Association of a TANK Gene Polymorphism with Outcomes of Hepatitis B Virus Infection in a Chinese Han Population

Abstract

The host genetic compound plays a vital role in determining clinical outcomes of hepatitis B virus (HBV) infection. The tumor necrosis factor receptor-associated factor family member-associated nuclear factor-κB (NF-κB) activator (TANK) takes part in the tumor necrosis factor-α (TNF-α)-mediated NF-κB signaling pathway and the interferon (IFN)-induction pathways that have relevance to HBV-related liver disease. In this report, we explored whether the intronic polymorphism rs3820998 of the TANK gene was associated with outcomes of HBV infection by binary logistic regression analysis. A total of 1305 unrelated Han Chinese patients recruited from Wuhan, including 180 acute-on-chronic hepatitis B liver failure (ACLF-HBV) patients, 331 HBV-related liver cirrhosis (LC) patients, 308 HBV-related hepatocellular carcinoma (HCC) patients, and 486 asymptomatic HBV carriers (AsC) were genotyped using the TaqMan probe method. Logistic analysis revealed that the single-nucleotide polymorphism (SNP) rs3820998 was significantly associated with susceptibility to ACLF-HBV (dominant model, OR 0.643, 95% CI 0.428,0.964, p=0.033; additive model, OR 0.640, 95% CI 0.414,0.990, p=0.045), and LC (recessive model, OR 0.398, 95% CI 0.164,0.966, p=0.042; additive model, OR 0.379, 95% CI 0.155,0.928, p=0.034). These results indicate that the G > T variant is a protective factor in the development of ACLF-HBV and LC, and that the SNP rs3820998 in the TANK gene may play a role in mediating susceptibility to ACLF-HBV and LC in a Chinese Han population.

Introduction

H epatitis B virus (HBV) infection is a worldwide health problem that frequently leads to acute, fulminant, chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). More than 2 billion people have been infected with HBV, of whom 400 million are chronic carriers all over the world. HBV-related liver diseases account for 600,000 to 1,200,000 deaths each year (1). We know that China is a country with a high HBV infection rate, and about 120 million people are HBV chronic carriers (2). The outcomes of HBV infection may be influenced by viral, environmental, and host genetic factors (3).

Epidemiological investigations have confirmed the pivotal role of genetic variations in human susceptibility to infectious diseases (4,5). The genetic background of the host not only affects chronic HBV clearance or chronicity at early stages, but it also persistently influences the long-term course of HBV infection (6). In recent years, many studies have been done on the host genetic variants involved in the outcomes of HBV infection. Segregation analysis and twin studies strongly support a role for host genetic components in determining the chronicity of HBV infection (7,8). Several studies revealed that variants in several host genes, including interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), myelin basic protein (MBP), vitamin D receptor (VDR), and estrogen receptor-1 (ESR-1), were associated with persistent HBV infection or HBV clearance (9 –13). Recently, a genome-wide association study demonstrated that genetic variants in the HLA-DP locus were strongly associated with chronic hepatitis B in Japanese and Thai populations (14). In addition, Albayrak et al. found that the role of HLA allele polymorphism was associated with the progression to chronic HBV infection in eastern Turkey, and that HBV infection is different in different racial populations (15).

The polymorphism locus rs3820998 in the tumor necrosis factor receptor-associated factor family member-associated nuclear factor-κB (NF-κB) activator (TANK) gene was obtained from genome-wide scan chip screening by Affymatrix SNP 6.0 arrays. The microarray data have been deposited in the National Center for Biotechnology Information's (NCBI's) Gene Expression Omnibus (GEO) public database (http://www.ncbi.nlm.nih.gov/geo/) following Minimum Information About a Microarray Experiment (MIAME) guidelines (GEO accession number GSE26034, data in press). The chip showed that rs3820998 might be associated with susceptibility to acute-on-chronic hepatitis B liver failure (ACLF-HBV) more than a control group of asymptomatic HBV carriers (AsC). A single-nucleotide polymorphism (SNP) is the most common genetic variation, and it refers to the stable substitution of a single base in the human genome. Some SNPs have been found to be associated with phenotype changes, and may affect gene transcription and amino acid composition if they are located in gene code regions. Thus, we hypothesized that genetic variants of the TANK gene may change TANK's activity, and thus affect TANK-mediated signal pathways.

The TANK gene is located in genomic region 2q24–q31, spanning roughly 99 thousand base pairs (kbp). The TANK gene encodes the protein named TANK. TANK, also known as I-TRAF (TRAF-interacting protein), was initially identified as a protein associated with TRAF1, TRAF2, and TRAF3 (9,16,17). TANK emerged as a bifunctional adaptor protein because it was found to function as an inhibitor of TRAF-mediated NF-κB activation, and also as a cofactor for the activation of NF-κB induced by TRAF2, TBK1, or IκB kinase epsilon (IKK) (18,19). The NF- κB signaling pathway has particular relevance to several liver diseases, including hepatitis (liver infection by Helicobacter and viral hepatitis induced by HBV and HCV), liver fibrosis, liver cirrhosis, and hepatocellular carcinoma (20). Oakley et al. found that an autocrine pathway that included angiotensin II, IKK, and phosphorylation of the NF-κB subunit RelA at serine 536 (P-Ser536-RelA) regulated myofibroblast survival and could be targeted to stimulate therapeutic regression of liver fibrosis (21). Moreover, TANK played an important role in interferon induction through both retinoic acid-inducible gene I and Toll-like receptor-dependent pathways. Specific knockdown of TANK resulted in reduced type I interferon production, increased viral titers, and enhanced cell sensitivity to viral infection (22). Given that TANK is associated with the NF-κB signaling and multiple antiviral pathways, we hypothesized that TANK gene polymorphisms likely influence clinical outcomes of chronic HBV infection.

However, very little work has been done to explore the association between TANK gene polymorphisms and outcomes of chronic HBV infection. In the present study, we investigated the association between TANK gene polymorphism rs3820998 and clinical outcomes of chronic HBV infection in a Chinese Han population.

Materials and Methods

Study subjects

The case-control population contained 1305 unrelated adult Chinese persons including 180 ACLF-HBV patients, 331 liver cirrhosis (LC) patients, 308 HCC patients, and 486 AsC. All subjects were recruited from the outpatient clinics and hospitalization wards at Tongji Hospital and Union Hospital, Wuhan, China, between September 2007 and August 2010. The diagnostic criteria for study inclusion were previous described (23,24), and were used with minor modifications (Supplementary Table 1; see online supplementary material at http://www.liebertonline.com). A questionnaire was used to record personal information including gender, age, birthplace, family history of HBV infection, serum total bilirubin (T-Bil), serum markers of HBV, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and HBV-DNA serum levels. Informed consent was obtained from each participant. The study was approved by the local Research Ethics Committee at the Tongji Hospital of Huazhong University of Science and Technology in June 2007.

DNA isolation and genotyping

We extracted genomic DNA from peripheral blood leukocytes of whole blood using a TIANamp blood DNA kit (Tiangen Biotech [Beijing] Co., Ltd., Beijing, China). The concentration and purity of the DNA samples were detected with a NanoDrop spectrophotometer. We excluded 75 samples that were genotyped unsuccessfully or were not in accord with standard conditions (1.6<DNA purity<1.9). DNA samples were diluted to 4 ng/μL and distributed in 96-well plates (DNA panels), each of which contained 94 samples and 2 DNA-free control water. For rs3820998 polymorphisms, genotyping was performed via the TaqMan method, according to the protocol of TaqMan SNP Genotyping Assays (Applied Biosystems, Foster City, CA).We customized the TaqMan probes with FAM (5′-TCTGAAGCTAACTGCT-MGB-3′), and VIC (5′-CTCTGAATCTAACTGC-MGB-3′), as well as the primers for PCR amplification (forward primer: 5′-CAACCCCACATCTTCTTCCG-3′; and reverse primer: 5′-TCTCACTCACCCACTCCCATC-3′) from Applied Biosystems. Reactions were accomplished in a 384-well format, in a total reaction volume of 5 μL, including 0.5 μL of each genomic DNA, 2.5 μL mix, 0.5 μL primers, 0.25 μL probes, and 1.25 μL DNA-free control water. The 384-well plates were then positioned in a thermal cycler (Applied Biosystems 7900HT Fast Real-Time PCR System) and heated for 2 min at 50° and 10 min at 95°, followed by 55 cycles at 95° for 15 sec, and 60° for 1 min. After PCR amplification, an end-point plate reading was performed to determine the fluorescence intensity in each well. According to the intensity of the VIC and FAM dye, we categorized each sample as a certain genotype, with VIC or FAM fluorescence alone indicating one of two homozygote genotypes, and a VIC and FAM mixed signal indicating a heterozygote genotype.

Statistical analysis

Statistical analysis was performed using Arlequin 3.1 software and SPSS 17.0 software. Genotype frequencies in each group were evaluated for Hardy-Weinberg equilibrium and minor allele frequencies (MAF) in each group were also evaluated by Arlequin 3.1 software. χ² tests were used to examine the differences in allele frequencies and genotype distributions between case groups and the control group. Each genotype was assessed with the use of dominant, recessive, and additive genetic models on binary logistic regression analysis, and the association between genotypes and risk of disease was estimated by p values, odds ratios (ORs), and 95% confidence intervals (95% CIs). An association was considered significant at a p value of less than 0.05 on binary logistic regression analysis involving recessive, dominant, or additive genetic models, and all statistical tests were two-sided.

Results

Population characteristics

A total of 1305 subjects, including 180 ACLF-HBV patients, 331 LC patients, 308 HCC patients, and 486 AsC were genotyped successfully. The parameters were gender, age, serum T-Bil, serum α-fetoprotein level (AFP), serum markers of HBV, AST, ALT, and HBV-DNA serum levels. From the subject profiles we noted that there were higher numbers of men than women in each group. There were no significant differences in the percentage of hepatitis B e antigen (HBeAg) positivity among the ACLF-HBV group, the LC group, and the AsC group. Although an effort was made to obtain a good match for age and sex between cases and controls, there were more men in the three case groups than in the AsC group (p<0.01). The characteristics of the study subjects are summarized in Table 1.

Table 1.

Demographic and Laboratory Parameters of the Subjects Enrolled in the Study

Groups	ACLF-HBV	LC	HCC	AsC
No. of subjects	180	331	308	486
Gender
Male, no. (%)	152 (84.4)	285 (86.1)	284 (92.2)	277 (56.99)
Female, no, (%)	28 (15.6)	46 (13.9)	24 (7.8)	209 (43.01)
Age (years) (±SD)	39.48±12.11	47.66±10.52	48.51±10.99	47.78±9.268
HBeAg-positive, no. (%)	17 (9.4)	24 7.3)	32 (10.4)	28 (5.76)
T-Bil (μmol/L)	360.33±153.74	83.29±120.90	39.93±77.88	13.23±3.86
AFP (ng/mL)	232.07±384.01	552.35±4254.37	11,383.01±20239.87	No
ALT (IU/L)	498.49±503.41	91.52±125.17	75.32±136.07	19.74±15.09
AST (IU/L)	359.81±409.34	102.75±118.97	98.69±115.57	28.67±10.10
HBV-DNA (copies/mL)	2.72E7±8.45E7	4.41E7±2.62E7	8.47E8±7.59E8	No

HBV, hepatitis B virus; LC, HBV-related liver cirrhosis (LC); HCC, HBV-related hepatocellular carcinoma; AsC, asymptomatic HBV carrier; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ACLF-HBV acute-on-chronic hepatitis B liver failure; AFP, α-fetoprotein; T-Bil, serum total bilirubin; HBeAg, hepatitis B early antigen; SD, standard deviation.

Allele and genotype distribution of rs3820998 in case and control groups

We detected the genotypes of 180 ACLF-HBV patients, 331 LC patients, 308 HCC patients, and 486 AsC at rs3820998 by the TaqMan-MGB probe method (Table 2). The results showed that the G/G genotype was most common rs3820998 polymorphism in all groups. There was a significant difference in allele frequencies of rs3820998 between the ACLF-HBV group and the AsC group (χ²=4.435, p=0.035). The genotype frequencies were consistent with Hardy-Weinberg equilibrium in all groups. MAF in each group was more than 5%. These two results indicated that these populations had a relatively stable genetic background and were suitable for further genetic statistical analysis.

Table 2.

Allele and Genotype Distribution of rs3820998 in Case and Control Groups

Group	ACLF-HBV	LC	HCC	AsC
Genotype
G/G	126 (70.00)	219 (66.16)	200 (64.94)	297 (61.11)
G/T	49 (27.22)	105 (31.70)	95 (30.84	168 (34.57)
T/T	5 (2.78)	7 (2.14)	13 (4.22)	21 (4.32)
Allele
G	301 (83.61)	543 (82.02)	495 (80.36)	762 (78.40)
T	59 (16.39)	119 (17.98)	121 (19.64)	210 (21.60)
p Value^*	0.038	0.073	0.348	Ref
HWE test, p	0.930	0.170	0.690	0.650
MAF	0.163	0.179	0.196	0.204

Comparisons are between AsC and the other groups. Statistically significant values are shown in bold.

HWE, Hardy-Weinberg equilibrium; MAF, minor allele frequency; ACLF-HBV, acute-on-chronic hepatitis B liver failure; LC, HBV-related liver cirrhosis; HCC, HBV-related hepatocellular carcinoma; HBV, hepatitis B virus; AsC, asymptomatic HBV carrier.

Logistic regression analysis of SNP rs3820998 in the TANK gene

On the basis of binary logistic regression analysis with adjustment for age and gender, a statistically significant association of rs3820998 with susceptibility to ACLF-HBV was observed under both the dominant and additive genetic models (dominant model, OR 0.643, 95% CI 0.428,0.964, p=0.033; additive model, OR 0.640, 95% CI 0.414,0.990, p=0.045; Table 3). Subjects with the genotypes G/T and T/T or only G/T had a decreased susceptibility to ACLF-HBV compared to those bearing the genotype G/G.

Table 3.

Association Analysis Between the Control and Case Groups

	ACLF-HBV versus AsC		LC versus AsC
Groups	p Value	OR (95% CI)	p Value	OR (95% CI)
Dominant model
T/T + G/T versus G/G	0.033	0.643 (0.428,0.964)	0.169	0.807 (0.594,1.096)
Recessive model
T/T versus G/T + G/G	0.562	0.706 (0.217,2.293)	0.042	0.398 (0.164,0.966)
Additive model
G/G	Ref	Ref	Ref	Ref
G/T	0.045	0.640 (0.414,0.990)	0.384	0.869 (0.634,1.192)
T/T	0.411	0.608 (0.185,1.9992)	0.034	0.379 (0.155,0.928)

Logistic regression models were used for calculating the odds ratios (95% confidential intervals) and corresponding P-values, controlling for age and sex as covariates. Significant associations (P<0.05) are in bold.

ACLF-HBV, acute-on-chronic hepatitis B liver failure; LC, HBV-related liver cirrhosis; HCC, HBV-related hepatocellular carcinoma; HBV, hepatitis B virus; AsC, asymptomatic HBV carrier; OR, odds ratio; CI, confidence interval.

Compared with the AsC group, a significant association was also observed between the polymorphism and susceptibility to LC (recessive model, OR 0.398, 95% CI 0.164,0.966, p=0.042; additive model, OR 0.379, 95% CI 0.155,0.928, p=0.034; Table 3). The data revealed that subjects with the genotype T/T had a lower susceptibility to LC than those with the genotypes G/T and G/G or only G/G. Furthermore, we also explored the association between the HCC group and rs3820998 by binary logistic regression analysis with adjustment for age and sex, but there was no significant association between the polymorphism and susceptibility to HCC (data not shown).

Discussion

In this study, we found that in accord with the findings of the chip that the SNP rs3820998, which was located at the intronic region of the TANK gene, was associated with susceptibility to ACLF-HBV in a Chinese Han population. Furthermore, the SNP rs3820998 was also associated with susceptibility to LC. To our knowledge, this is the first report of a genetic association between a TANK gene polymorphism and outcomes of HBV infection, confirming that TANK plays a role in the pathogenesis of ACLF-HBV and LC.

A few genetic variants of the TANK gene have been examined to explore their association with human disease. Wang et al. found that the SNP rs1921310 in the TANK gene was slightly associated with non-Hodgkin's lymphoma (25). However, for the associations between TANK gene polymorphisms and liver disease, very little work has been done. In this study, we investigated the association between the polymorphism rs3820998 in the TANK gene and outcomes of HBV infection in a Chinese Han population. The results indicated that the SNP rs3820998 was associated with susceptibility to ACLF-HBV (dominant model, OR 0.643, 95% CI 0.428,0.964, p=0.033; additive model, OR 0.640, 95% CI 0.414,0.990, p=0.045), and LC (recessive model, OR 0.398, 95% CI 0.164,0.966, p=0.042; additive model, OR 0.379, 95% CI 0.155,0.928, p=0.034).

During hepatitis viral infections the NF-κB signaling pathway is maintained in an activated state through the induction of inflammatory mediators such as TNF-α. Most of the biological effects of TNF-α are triggered by signaling cascades, and ultimately are caused by NF-κB and AP-1 (activating protein-1) activation (26,27). In chronic HBV infection, activation of NF-κB was associated with persistently elevated expression of proinflammatory cytokines, chemokines, and matrix metalloproteinases (20). It was reported that inflammation-associated cytokines including proinflammatory cytokines were involved in the development and progression of liver fibrosis (28). TANK took part in the TNF-α-mediated NF-κB signaling pathway. Reduced TANK expression by RNA interference attenuated TNF-α-mediated induction of a subset of NF-κB target genes through decreased p65 transactivation potential (29). NF-κB was a critical activator of innate immune responses (20), and it can repress HBV replication through both the repression of viral gene expression and the disruption of viral capsid integrity (30). The NF-κB signaling pathway has particular relevance to liver cirrhosis (20). NF-κB promotes survival of hepatic myofibroblasts and fibrogenesis (21). Furthermore, the activation of NF-κB in hepatic stellate cells and hepatic myofibroblasts appeared to promote hepatic fibrosis via multiple mechanisms, including direct fibrogenic effects, antiapoptotic effects, and the secretion of macrophage-recruiting chemokines (31). The SNP rs3820998 showed a significant association with susceptibility to ACLF-HBV and LC. As the SNP rs3820998 is located in the intron of the TANK gene, we hypothesize that it might regulate gene expression by causing alternative splicing, changing the binding to a transcription factor, or even translating into microRNA with an adjacent sequence. Also, the polymorphism may possibly be in linkage disequilibrium with adjacent SNPs. Thus the G > T variant might weaken the NF-κB signaling pathway by altering TANK expression, thus ultimately reducing the risk of progression to ACLF-HBV or LC. As the genetic basis of many diseases is complex, differences in one or even several loci of a gene are likely to be inadequate to affect clinical outcomes. Therefore, although ACLF-HBV and LC have similar genetic variations with regard to the TANK gene, it is possible that other genetic factors affect final outcomes, such as polymorphisms in other genes: TNF-α/β (32), estrogen receptor-α (13), and cytokine genes (12,33,34). Thus the final outcome of HBV infection may not be determined entirely by a single genetic variation, but likely results from the effects of many types of genetic variations.

In addition to those mentioned above, TANK plays an important role in type I interferon induction, through both retinoic acid-inducible gene I- and Toll-like receptor-dependent pathways (22). Type I IFNs play a key role in host defense by modulating the innate and adaptive immune responses. Type I IFNs may directly act on CD8⁺ T cells, B cells, NK cells, and DCs, enhancing their functions (35). It was reported that cytotoxic T lymphocytes (CTL) are thought to contribute to viral clearance and liver cell injury during HBV infection (36). Thus we hypothesize that the G>T variant likely improves type I IFN production, and indirectly allows the CTL to recognize and kill target cells, so subjects with HBV infection are more likely to keep the virus under control.

Conclusion

We have demonstrated that the SNP rs3820998 is associated with ACLF-HBV and LC in a Chinese Han population. These findings not only provide clues to the pathogenesis of ACLF-HBV and LC, but they also indicate that people with the SNP after HBV infection have a decreased susceptibility to ACLF-HBV compared to those who do not carry the SNP in a Chinese Han population. No association between the SNP rs3820998 and HCC was detected. More studies are required to explore the importance of the TANK gene in disease progression in those with chronic HBV infection. Further investigations with larger sample sizes, multiple centers, and haplotype analysis with other SNPs, may be required to confirm and expand the findings detailed here. Our conclusions require verification in other populations. Functional studies are also needed to further explore the role of TANK in the progression of HBV infection.

Footnotes

Acknowledgments

This study was funded by the National Basic Research Program of China (no. 2007CB512903), and the National Natural Science Foundation of China (no. 30872237).

Author Disclosure Statement

No competing financial interests exist.

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