The relationship between tumour necrosis factor-α gene polymorphism and susceptibility and clearance of the persistent hepatitis B virus infection in a Chinese population: a meta-analysis

Authors

  • T.-C. Zhang,

    1. Jiangxi Province Centre For Disease Control And Prevention, Nanchang, China
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    • Tianchen Zhang and Yuqin Zhao contributed equally to this work and should be considered as co-first authors.
  • Y.-Q. Zhao,

    1. Department of Epidemiology and Biostatistics, School of Public Health, Nanchang University, Nanchang, China
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    • Tianchen Zhang and Yuqin Zhao contributed equally to this work and should be considered as co-first authors.
  • G.-L. Hu,

    1. Jiangxi Province Centre For Disease Control And Prevention, Nanchang, China
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  • X.-Q. Liu,

    Corresponding author
    1. Jiangxi Province Centre For Disease Control And Prevention, Nanchang, China
    • Corresponding author: X.-Q. Liu, Jiangxi Province Centre For Disease Control and Prevention, 555 Beijing East Road, Nanchang, Jiangxi 330029, China

      E-mail: jorangezhang@163.com

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  • X.-K. Huang

    1. Jiangxi Province Centre For Disease Control And Prevention, Nanchang, China
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Abstract

To date, many studies conducted in the Chinese population have determined the correlation between the tumour necrosis factor-α (TNF-α)-238G/A, -308G/A, -857C/T and -863C/A polymorphisms and persistent hepatitis B virus (HBV) infection. However, their results remain inconclusive. With the aim of confirming this correlation, we performed a meta-analysis of 19 studies. The dichotomous data are presented as the OR with a 95% CI. The results of our study indicate that carriers of the TNF-α-857T allele among the pooled Chinese population were more likely to show spontaneous clearance of HBV (T vs C: OR = 0.824, 95% CI = 0.713–0.953, p 0.009; TT vs CC: OR = 0.701, 95% CI = 0.507–0.970, p 0.032; TC vs CC: OR = 0.804, 95% CI = 0.683–0.947, p 0.009; TT + TC vs CC: OR = 0.835, 95% CI = 0.716–0.974, p 0.021). The TNF-α-308A allele was associated with significantly reduced persistent HBV infection risk in the Chinese (A vs G: OR = 0.585, 95% CI = 0.456–0.751, p 0.002; AG vs GG: OR = 0.519, 95% CI = 0.341–0.789, p <0.000; AA + AG vs GG: OR = 0.512, 95% CI = 0.339–0.772, p 0.001). Persistent HBV infection susceptibility is associated with the TNF-α-308G/A gene polymorphism in the Chinese population, whereas HBV clearance is associated with the TNF-α-857C/T gene polymorphism.

Introduction

Hepatitis B is caused by the hepatitis B virus (HBV) and is a major global health concern and the most serious type of viral hepatitis. It can progress to chronic liver diseases, resulting in cirrhosis or cancer, and is potentially life-threatening. According to a World Health Organization (WHO) report, 2 billion people worldwide have been infected with the virus, and approximately 600 000 people die annually because of the consequences of hepatitis B. According to a report by the Centers for Disease Control and Prevention (CDC) of the USA, approximately 90% of infected infants and 30% of infected children aged <5 years of age become chronically infected, whereas 2–6% of adults show chronic infection. The variable pattern and clinical outcome of the infection are mainly determined by virological, host immunological, genetic and experimental factors [1].

Multiple cytokines participate in the process of viral clearance via the host immune response to HBV, including tumour necrosis factor-α (TNF-α), transforming growth factor-β and interleukin -10. Tumour necrosis factor-α plays a key role in various types of viral infections. The TNF-α gene is located 850 kb telomeric to the class III HLA-DR locus of the short arm of chromosome 6, and is closely linked to the human leucocyte antigen (HLA) gene cluster [2]. Tumour necrosis factor-α can regulate interferon-γ secretion by T helper type 1 cells and natural killer cells. It is a potent proinflammatory cytokine, mainly produced by activated macrophages, and exhibits a wide range of biological properties, including polarization of a T helper type 1 response, immune response to infectious agents, and direct antiviral effects [3]. Several lines of evidence indicate that TNF-α is important for HBV infection. It suppresses HBV expression and replication in the liver, and so induces HBV clearance. Moreover, TNF-α affects the expression of HLA-II molecules and, hence, viral antigen presentation. HLA polymorphisms are known to be associated with HBV infection outcomes [4]. Recent evidence indicates that TNF-α can induce the non-cytolytic suppression of HBV expression and replication in the liver; moreover, it can inhibit the transcriptional activity of the HBV core promoter in vitro [5]. More than ten single-nucleotide polymorphisms are present in the HBV promoter region, such as those at locations -163G/A, -238G/A, -244A/G, -308G/A, -376G/A, -575A/G, -857C/T, -863C/A, -1031T/C, -1125G/C and -1196C/T from the transcription start site. To date, more than 20 studies have investigated the -238G/A, -308G/A, -857C/T and -863C/A sites in the Chinese population but have yielded inconsistent results. This inconsistency is likely to be, in part, because these studies were limited by the small sample size and, therefore, may be underpowered for drawing a comprehensive and reliable conclusion.

Meta-analysis is a powerful method for quantitatively summarizing the results of different studies. An advantage is that it increases the sample size, which may reduce the probability that random error will result in a false-positive or false-negative association. Therefore, we performed a meta-analysis with the goal of quantitatively assessing the association of TNF-α-238G/A, -308G/A, -857C/T, and -863C/A genetic polymorphisms with persistent HBV infection cases among the Chinese population.

Materials and methods

Literature search strategy

The Medline, PubMed, Embase, Web of Science and Chinese Biomedical Literature Database on disc (CBM disc) databases were searched (the last search was updated on 26 November 2012) using the search terms “hepatitis B” or “HBV”, “polymorphism”, “Tumour necrosis factor-α” or “TNF-α”. All searches were retrieved and their bibliographies were checked for other relevant publications. Review articles and bibliographies of relevant identified studies were hand-searched. Only published studies with full-text articles were included. The topic of the studies included TNF-α gene polymorphism and persistent hepatitis B virus infections. The following types of studies were excluded: meta-analysis, reviews, studies unrelated to HBV infection and those that were conducted in non-Chinese patients. When more than one of the same patient population was included in several studies, only the study with the largest sample size or the complete study was used for this meta-analysis. A flow diagram of the study selection process is shown in Fig. 1.

Figure 1.

A flow diagram of the study selection process.

Inclusion and exclusion criteria

The inclusion and exclusion criteria were established on the basis of discussion and consensus. The inclusion criteria for patients (diagnostic criteria) were as follows: (i) individuals who spontaneously recovered without treatment and showed serological evidence of previous infection (antibodies against hepatitis B core antigen and hepatitis B surface antigen) with hepatitis B surface antigen undetectable at two time-points separated by a minimum of 6 months were self-limiting infection controls; vaccinated patients were excluded. (ii) Patients who had been positive for HBV surface antigen for more than 6 months were included as persistent HBV infection cases. (iii) Patients who did not show detectable HBV infection were defined as healthy controls. The inclusion criteria for studies were as follows: (i) case–control studies; (ii) studies that aimed to examine the association of the TNF-α-238, -308, -857 and/or -863 polymorphisms with clearance and/or susceptibility of persistent HBV infection; (iii) studies that provided the number of persistent HBV infection cases or controls and the frequency of TNF-α-238, -308, -857 and/or -863 genotypes; (4) studies in which the genotype was tested in healthy controls to ensure their compliance with the Hardy–Weinberg equilibrium.

The exclusion criteria were as follows: (i) studies that did not fit the diagnostic criteria; (ii) studies conducted in animals; (iii) studies that were not case–control studies; (iv) studies that reported data that were not relevant to the aim of the present study; (v) studies in which the data of the healthy control group deviated from the Hardy–Weinberg equilibrium; (vi) studies that did not include the Chinese Han population.

Data extraction

All of the data were extracted independently by two reviewers (T.-C. Zhang and Y.-Q. Zhao) according to the pre-specified selection criteria. Any disagreement among the authors was resolved by discussion. The following data were extracted: study design and period, statistical methods, population, number of persistent HBV infection cases (including asymptomatic carriers and chronic liver diseases), self-limiting infection controls and healthy controls studied, and the study results.

Statistical analysis

Allele frequencies at the TNF-α-238G/A, -308G/A, -857C/T, and -863C/A single-nucleotide polymorphisms from the respective studies were determined using the allele-counting method. A χ2 test was used to determine if observed frequencies of genotypes corresponded to the Hardy–Weinberg equilibrium. Statistical analysis was conducted using Stata 9.0 (StataCorp, College Station, TX, USA) and a p-value ≤0.05 was considered statistically significant. Dichotomous data are presented as the OR with 95% CI. Statistical heterogeneity was measured using the Q-statistic (p≤ 0.10 was considered to be representative of statistically significant heterogeneity). We also quantified the effect of heterogeneity using the I2 statistic, which measures the degree of inconsistency in the studies by calculating what percentage of the total variation across studies is due to heterogeneity rather than by chance. A fixed effects model was used when there was no heterogeneity in the results of the trials; otherwise, the random effects model was used. For dichotomous outcomes, patients with incomplete or missing data and small sample studies were included in the sensitivity analyses by counting them as treatment failures. To establish the effect of clinical heterogeneity between studies on the conclusions drawn from the meta-analyses, we conducted a subgroup analysis based on race. Several methods were used to assess the potential for publication bias. Visual inspection of asymmetry in funnel plots was conducted. Begg's rank correlation method and Egger's weighted regression method were also used to statistically assess the publication bias (p≤ 0.05 was considered to indicate statistically significant publication bias).

Results

Characteristics of studies

There were 19 relevant studies identified in our search. The studies comprised 5267 persistent HBV infection cases, 2021 self-limiting infection controls and 804 healthy controls, and these were included in our meta-analysis. We identified -308G/A, -857C/T and -863C/A single-nucleotide polymorphisms in our search; the characteristics of each study are presented in Appendix 1.

Quantitative data synthesis

The aim of this study was to perform a meta-analysis to quantitatively summarize the results obtained from various selected studies. Therefore, we compared the persistent HBV infection cases with healthy controls, and the persistent HBV infection cases with self-limiting infection controls. We also compared persistent HBV infection cases with healthy controls to determine the relationship of TNF-α-238G/A and -308G/A polymorphisms with persistent HBV infection susceptibility. Moreover, we compared persistent HBV infection cases with self-limiting infection controls to discover the association of TNF-α-238G/A, -308G/A, -857C/T and -863C/A polymorphisms with HBV infection clearance. Four genetic models (allele model, Co-Dominant model, Recessive model and Dominant model) were performed for each single-nucleotide polymorphism.

As shown in Table 1, the carriers of the TNF-α-857 T allele were more likely to show spontaneous clearance of HBV than were those carrying the TNF-α-857C allele genotypes, in the Chinese Han pooled population (T vs C: OR = 0.824, 95% CI = 0.713–0.953, p 0.009; TT vs CC: OR = 0.701, 95% CI = 0.507–0.970, p 0.032; TC vs CC: OR = 0.804, 95% CI = 0.683–0.947, p 0.009; TT + TC vs CC: OR = 0.835, 95% CI = 0.716–0.974, p 0.021). However, the TNF-α-238G/A, -308G/A and -857C/T polymorphisms exhibited no association with persistent hepatitis B infection clearance in the Chinese Han population.

Table 1. Characteristics and tumour necrosis factor-α (TNF-α) -238, -308, -857, -862 polymorphism genotype distributions in studies included in the meta-analysis
SNPsAuthorsYearRegionEthnicitySourceGenotypes
PHISIHC
Sample sizeSample sizeSample sizep value for HWE
  1. HBV, hepatitis B virus; HC, healthy control; HWE, Hardy–Weinberg equilibrium; PHI, persistent hepatitis B virus infection; SI, self-limiting infection; SNP, single-nucleotide polymorphism.

TNF-α-238
(GG/GA/AA)Wang [3]2012NanjingHanHospital-based57/5/059/2/0
Zhang [13]2011ShaanxiHanHospital-based180/17/1255/25/00.43
Wang [14]2010BeijingHanHospital-based139/19/0719/77/2
Kao [15]2010TaipeiUndescribedHospital-based268/6/0187/7/0
Lu [17]2004BeijingHanHospital-based203/4/0138/10/0
Li [18]2005BeijingHanHospital-based589/64/0232/12/0
Li [20]2006FuzhouHanHospital-based95/26/142/21/00.11
Chen [21]2010Hong KongUndescribedHospital-based285/18/1340/20/1
Chen [23]2011ZhengzhouHanHospital-based120/6/0115/11/00.61
Zhang [19]2005HubeiHanHospital-based126/5/0121/5/00.82
Xing [24]2007ShandongHanHospital-based135/8/090/5/00.79
Zhang [29]2004HubeiHanHospital-based126/5/0157/7/0
TNF-α-308
(GG/GA/AA)Wang [3]2012NanjingHanHospital-based51/10/151/9/1
Zhang [13]2011ShaanxiHanHospital-based179/19/0251/28/10.82
Wang [14]2010BeijingHanHospital-based700/92/6143/15/0
Kao [15]2010TaipeiUndescribedHospital-based221/38/15154/39/1
Du [16]2006BeijingHanHospital-based179/15/2128/10/5
Li [20]2006FuzhouHanHospital-based91/31/044/19/00.16
Chen [21]2010Hong KongHanHospital-based250/51/3323/36/2
Chen [23]2011ZhengzhouHanHospital-based118/8/0111/14/10.46
Zhang [19]2005HubeiHanHospital-based125/6/0108/18/00.39
Zhou [25]2004BeijingHanHospital-based413/43/083/20/0 0.32
Jiang [26]2009ShanghaiHanHospital-based145/18/671/38/100.14
Xu [27]2005ChangshaUndescribedHospital-based107/20/080/10/00.58
Zhang [29]2004HubeiHanHospital-based125/6/0143/22/0
TNF-α—857
(CC/CT/TT)Kao [15]2010TaipeiUndescribedHospital-based204/67/3142/51/1
Du [16]2006BeijingHanHospital-based156/22/18112/6/25
Li [18]2005BeijingHanHospital-based479/128/34173/60/11
Chen [21]2010Hong KongHanHospital-based210/79/15234/105/22
Qiu [22]2012HarbinHanHospital-based345/189/37100/70/19
Wan [30]2010GuangxiHanHospital-based40/29/534/26/4
Zhang [28]2004HubeiHanHospital-based106/22/3129/36/0
TNF-α–863
(CC/CA/AA)Kao [15]2010TaipeiHanHospital-based120/125/29107/65/22
Du [16]2006BeijingHanHospital-based122/50/2493/23/27
Chen [21]2010Hong KongHanHospital-based192/92/20220/116/25
Qiu [22]2012HarbinHanHospital-based333/202/36137/48/4
L iu [28]2005BeijingHanHospital-based127/50/2697/24/27
Zhang [29]2004HubeiHanHospital-based96/29/6102/60/3
Wan [30]2010GuangxiHanHospital-based50/15/938/24/2

We found no evidence of an association between the TNF-α-238G/A single-nucleotide polymorphisms and the susceptibility to persistent hepatitis B infection in the pooled Chinese population (Table 2). As shown in Table 3, the results of our meta-analysis indicate that TNF-α-308A is significantly associated with reduced persistent HBV infection susceptibility in the Chinese Han population (A vs G: OR = 0.585, 95% CI = 0.456–0.751, p 0.002; AG vs GG: OR = 0.519, 95% CI = 0.341–0.789, p <0.000; AA + AG vs GG: OR = 0.512, 95% CI = 0.339–0.772, p 0.001).

Table 2. Summary about meta-analysis on tumour necrosis factor-α (TNF-α) -238, -308, -857 and -862 in Chinese pooled population, persistent hepatitis B virus infection versus self-limiting controls
SNPGenetic modelsComparisons n OR (95% CI)HomogeneityPublication bias
ORCIp value Q PhI² (%)ModelP for Begg' testP for Egger' test
  1. SNP, single-nucleotide polymorphism.

  2. Bold: Allele, Recessive and Dominant, Statistically significant at p 0.05; Co-dominant: Statistically significant at p 0.0167.

-238 C/AAlleleA/G70.9440.596–0.4950.80612.200.05850.8Random1.0000.700
Co-dominantAA/GG20.8950.117–6.8740.9150.000.9450.0Fixed1.000
AG/GG70.9310.573–1.5130.77412.890.04553.5Random1.0000.724
RecessiveAA/AG+GG20.9080.119–6.9580.9260.010.9370.0Fixed1.000
DominantAA+AG/GG70.9360.579–1.5130.78812.750.04752.9Random1.0000.711
-308 C/AAlleleA/G60.8820.635–1.2240.45310.380.06551.8Random1.0000.915
Co-dominantAA/GG60.8880.258–3.0610.85110.990.05254.5Random0.0600.267
AG/GG60.9090.259–3.1930.88211.340.04555.9Random0.0600.281
RecessiveAA/AG+GG60.8120.635–1.0380.0967.040.21828.9Random0.7070.114
DominantAA+AG/GG60.8420.667–1.0640.1496.620.25124.5Fixed0.7070.427
-863 C/AAlleleA/C71.1460.931–1.4100.19815.150.01960.4Random1.0000.951
Co-dominantAA/CC71.0450.676–1.6160.84212.370.05451.5Random0.5480.282
AC/CC71.3641.000–1.8630.05018.210.00667.1Random0.7640.830
RecessiveAA/AC+CC70.9480.606–1.4850.81713.600.03455.9Random0.3680.253
DominantAA+AC/CC71.2220.955–1.5640.11214.000.03057.1Random0.7640.529
-857 C/TAllele T/C 7 0.824 0.7130.953 0.009 2.23 0.897 0.0 Fixed 0.368 0.239
Co-dominant TT/CC 7 0.701 0.5070.970 0.032 3.97 0.410 0.0 Fixed 0.221 0.298
TC/CC 7 0.804 0.6830.947 0.009 1.35 0.969 0.0 Fixed 0.764 0.767
RecessiveTT/TC+CC71.0300.746–1.4230.8568.870.18132.3Fixed0.0720.070
Dominant TT+TC/CC 7 0.835 0.7160.974 0.021 1.19 0.978 0.0 Fixed 0.368 0.104
Table 3. Summary about meta-analysis on tumour necrosis factor-α (TNF-α) -238, -308 in Chinese pooled population, persistent hepatitis B virus infection versus Healthy controls
SNPGenetic modelsComparisons n OR (95% CI)HomogeneityPublication Bias
ORCIp value Q PhI² (%)Modelp for Begg' testp for Egger' test
  1. SNP, single-nucleotide polymorphism.

  2. Bold: Allele, Recessive and Dominant, Statistically significant at p 0.05; Co-dominant: Statistically significant at p 0.0167.

-238 C/AAlleleA/G50.8350.600–1.1620.2842.330.6750.0Fixed0.8060.735
Co-dominantAA/GG22.4320.252–23.4670.4420.250.6180.0Fixed1.000
AG/GG50.7510.514–1.0980.1402.390.6650.0Fixed1.0000.798
RecessiveAA/AG+GG22.6120.271–25.2110.4070.190.6660.0Fixed1.000
DominantAA+AG/GG50.7760.532–1.1320.1882.500.6450.0Fixed1.0000.913
-308 C/A Allele A/G 7 0.585 0.4560.751 0.002 6.35 0.385 5.5 Fixed 1.000 0.752
Co-dominantAA/GG31.0410.375–2.8900.9390.450.7990.0Fixed1.0000.072
AG/GG 7 0.519 0.3410.789 0.000 13.44 0.037 55.5 Random 1.000 0.929
RecessiveAA/AG+GG30.4000.155–1.0300.0580.020.9890.0Fixed1.0000.940
Dominant AA+AG/GG 7 0.512 0.3390.772 0.001 13.47 0.036 55.5 Random 0.764 0.849

Heterogeneity

Heterogeneity among the studies was calculated using the Q-statistic (Q > 0.10) and the I2 statistic (I = 0.0%). Heterogeneity was found in some groups, and therefore, the random-effects model was used. Importantly, no I2 heterogeneity exceeding 80.0% was identified.

Sensitivity analysis

Each single study involved in the meta-analysis was removed after every test to investigate the influence of the individual dataset on the pooled ORs. The corresponding pooled ORs were not materially altered (data not shown), indicating that our results were statistically strong.

Publication bias

Begg's funnel plot and Egger's test were performed to assess the publication bias of the literature, and no asymmetry of the funnel plot was found, indicating the absence of a publication bias in our meta-analysis.

Discussion

A number of recent studies have identified polymorphisms that affect susceptibility to infectious diseases. It is believed that host genetic factors involving genetic polymorphisms are responsible for the susceptibility and clinical outcomes of infectious diseases [6], because the differences in the susceptibility to infection or severity of disease cannot be solely attributed to the virulence of an organism. The role of TNF-α in the inflammation process has attracted much attention with regard to the TNF-α gene regulation and the possibility of synthesis of TNF-α variants. Previous work in animals has shown that TNF-α suppresses HBV protein expression and virus replication [7]. Polymorphisms in the TNF-α gene promoter have been shown to affect cytokine transcription rate and release. Many studies in the Chinese population have attempted to identify TNF-α promoter polymorphisms and their associated effects on persistent HBV infection; however, the results of these studies are conflicting. It is likely that these inconsistencies are induced by inadequate sample size.

In this study, the results of the meta-analysis, which examined the relationship of TNF-α-238G/A, -308G/A, -857C/T, and -863C/A polymorphisms with persistent HBV infection in the Chinese population, revealed a significantly decreased risk of susceptibility to persistent HBV infection because of the presence of the TNF-α-308 A allele in the Chinese pooled population. The G→A nucleotide substitution at position -308 in the promoter region of the TNF-α gene was associated with elevated TNF-α gene transcriptional activity [8, 9]. Interestingly, TNF-α-238G/A, -857C/T or -863C/A was not found to be associated with spontaneous HBV clearance in this study. The TNF-α promoter alleles associated with higher plasma levels, the presence of the -308A allele (TNF-α-308A/G or A/A) variant, was strongly associated with the resolution of HBV infection. However, our results pertaining to the relationship between TNF-α-308G/A and persistent HBV infection susceptibility differed from those obtained in the Japanese, Italian, Korean and Mongoloid populations. There are three reasons for the differing opinions concerning the TNF-α-308 gene promoter polymorphisms and chronic HBV patient prognosis. The most important factor is the sample size, followed by heterogeneity, and then the difference in the type of HBV patients included in each study [10].

The results of this study suggest that TNF-α-857T carriers are more likely to show spontaneous clearance of HBV. Whereas previous studies did not find an association between the TNF-α-857T allele and spontaneous HBV clearance, this study found a common trend within these studies; specifically, the OR values of each study were less than 1 when the TNF-α-857 T and C allele were compared (Fig. 2). This finding indicates that the negative results of those studies might be a result of inadequate sample size. The partial explanation for this conclusion may be that the OCT1 transcription factor binds TNF-α-857T but not TNF-α-857C and functionally interacts with NF-κB, which gives rise to increased TNF-α production in vivo.

Figure 2.

Forest plot of the tumour necrosis factor-α (TNF-α) -857C/T polymorphism and clearance of hepatitis B virus infection(T allele vs C allele).

Importantly, the results of this meta-analysis were not identical to those of two other meta-analyses [11, 12]. The reasons for this inconsistency is probably because each study had different research subjects; namely, our study was conducted in Chinese people, whereas the other studies were conducted in Asian patients. In addition, these studies yielded the same or overlapping data.

This study has some limitations. First, as only published studies were included in the meta-analysis, publication bias may have occurred, even though it was not found by statistical analysis. Second, meta-analysis essentially remains an observational study that is subject to the methodological deficiencies of the included studies. Third, this meta-analysis was based on unadjusted estimates; however, a more precise analysis could be performed with additional datasets. Finally, the major HBV genotypes in the Chinese are B and C, but most of the studies did not analyse them separately, and therefore, because of the methodological limitations of this study, we could not correct for this.

In conclusion, despite the limitations mentioned above, the results of this meta-analysis indicate that in the Chinese population, persistent HBV infection susceptibility is associated with TNF-α-308G/A gene polymorphism and that the HBV clearance is associated with TNF-α-857C/T gene polymorphism.

Transparency Declaration

The authors declare no conflicts of interest.

Appendix 1

Findings of the studies included in this meta-analysis.

StudiesCase of PHICase of HCCase of SIStudied PolymorphismsFindings
  1. PHI, persistent HBV infection; SI, self-limiting infection; HC, healthy control; CHB, chronic hepatitis B; SR, self-limiting recovery; LC, liver cirrhosis.

Wang [3]62 61-308, -238-308 and -238 were not different between the clearance and the persistence group
Zhang [13]198280 -308, -238Altered TNF-a and IFN-c levels associated with PD1 but not TNFA polymorphisms in patients with chronic HBV infection
Wang [14]798 158-308, -238The results of the present study indicate an association between -308 and HBV related disease progression in the Chinese Han population
Kao [15]274 194-238, -308, -863, -857, -1031The A allele in the -863 promoter region of the TNF-a gene was present in 154 (56.2%) chronic HBV-infected patients and 87 (44.8%) patients who recovered from HBV infection (odds ratio 1.58; p <0.01).
Du [16]196 143-238, -308, -863, -857, -1031,The presence of the -238GG genotype was significantly correlated with persistence HBV infection, and -857 TT genotype appeared in relation to the spontaneous clearance of HBV.
Lu [17]207 148-238The frequency of -238 G allele was significantly higher in patients with chronic HB that in individuals with self-limited HBV infection
Li [18]651 244-238, -857The frequency of -238GG genotype in self-limited was significantly higher than in chronic HB group and in asymptomatic carrier group. The frequency of -857 CC in chronic HB group was significantly higher than in asymptomatic carrier group and n self-limited group
Li [20]12263 -308, -238The presence of G/A genotype at the position -238 may contribute to virus elimination, whereas the presence of G/G genotype at the position -238 may lead to virus persistent infection.
Chen [21]361 304-238, -308, -863, -857TNF 308 A/G genotype was significantly higher in controls than in the patient group
Qiu [22]571 189-863, -857,The frequency of -857CC genotype was significantly higher in CHB and LC individuals compared with that of SR subjects; A significant difference in the distribution of the allele -857C was observed for both CHB vs. SR and LC vs. SR; The frequency of -863AA genotype was significantly higher in CHB and LC patients than that of SR subjects.
Chen [23]126126 -238, -308, -863, -857, -1031No significant differences in genotype and allele distributions were observed between the control and cases in overall group.
Zhang [19]131126 -238, -308, -863, -857TNF-α-308, -863 and -857 were associated with clearance of persistent HBV infection in a Chinese Han population
Xing [24]150 100-238, -308Frequencies of the TNF-α-308GG genotype and G allele in patients with HBV infection were significantly higher than those in healthy controls
Zhou [25]456103 -308TNF-α-308 A allele was significantly lower in CHB group than that of health subjects.
Jiang [26]169119 -308TNF-α-308 GG genotype and G allele frequency in patients with post-hepatitis B cirrhosis were significantly higher than those in healthy controls
Xu [27]12790 -308The frequencies of the TNFG⁄A genotype and the TNFGG allele were greater in patients with chronic severe HBV infection than in healthy controls
Liu [28]203 148-238, -308, -863, -857, -1031The frequencies of -238GG genotype in chronic hepatitis B patients were significantly higher than that in self-limited infection subjects. The frequencies of -857TT genotype in chronic hepatitis B patients were clearly lower than that in self-limited infection subjects.
Zhang [29]131 165-238, -308, -863, -857TNF-α-308 and -863 were associated with clearance of persistent HBV infection in a Chinese Han population
Wang [30]74 64-863, -857TNF-α-857C /A polymorphism is associated with outcome of HBV infection among Guangxi population

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