Tumor necrosis factor-α-308A allele may have a protective effect for chronic hepatitis B virus infection in Mongoloid populations☆

Article Outline

• Summary
• Introduction
• Materials and methods
  • Search strategy
  • Inclusion criteria
  • Definitions
  • Data abstraction
  • Statistical analysis
• Results
  • Meta-analysis results
  • Publication bias
• Discussion
• Acknowledgements
• References
• Copyright

Summary 

Objectives

Previous studies on the tumor necrosis factor-α (TNF-α)-308 gene promoter polymorphism in chronic hepatitis B virus (HBV) infection have reported conflicting results.

Methods

We carried out a meta-analysis of 21 studies in relation to the TNF-α-308 gene promoter, involving a total of 4230 chronic HBV infection cases and 2905 controls.

Results

The overall meta-analysis indicated that −308A heterozygotes (GA) had a significant 27% decreased risk of developing chronic hepatitis B (CHB) (odds ratio (OR) 0.73; 95% confidence interval (CI) 0.57–0.93; p=0.012). For −308A allele homozygotes (AA) and carriers (GA+AA), the pooled odd ratios both indicated a significantly decreased risk of CHB (OR 0.28; 95% CI 0.19–0.43; p=0.0001; and OR 0.70; 95% CI 0.55–0.89; p=0.004, respectively). In subgroup analyses by ethnicity, a significantly decreased risk was associated with −308 variant genotypes (GA and AA) in Mongoloid populations in all genetic models. However, no significant associations were found in Caucasoids. Moreover, in the subgroup analyses by control group, significantly decreased risk was associated with −308 variant genotypes (GA and AA) in the group of spontaneously recovered cases in all genetic models; however, no significant associations were found in the group of healthy cases.

Conclusions

The TNF-α-308A allele is a protective factor for chronic HBV infection, especially in Mongoloids.

Keywords: Tumor necrosis factor-α 308 gene, Polymorphism, Chronic hepatitis B, Case–control study, Meta-analysis

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Introduction 

Hepatitis B is becoming a severe public health problem that should be resolved with urgency. It is estimated that there are more than 350 million people infected with the hepatitis B virus (HBV) worldwide.¹ HBV infection causes various clinical outcomes in patients; 90–95% of adults infected with HBV might successfully eliminate the virus through self-limiting hepatitis and only 5–10% of them become chronic HBV carriers; 20–30% of the chronic infections lead to liver cirrhosis and 5% develop hepatocellular carcinoma in a long run of disease course.²

The risk of progression to chronic hepatitis depends on several factors: viral strain, genotype, and host factors such as age, gender, ethnic background, immune status, etc.³, ⁴ Several cytokines that participate in the process of viral clearance via host immune response to HBV have been identified.⁵ In particular, tumor necrosis factor-α (TNF-α) is an important cytokine in the immune pathogenesis of HBV infection. The TNF-α gene is located 850kb telomeric of the class III HLA-DR locus of the short arm of chromosome 6, and is closely linked to human leukocyte antigen (HLA) gene clusters.⁶ Recent evidence suggests that TNF-α can induce the non-cytolytic suppression of HBV expression and replication in the liver.⁷ TNF-α can also inhibit the transcriptional activity of the HBV core promoter in vitro.⁸ Moreover, TNF-α affects the expression of HLA-II molecules, and hence, viral antigen presentation.⁹

The polymorphisms in the promoter region of the TNF-α gene have been extensively studied in relation to HBV infection. To date, there have been 181 single nucleotide polymorphisms (SNPs) in the TNF-α gene reported in the National Center for Biotechnology Information (NCBI) database, with more than 10 SNPs in the promoter region, including those at −163G/A, −238G/A, −244A/G, −308G/A, −376G/A, −575A/G, −857C/T, −863C/A, −1031T/C, −1125G/C, and −1196C/T base pairs from the transcription start site.¹⁰, ¹¹, ¹², ¹³ The −308 polymorphism in the TNF-α gene has been studied more than the other polymorphisms. TNF-α-308G/A is associated with an increased production of TNF-α,¹⁴ which is a central mediator of the immune response.

Considerable evidence suggests that TNF-α-308 gene promoter polymorphism is associated with clearance or susceptibility of chronic HBV infection.¹⁵, ¹⁶, ¹⁷, ¹⁸, ¹⁹, ²⁰, ²¹, ²², ²³, ²⁴, ²⁵, ²⁶, ²⁷, ²⁸, ²⁹, ³⁰, ³¹, ³², ³³, ³⁴, ³⁵ However, association studies have many limitations and often give inconsistent results. These studies are based on limited sample size, and participant characteristics (such as ethnicity, age, gender, etc.) are different from each other. Therefore, every single study may be underpowered to achieve a comprehensive and reliable conclusion.

To better address the association between the commonly studied TNF-α-308 gene promoter with susceptibility to chronic HBV infection, we performed a meta-analysis from all eligible studies.

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Materials and methods 

Search strategy 

Epidemiological genetic association studies published before July 2008 on HBV infection and polymorphism in the TNF-α-308 gene promoter were sought by computer-based searches, scanning of the reference lists of articles identified for all relevant studies and review articles (including meta-analyses), hand-searching of relevant journals, and correspondence with authors of included studies. Computer searches of PubMed, Web of Science, EMBASE, and the China Biological Medicine Database (CBMdisc) used keywords related to the TNF-α-308 gene in combination with words related to HBV infection and polymorphism, without language restriction. All relevant studies identified were included apart from five in which the data were duplicated or overlapped.

Inclusion criteria 

The inclusion criteria were: (1) evaluation of the TNF-α-308 gene promoter polymorphism and chronic HBV infection, (2) case–control studies, and (3) sufficient published data for estimating an odds ratio (OR) with 95% confidence interval (CI).

Definitions 

The definition of spontaneously recovered (SR) infection was as follows: positive for both anti-hepatitis B surface antigen (anti-HBs) antibodies and anti-hepatitis B core antigen (anti-HBc) antibodies, definitely negative for hepatitis B surface antigen (HBsAg), normal liver function tests, and no history of acute/chronic hepatitis B and HBV vaccination. Chronic hepatitis B (CHB) was diagnosed if serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were continuously abnormal and HBsAg was seropositive without anti-HBs from the sixth month of acute infection. An asymptomatic carrier was a person who had contracted HBV, but who displayed no symptoms. Chronic infection included asymptomatic carriers, chronic hepatitis B, and liver cirrhosis.

Data abstraction 

The following information was abstracted from each study, according to a fixed protocol: study design, geographical location, ethnic group of participants, definition and numbers of cases and controls, DNA extraction and genotyping methods, frequency of genotypes, mean age of cases, and proportion of cases who were male. Different ethnicity descents were categorized as Caucasoid (e.g., people of European continental ancestry) and Mongoloid (e.g., people of East Asia, etc.). When studies included subjects of more than one ethnicity, genotype data were extracted separately. The control group was divided into an SR group and a healthy group. Information was carefully extracted from all eligible publications independently by two of the authors (Zheng and Qiu) according to the inclusion criteria listed above. Disagreement was resolved by discussion between the two authors. If two authors could not reach a consensus, another author (Chen) was consulted to resolve the dispute and a final decision was made by a majority vote.

Statistical analysis 

ORs with 95% CIs were applied to assess the strength of association of TNF-α-308 gene promoter polymorphism with chronic HBV infection. The unadjusted OR of each study was first calculated in a 2×2 table. The pooled ORs for the risk associated with the genotypes of GA, AA, and GA+AA (A-allele carriers) compared with the GG genotype were calculated. One-way sensitivity analyses were performed to assess the stability of the results, namely, a single study in the meta-analysis was deleted each time to reflect the influence of the individual data-set to the pooled OR.³⁶ Heterogeneity was evaluated using the Chi-square test.³⁷ A p-value of <0.1 was considered significant for heterogeneity. Fixed-effect models (Mantel–Haenszel method) were used throughout, unless statistical heterogeneity was significant, in which case, a random-effects model (DerSimonian and Laird method) was used. The significance of the pooled OR was determined by the Z-test, and p<0.05 was considered as statistically significant. An estimate of potential publication bias was carried out by funnel plot, in which the standard error of log(OR) of each study was plotted against its log(OR). An asymmetric plot suggests a possible publication bias. Funnel plot asymmetry was assessed by the method of Egger's linear regression test, a linear regression approach to measure funnel plot asymmetry on the natural logarithm scale of the OR. The significance of the intercept was determined by the t-test suggested by Egger (p<0.05 was considered representative of statistically significant publication bias).³⁸

Analysis was performed using the statistical software Intercooled Stata version 8.0 for Windows (Stata Corporation, College station, TX, USA). All p-values were two-sided.

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Results 

Twenty-one studies with a total number of 4230 cases and 2905 controls were included in this analysis (Table 1, Table 2).¹⁵, ¹⁶, ¹⁷, ¹⁸, ¹⁹, ²⁰, ²¹, ²², ²³, ²⁴, ²⁵, ²⁶, ²⁷, ²⁸, ²⁹, ³⁰, ³¹, ³², ³³, ³⁴, ³⁵ All studies used healthy volunteers or SR patients as control subjects. In four of these studies,¹⁷, ²¹, ³¹, ³⁵ the ORs were presented separately according to the different control groups (Table 1, Table 2). Sample sizes in the 21 studies ranged from 110 to 1400. There were six studies of Caucasoids¹⁵, ²¹, ²³, ²⁵, ³¹, ³⁵ and 15 studies of Mongoloids.¹⁶, ¹⁷, ¹⁸, ¹⁹, ²⁰, ²², ²⁴, ²⁶, ²⁷, ²⁸, ²⁹, ³⁰, ³², ³³, ³⁴ Almost all of the cases were histologically confirmed. No significant differences were found in the age distributions between the cases and controls. Genotyping methods used in the studies included PCR-restriction fragment length polymorphism (RFLP), PCR- sequence specific primer (SSP), single-base primer extension assay, direct sequencing, hybridization and gene chips. The frequency of GG genotype was 77.0% in Caucasoids and 85.5% in Mongoloids; the frequency of the GA genotype was 21.8% in Caucasoids and 12.3% in Mongoloids; and the frequency of the AA genotype was 1.2% in Caucasoids and 2.2% in Mongoloids. We found the −308G/G genotype in 73.8% of our healthy volunteers in the meta-analysis, a rate that is different from the prevalence rates reported in different regions of the world. The rates reported were 60.5% in southeast England, 77–78% in Italy, 81.6% in Gambia and 96% in Japan.¹¹, ²⁵, ³⁹, ⁴⁰

Table 1. Main characteristics of all studies included in the meta-analysis

CI, chronic infection, including asymptomatic carriers, chronic hepatitis B, and liver cirrhosis; CHB, chronic hepatitis B; LC, liver cirrhosis; SR, spontaneously recovered; PCR, polymerase chain reaction; RFLP, restriction fragment length polymorphism; SSP, sequence-specific primer; DS, direct sequencing; SBPEA, single-base primer extension assay.

Table 2. Detailed information of genotype GG, GA, and AA in the studies included in the meta-analysis

First author (year)	Ethnicity (country)	Case			Control
		AA, n (%)	GA, n (%)	GG, n (%)	AA, n (%)	GA, n (%)	GG, n (%)
TNF-α-308 polymorphism (control=spontaneously recovered)
Xing (2007)18	Mongoloid (China)	30 (20.0)	75 (50.0)	45 (30.0)	35 (35.0)	59 (59.0)	6 (6.0)
Kummee (2007)17	Mongoloid (Thailand)	0 (0)	22 (14.7)	128 (85.3)	0 (0)	18 (18)	82 (82)
Somi (2006)21	Caucasoid (Iran)	2 (2)	20 (20)	78 (78)	1 (1)	20 (22)	70 (77)
Du (2006)19	Mongoloid (China)	2 (1.03)	15 (7.65)	179 (91.33)	5 (3.5)	10 (6.99)	128 (89.51)
Cheong (2006)20	Mongoloid (Korea)	1 (0.25)	45 (10.92)	366 (88.83)	1 (0.5)	28 (13.7)	175 (85.8)
Liu (2005)26	Mongoloid (China)	2 (1.0)	16 (8.0)	182 (91.0)	5 (3.5)	10 (6.9)	129 (89.6)
Niro (2005)25	Caucasoid (Italy)	2 (1)	28 (15)	154 (84)	0 (0)	21 (22)	75 (78)
Zhang (2004)30	Mongoloid (China)	0 (0)	6 (4.6)	125 (95.4)	0 (0)	22 (13.3)	143 (86.7)
Kim (2003)32	Mongoloid (Korea)	1 (0.1)	68 (6.5)	971 (93.4)	0 (0)	32 (11.3)	251 (88.7)
Ben-Ari (2003)31	Caucasoid (Israel)	0 (0)	13 (16.9)	64 (83.1)	0 (0)	2 (20.0)	8 (80.0)
Hohler (1998)35	Caucasoid (Germany)	3 (4)	21 (30)	47 (66)	0 (0)	10 (31)	22 (69)
TNF-α-308 polymorphism (control=healthy)
Tao (2008)16	Mongoloid (China)	3 (2.9)	3 (2.9)	96 (94.2)	5 (10)	0 (0)	44 (90)
Basturk (2008)15	Caucasoid (Turkey)	0 (0)	5 (10.0)	45 (90.0)	4 (6.7)	17 (28.3)	39 (65.0)
Kummee (2007)17	Mongoloid (Thailand)	0 (0)	22 (14.7)	128 (85.3)	1 (0.6)	26 (17.3)	123 (82)
Suneetha (2006)23	Caucasoid (India)	1 (0.4)	65 (30.4)	148 (69.2)	2 (0.5)	136 (33.3)	270 (66.2)
Somi (2006)21	Caucasoid (Iran)	2 (2)	20 (20)	78 (78)	1 (1)	13 (15)	75 (84)
Li (2006)22	Mongoloid (China)	0 (0)	31 (25.4)	91 (74.6)	0 (0)	19 (30.2)	44 (69.8)
Zhou (2005)29	Mongoloid (China)	0 (0)	19 (8.6)	203 (91.4)	0 (0)	20 (19.4)	83 (80.6)
Zhang (2005)28	Mongoloid (China)	0 (0)	6 (4.6)	125 (95.4)	0 (0)	18 (14.3)	108 (85.7)
Xu (2005)24	Mongoloid (China)	0 (0)	20 (15.7)	107 (84.3)	0 (0)	10 (11.1)	80 (88.9)
Mao (2005)27	Mongoloid (China)	38 (24.3)	72 (46.2)	46 (29.5)	36 (40.9)	48 (54.5)	4 (4.5)
Ben-Ari (2003)31	Caucasoid (Israel)	0 (0)	13 (16.9)	64 (83.1)	0 (0)	6 (12.5)	42 (87.5)
Miyazoe (2002)34	Mongoloid (Japan)	0 (0)	6 (3)	207 (97)	0 (0)	2 (4)	50 (96)
Lin (2002)33	Mongoloid (China)	0 (0)	21 (19.8)	85 (80.2)	0 (0)	11 (10.2)	97 (89.8)
Hohler (1998)35	Caucasoid (German)	3 (4)	21 (30)	47 (66)	6 (6)	20 (20)	73 (74)

Meta-analysis results 

The overall meta-analysis indicated that −308A heterozygotes (GA) had a significant, approximately 27% decreased risk of developing CHB (OR 0.73; 95% CI 0.57–0.93; p=0.012). For the homozygotes (AA) and the −308A allele carriers (GA+AA), the pooled ORs indicated a significantly decreased risk of CHB (OR 0.28; 95% CI 0.19–0.43; p=0.0001; and OR 0.70; 95% CI 0.55–0.89; p=0.004, respectively). In the subgroup analyses by ethnicity, a significantly decreased risk was associated with −308 variant genotypes (GA and AA) in Mongoloid populations in all genetic models (Table 3 and Figure 1). However, no significant associations were found in Caucasoids (Table 3). Moreover, in the subgroup analyses according to the control group, a significantly decreased risk was associated with −308 variant genotypes (GA and AA) in the SR control group in all genetic models (Table 3); however, no significant associations were found in the healthy control group (Table 3). The Q-test suggested significant between-study heterogeneity in all the comparisons except for Caucasoids (Table 3). Although the genotype distribution in the seven studies did not follow Hardy–Weinberg equilibrium,¹⁶, ¹⁸, ¹⁹, ²³, ²⁶, ²⁷, ³⁵ the corresponding pooled ORs were not materially altered with or without including these studies (data not shown). Similarly, no other single study influenced the pooled OR qualitatively as indicated by sensitivity analyses.

Table 3. Main results of pooled odds ratios in the meta-analysis

OR, odds ratio; CI, confidence interval; SR, spontaneously recovered.

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• Figure 1. 

  Forest plot of chronic hepatitis B virus infection risk associated with TNF-α-308G/A polymorphism for GA+AA vs. GG. For the −308A allele carriers (GA+AA), the pooled odds ratios indicated a significantly decreased risk of chronic hepatitis B (OR 0.70; 95% CI 0.55–0.89; p=0.004). In the subgroup analyses by ethnicity, significantly decreased risk was associated with −308 variant genotypes (GA and AA) in Mongoloid populations (OR 0.59; 95% CI 0.43–0.82; p=0.002). However, no significant associations were found in Caucasoids. OR: odds ratio; CI: confidence interval.

Publication bias 

Begg's funnel plot and Egger's test were performed to assess the publication bias of the literature. The shapes of the funnel plots did not reveal evidence of obvious asymmetry in all comparison models (Figure 2). The Egger's test results suggested that publication bias was evident for AA vs. GG (p=0.003), but not evident for GA vs. GG (p=0.681) and GA+AA vs. GG (p=0.300). The Duval and Tweedie non-parametric ‘trim and fill’ method was used to adjust for publication bias. Meta-analysis with and without the ‘trim and fill’ method did not draw different conclusions, indicating that our results were statistically robust.

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• Figure 2. 

  Begg's funnel plot (using odds ratio of chronic hepatitis B virus infection risk in GA+AA genotype when compared to GG genotype) of TNF-α-308G/A polymorphism and chronic hepatitis B virus infection risk for the genotype GA+AA vs. GG (p=0.300). The horizontal line represents the meta-analysis summary estimate, and the diagonal lines pseudo 95% confidence interval limits about the effect estimate. In the absence of publication bias, studies will be distributed symmetrically above and below the horizontal line. OR: odds ratio; CI: confidence interval.

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Discussion 

Genetic susceptibility to chronic HBV infection has been a research focus in the scientific community. Wide variations have been documented in the frequencies of cytokine polymorphisms among different healthy populations, including the TNF-α-308 polymorphism, which has been most widely investigated in healthy populations⁴¹ and has been demonstrated to influence TNF-α expression.¹⁹, ⁴²

The studies of TNF-α-308 gene promoter polymorphism in chronic HBV infection have reported conflicting results. The association between TNF-α-308 gene promoter polymorphism and outcome of HBV infection has been investigated by several research groups from different regions of the world.²⁰, ²⁴, ³¹, ³², ³⁴, ³⁵, ⁴³ Miyazoe et al.³⁴ reported that inheritance of IL-10 gene promoter polymorphism was involved in a host genetic factor that was relevant to disease progression, whilst polymorphism in the TNF-α-308 gene promoter was not associated. Similarly, other studies²⁵, ³¹ have shown that polymorphisms of TNF-α-308 gene promoter in HBV carriers do not differ from those in healthy volunteers. Moreover, one study from Iran reported that TNF-α-308 gene promoter polymorphism was not associated with development of chronic HBV infection.²¹ On the other hand, Kim et al.³² found that TNF-α-308G/A or A/A polymorphisms were associated with the resolution of HBV infection. Recently, several researchers from different geographical regions of the world demonstrated that the TNF-α-308G/G polymorphism was associated with either higher risk of persistent HBV infection or unfavorable prognosis of chronic hepatitis B such as end-stage liver disease.¹⁹, ²⁰, ²⁵ However, studies with larger series of patient populations are needed to reveal the significance of the data, since statistically significant difference was lost after Bonferroni correction.

The present meta-analysis of 21 studies, involving a total of 4230 cases and 2905 controls (counting every study's cases and controls only once), provides the most comprehensive assessment so far of the relevance to chronic HBV infection of TNF-α-308 gene promoter polymorphism. Our results indicate that −308 heterozygote GA carriers had a nearly 27% decreased risk of developing CHB, homozygote AA carriers had a roughly 72% decreased risk, and the −308A allele carriers had a nearly 30% decreased risk. The decreased risks appeared to be more evident in the Mongoloid and SR groups, but not in the Caucasoid and healthy control groups, suggesting a possible role of ethnic differences in genetic backgrounds and the environment they lived in.⁴⁴ It is also likely that the observed ethnic differences may be due to chance, because studies with small sample size may have had insufficient statistical power to detect a slight effect or may have generated a fluctuated risk estimate.⁴⁵ Considering the limited studies and population numbers of Caucasoids included in the meta-analysis, our results should be interpreted with caution.

Heterogeneity is a potential problem when interpreting the results of all meta-analyses.⁴⁶ Significant between-study heterogeneity existed in all comparisons except for Caucasoids. The important factor contributing to the heterogeneity was that the genotype distribution of controls in several studies¹⁶, ¹⁸, ¹⁹, ²³, ²⁶, ²⁷, ³⁵ did not follow Hardy–Weinberg equilibrium, indicating that these groups might not represent the general population very well.

Some limitations of this meta-analysis should be acknowledged. Firstly, the associations were investigated in all kinds of cases (asymptomatic carriers, chronic hepatitis B, liver cirrhosis), and there may be specific genetic effects among these cases, but we could not obtain enough information to further estimate these effects. Secondly, in the subgroup analyses, the number of Caucasoids was relatively small, not having enough statistical power to explore the real association. Thirdly, our results were based on unadjusted estimates; a more precise analysis should be conducted with individual data, which would allow for the adjustment by other co-variates including age, ethnicity, family history, environmental factors, and lifestyle.

Despite these limitations, this meta-analysis suggests that TNF-α-308A allele is a protective factor for chronic HBV infection, especially in the Mongoloid and SR control groups. However, it is necessary to conduct large trials using standardized unbiased methods, homogeneous CHB patients and well matched controls, with the assessors blinded to the data. Moreover, gene–gene and gene–environment interactions should also be considered in the analysis. Such studies taking these factors into account may eventually lead to a better, more comprehensive understanding of the association between TNF-α-308 gene promoter polymorphism and chronic HBV infection.

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Acknowledgements 

We are very grateful to the reviewers and editors for their critical reviews and scientific editing of the manuscript.

Financial Support: This work was supported by grants from Scientific Research Foundation of Wenzhou, Zhejiang Province, China (H20090014, Y20090269) and Fresh Talent Program for Science and Technology Department of Zhejiang Province (2007R40G2090032).

Conflict of interest: No conflict of interest to declare.

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