to a statistically significant conclusion. This meta-analysis study included all the case-control studies that have discussed the major polymorphisms in the IFN-γ gene among TB patients as well as healthy individuals. The polymorphisms found at different positions within this gene have varying effects in individuals. The results also varied with varying ethnicities. The most common and the most studied IFN-γ polymorphism is at +874 position, others are at +2109,[46] +875,[47] +3234 and-1616 position[48] in IFN-γ gene. This meta-analysis evaluated the genotypic frequencies of +874 T/A polymorphic site within the IFN-γ gene among patients of different ethnic groups with PTB or EPTB patients and healthy control group in 50 selected case-control studies which is more than the previous meta-analyses. Among the 50 selected studies undertaken for +874T/A polymorphism, AA genotype showed the positive association with TB risk among individuals in 29 studies whereas 21 did not show any correlation of +874 T/A polymorphism with disease susceptibility. The susceptibility or resistance to TB might depend on the IFN-γ levels, as the TB patients' peripheral blood mononuclear cells produce less amount of IFN-γ.[49],[50] Diseased individuals with AA genotype were found to produce low levels of IFN-γ, which may lead to decreased cellular immunity while the Individuals with T allele were found to have high level of IFN-γ which helps the host's defense to get rid of Mtb infection.[43] This was also confirmed by some meta-analyses.[51],[52] In the present meta-analysis, we also found that AA genotype is positively correlated with TB disease, either pulmonary or extra-pulmonary, which is in consonance with 29 studies.

Effect of this polymorphism is not limited to TB only, but various meta-analysis studies have already proved that +874 IFN-γ gene polymorphism is associated with asthma risk[16] and hepatocellular carcinoma risk.[53] This polymorphism also increases the risk of Hepatitis virus-related diseases, mainly in the Asian population.[17] Significant association of +874 IFN-γ is also seen in patients with autoimmune diseases like Systemic Lupus Erythromatosus.[15]

In a gene polymorphism study, population varying in their ethnic background also varies in their allelic frequencies because of which susceptibility to a disease may also vary in different ethnic groups. Therefore, this meta-analysis was performed by categorizing studies in five different ethnic groups, namely, Asians, East Asians, Europeans, Americans, and Africans. East Asians are categorized separately from Asians because they have distinct genetic makeup and these groups must be evaluated independently. Earlier, the majority of the studies had considered all the Asians altogether. To the best of our knowledge, this is the first meta-analysis which has considered these two distinct ethnic groups independently. The alteration in cytokine level as the effect of gene polymorphism further impacts different TB forms in different ways. Hence, this study was conducted to investigate the influence of + 874 IFN-γ gene polymorphism on susceptibility to PTB and EPTB in these five ethnic groups. This meta-analysis inferred that the East Asian group of patients to be more susceptible to both PTB and EPTB because of the presence of frequent AA genotype (+874 IFN-γ T to A SNP) as compared to the control group. On the other hand, Asians with 'A' allele or AA genotype (+874 IFN-γ T to A SNP) are found to be more susceptible to only EPTB. TT genotype was found to have reduced EPTB risk in East Asians but no prominent role of TT genotype was observed in other ethnic groups with EPTB patients. This result was in consonance with the result of a meta-analysis by Tian et al. that T-allele carriers in Asians (including East Asians) to have a decreased risk.[21] Mandal et al. got the same result with respect to EPTB.[54] A meta-analysis by Wei et al. confirmed that Africans also have an increased risk to TB because of IFN-γ +874 T/A polymorphism[22] which was also supported by our analysis. In addition, this meta-analysis also confirmed significant risk specifically for PTB patients with AA genotype. However, no concordance was found with EPTB in Africans. Another ethnic group included in this study was European, which confirmed the role of 'A' allele or AA genotype in an increased risk of TB if both PTB and EPTB were considered together. There was only a single study with EPTB patients on Europeans. However, when a study with EPTB cases was removed from the analysis, NA with TB risk was observed in Europeans. Hence, PTB and EPTB case-control studies when considered individually were able to make confirmation of IFN-γ +874 T/A polymorphism association with TB risk. This clearly confirms that there is a great need of more case-control studies to reach a robust conclusion that whether IFN-γ +874 T/A polymorphism increases the risk of TB only in pulmonary or in extra-pulmonary infections also. As concluded by this meta-analysis, these variations in susceptibility to TB in different groups based on ethnicity confirmed the impact of genetic and regional background on disease outcome which previous studies failed to do so to the best of our knowledge. Therefore, this study overcomes the limitations of previous meta-analyses and provides superiority over previous studies.

Furthermore, to precisely investigate the genetic contribution of this variant with PTB and EPTB risk and to evaluate the sufficient level of evidence, TSA was conducted. The inferences of TSA found robust conclusions for East Asians fulfilling the RIS for patients with PTB as well as for cumulative studies. Whereas insignificant cumulative evidence was observed when East Asian EPTB patients were considered separately which is also confirmed by a study by Mandal et al.[54] This suggests that there are enough evidence in the East Asian population only with PTB patients but not with EPTB patients to confirm the significant association of IFN-γ +874 T/A polymorphism with TB susceptibility. Hence, more case-control studies based on EPTB patients are needed to make this association more evident. However, no statistically significant cumulative evidence was observed in remaining ethnic groups saying that further trials are necessary to evaluate a significant level of evidence. Therefore, it is confirmed that IFN-γ +874 T/A polymorphism (AA genotype) has surely increased the risk for susceptibility toward TB but more case-control studies need to be added specifically considering the ethnicity as well as focusing on the type of TB infection.


  Conclusions Top


In conclusion, this meta-analysis provided a confirmed and consistent association of TB and polymorphism in the IFN-γ gene at +874T/A position. We concluded that East Asian group of the population has more threat of developing TB or increasing the severity of disease in response to AA genotype of IFN-γ +874 T/A polymorphism including both PTB and EPTB. Africans and Americans with +874T/A gene polymorphism are more susceptible to PTB risk. However, more studies are required to describe the TB susceptibility in various other ethnic populations. Conclusively, this meta-analysis reinforces the importance of +874T/A IFN-γ gene polymorphic site as a genetic marker in resisting TB.

Acknowledgments

The Junior Research Fellowship to PT from the Council of Scientific and Industrial Research, Government of India is thankfully acknowledged.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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