Hepatitis Research and TreatmentVolume 2012 (2012), Article ID 493219, 6 pagesdoi:10.1155/2012/493219

Review Article

The TNF-α -308 Promoter Gene Polymorphism and Chronic HBV Infection

Sirous Tayebi and Ashraf Mohamadkhani

Digestive Disease Research Centre, Tehran University of Medical Sciences, Shariati Hospital, North Kargar Ave, Tehran 14114, Iran

Received 18 May 2012; Revised 13 September 2012; Accepted 1 October 2012

Academic Editor: Piero Luigi Almasio

Copyright © 2012 Sirous Tayebi and Ashraf Mohamadkhani. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

Background and Aims. TNF-α -308 allele promoter polymorphism has been known to be a potential prognostic factor in patients with chronic HBV infection. We tried to determine how TNF-α -308 allele promoter polymorphism would affect the prognosis in patients with chronic HBV infection. Methods. We searched MEDLINE, EMBASE, and reference lists of relevant review articles related to the association between “TNF-α G-308A promoter polymorphism” with “chronic HBV infection”. We only focused on searching -308 locus in published studies. We reviewed 21 original articles about TNF-α -308 allele polymorphism and its effect on prognosis in patients with chronic HBV infection and discussed the results. Results. conflicting results were observed. The results were divided into 3 groups including neutral, negative, and positive associations between TNF-α -308 allele polymorphism and prognosis in patients with chronic HBV infection. We summarized the primary data as a table. Conclusions. Authors concluded that although there is an upward trend in evidence to claim that there is a positive relation between TNF-α G-308A promoter polymorphisms and resolution of chronic HBV infection, due to many biases and limitations observed in reviewed studies, an organized well-designed study is needed for clarifying the real association.

1. Introduction

It is believed that during chronic hepatitis B infection, the host immune response is responsible for both hepatocellular damage and viral clearance [1, 2]. Hepatocyte damage persuades an inflammatory response through activation of tissue macrophage Kupffer cells [3]. These activated cells secrete antiviral cytokines which is thought to be central in suppression or clearance of HBV from the infected liver [4]. Cytokines are proteins or glycoproteins produced by cells acting on their specific receptors on the other cells’ surfaces. They are central mediators of inflammatory events such as infection or peripheral trauma. Several cytokines have been identified that participate in the process of viral clearance via host immune response to HBV. They include TNF-α, TGFβ, PGF, and other factors contributing towards the fibrogenesis [5, 6]. Among these, TNF-α is the most important cytokine in host immune response to viral infection [7, 8]. TNF-α is a pleiotropic cytokine, located 850 kb telomeric of class II HLA-DR locus of the short arm of chromosome 6, which induces cellular responses such as proliferation, production of inflammatory mediators, and cell death [9]. In the liver, TNF-α is involved in pathophysiology of viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease and ischemia-reperfusion (I/R) injury. This cytokine shows a remarkable functional duality; it is not only a mediator of hepatotoxicity but also an inducer for hepatocyte proliferation and liver regeneration. TNF-α is produced mainly by macrophages and also by a broad variety of other cell types including lymphoid cells, mast cells, endothelial cells, fibroblasts, and neurons [9]. Circulating TNF-α level increases during HBV infection [10]. Increased hepatic level of TNF-α is associated with suppression of HBV replication in transgenic mice which expresses HBV in the liver [9]. TNF-α inhibits HBV replication by noncytopathic suppression mediated by NF-κB pathway [11].

The way that TNF-α inhibits HBV replication differs from other cytokine inhibitors because it targets the stability of nascent nucleocapsids. The maintenance of the cccDNA pool is thought to be critical for HBV persistence in infected hepatocytes and TNF-α mediated decline of nuclear cccDNA levels may be via preventing the formation of nucleocapsids that delivers cccDNA to the nucleus [7]. Type I IFNs likely suppress HBV mRNA transcription and type II IFNs might regulate the activity of La proteins, which may play a putative role in HBV mRNA stability [35]. TNF-α might also require both proteasome activity and iNOS activity [36]. TNF-α has also been shown to be effective in angiogenesis processes. Neoangiogenesis in the liver of HBV-infected patients suggests that TNF-α might also have a role in the development of viral hepatitis-associated liver tumors [37]. Locus -308 has been much more considered than any other loci (-238, -863) in correlation between genetic materials and clinical manifestation. The results from other loci in correlation with chronic HBV infection or other diseases from different studies were not highly significant. Although one study has claimed that TNF-α 238A allele may increase the risk of chronic HBV infection in European populations [38], when seeking for correlation of this locus with cancer, the results are not significant [39]. When comparing these results with studies about locus -308, we found that not only is locus -308 important in breast cancer but also in association with other diseases like essential hypertension [40]. Few studies found both -238 and -308 loci significantly important in correlation with diseases [41–43]. Many studies found both -308 and -238 loci nonsignificant when seeking for correlation between clinical manifestations and genetic materials [15, 44–47]. When comparing locus -308 with other loci (-238, -836), the correlation of locus -308 with other diseases such as Guillain-Barré syndrome [48], tuberculosis [49], and ANCA-associated vasculitis [50] has recently been approved. Based on the reasons mentioned above, we were trying to investigate only about correlation of locus -308 with HBV infection (and not with other diseases).

The significant role of tumor necrosis factor (TNF-α) in inflammation process has been attracted a great attention in both the regulation of the TNF-α gene and the possibility of TNF-α variants production. Polymorphisms in particular, at positions -308, are reportedly capable of altering TNF-α expression. However, population-based studies have yielded contradictory results regarding the relationships of these polymorphisms with the progression of HBV infection.

We suppose that binding of cellular factors to TNF-α promoter might be influenced by this polymorphism and affects gene expression and disease outcome. For better understanding of association between commonly studied TNF-α G-308A promoter polymorphism and susceptibility to chronic HBV infection, we classified the previous findings from all eligible studies.

2. Search Strategy

We searched MEDLINE, EMBASE, and reference lists of relevant review articles. All titles and abstracts and original articles of the included studies were independently reviewed by two review authors to see whether the study is discussing about TNF-α -308 locus or not. All searches were updated in August 2012.

3. Selection Criteria

Any studies about the association between “TNF-α gene promoter polymorphism” with “chronic HBV infection” were included. We only focused on -308 locus. This paper does not discuss the other factors affecting prognosis of chronic HBV infection (other loci such -238, -863). This is only a review article to clarify the relation between TNF-α -308 gene promoter polymorphism and prognosis in patients with chronic HBV infection, so the other results from studies, not related to -308 locus, were not mentioned in this paper.

4. Results

It has always been a challenging field talking about the effects of TNF-α -308 gene promoter polymorphisms in chronic HBV infection making us confront with conflicting results. There are 3 different kinds of results about the relationship between TNF-α -308 gene promoter polymorphism and prognosis in patients with chronic HBV infection:

The first group of studies is about to say “there is no association”. One study from Japan showed that allelic distributions of both gene promoters (including TNF-α and IL-10) were not significantly different between HBV carriers and health volunteers [33]. Another study from Italy demonstrated that TNF-α gene promoter polymorphisms do not appear to be determinant of HBV seroclearance [26]. Despite the fact of high prevalence of TNF-α gene promoter polymorphism in -308 locus in Iran, it has no association with development of chronic HBV infection [21].

The second groups of studies demonstrates that TNF-α -308 gene promoter polymorphisms are associated with either “unfavorable prognosis of chronic HBV infection” or high risk of persistent HBV infection. Korean patients with TNF-α -308 gene promoter polymorphisms had higher risks of persistent HBV infection [23]. The genotype -308 G/G and haplotype TCGG are associated with an unfavorable prognosis in patients with chronic HBV infection [26]. In Chinese people, frequency of haplotype GGCCT (-238, -308, -857, -863, -1031) in patients with chronic HBV infection was significantly lower than that in spontaneously recovered group [51].

The third group of studies are about to say “there is a positive association between TNF-α-308 gene promoter polymorphisms and resolution of HBV infection”. It has been shown that TNF-α-308 G/A or A/A promoter polymorphisms are associated with HBV clearance [32]. A meta-analysis about TNF-α -308 gene promoter polymorphisms has claimed that TNF-α -308 A allele may have a protective effect on the prognosis of chronic HBV infection in Mongoloid populations [52].

As a comprehensive view so far, we summarized all the basic data extracted as a table showing only the number of patients who are different at polymorphism. The most important point about these studies is that they have been designed differently and the methods of the studies vary from “response to special treatment” to “simple study of 2 groups of HBV patients in prognosis”, so it is not really logical to include all these studies into one meta-analysis. For example, in some studies, control group includes healthy people while the other studies used spontaneously recovered HBV patients as control group which makes it very difficult to get one unique conclusion from these studies. However, all these studies were to find and clear one big problem and it is the effect of TNF-α gene polymorphism on HBV prognosis (see Table 1).

Table 1: Information of TNF-α gene polymorphism.

Year
Country
Ethnicity
Chronic HBV Carrier
Recovered HBV infection
Reference

A/A
G/A
G/G
A/A
G/A
G/G

2010
Taiwan
Mongoloid
15
38
221
1
39
154
[12]

2010
China
Mongoloid
3
51
250
2
36
323
[13]

2009
South Korea
Mongoloid
1
5
116
1
6
96
[14]

2008
China
Mongoloid
0
6
23
0
15
142
[15]

2008
Turkey
Caucasoid
0
5
45
4
17
39
[16]

2008
China
Mongoloid
3
3
96
5
0
44
[17]

2007
Thailand
Mongoloid
0
22
128
0
18
82
[18]

2007
China
Mongoloid
30
75
40
35
59
6
[19]

2007
Thailand
Mongoloid
0
22
128
1
26
123
[18]

2006
India
Caucasoid
1
65
148
2
136
270
[20]

2006
Iran
Caucasoid
2
20
78
1
20
70
[21]

2006
China
Mongoloid
0
31
91
0
19
44
[22]

2006
South Korea
Mongoloid
1
45
366
1
28
175
[23]

2006
Iran
Caucasoid
2
20
78
1
13
75
[21]

2006
China
Mongoloid
2
15
179
5
10
128
[24]

2005
China
Mongoloid
0
6
125
0
18
108
[25]

2005
Italy
Caucasoid
2
28
154
0
21
75
[26]

2005
China
Mongoloid
0
20
107
0
10
80
[27]

2005
China
Mongoloid
38
72
46
36
48
4
[28]

2005
China
Mongoloid
0
19
203
0
20
83
[29]

2005
China
Mongoloid
2
16
182
5
10
129
[30]

2004
China
Mongoloid
0
6
125
0
22
143
[31]

2003
South Korea
Mongoloid
1
68
971
0
32
251
[32]

2002
Japan
Mongoloid
0
6
207
0
2
50
[33]

2002
China
Mongoloid
0
21
85
0
11
97
[34]

5. Discussion

Past animal researches showed that suppression of HBV protein expression and virus replication are affected by TNF-α [53, 54]. Polymorphisms in the promoter of TNF-α gene have been accounted to affect the transcription rate and cytokine release. Many studies have attempted to identify the polymorphisms of TNF-α promoter and its effect on persistent HBV infection [55, 56]. Nearly 11 single nucleotide polymorphisms (SNPs) in the promoter region of the TNF-α gene have been known so far including -163 G/A, -238 G/A, -244 A/G, -308 G/A, -376 G/A, -575 A/G, -857 C/T, -863 C/A, -1031 T/C, -1125 G/C, and -1196 C/T base pairs [51, 57–59]. This polymorphism can affect the TNF-α gene transcriptional activity and has different effects on serum TNF-α level [60, 61]. While the presence of A allele in -863 locus is associated with a lower serum TNF-α level, the presence of C allele in -1031, A allele in -308, and A allele in -238 loci are associated with higher TNF-α level in humans [62]. Generally, there is still no worldwide agreement on association between polymorphisms and cytokine production [63]. However, among all these polymorphisms, -308 locus has been studied widely more than the others.

As mentioned above, there are 3 different attitudes towards the effects of TNF-α -308 gene promoter polymorphisms on the prognosis in patients with chronic HBV infection. What can cause these three different results is to some extent clear. The most important factor is the “sample size” issue. Small sample size studies cannot have enough statistical power to show us real accuracy of the expected effects [64–68]. Heterogeneity is in the second level. Different numbers of people from Mongoloid and Caucasoid populations have participated in the studies considering that ethnic differences can play a major role in results from genetic studies [69–71]. As a third reason, different types of HBV patients were observed in the studies including patients with cirrhosis, asymptomatic carriers, and chronic HBV patients. Since we are discussing the genetic effects on prognosis of chronic HBV patients it is important to categorize participations into different stages of HBV infection. Other factors affecting the results including age, lifestyle, environmental factors, family history, and history of other liver diseases in patient should be considered in matching control group with patients. The results from each type of HBV patients should be interpreted and discussed separately especially when observing different conclusions about one unique issue.

These studies may offer the association of TNF-α gene polymorphisms with clearance or susceptibility of chronic HBV infection. Noted TNF-α gene expression is complex and firmly regulated at the transcriptional, posttranscriptional, and translational levels. However, transcriptional regulation of the TNF-α gene has been thought to elucidate molecular mechanisms [72].

6. Conclusion

There are many limitations and biases in the discussed studies which make our interpretation difficult to conclude a unique final decision about the effects of TNF-α -308 gene promoter polymorphisms on prognosis of chronic HBV infection. We suggest that researchers should design well-defined studies which is better to be a collaborative research program, because of different variations in genetic polymorphism, and it is really important for HBV communities and experts to introduce one or 2 well-designed methods which are able to evaluate the effect of polymorphism on HBV prognosis correctly. Single or separate studies with different methods in this challenging field lead us nowhere.

References

Z. Shokrgozar, S. Tayebi, Z. Minucheher, and A. Mohamadkhani, “Hepatitis B virus genome asymmetry in hepatocellular carcinoma,” Middle East Journal of Digestive Diseases, vol. 4, no. 3, pp. 150–157, 2012.

R. Malik, P. Kennedy, D. Suri, A. Brown, R. Goldin, J. Main, et al., “The role of liver fibrosis assessment in the management of patients with chronic hepatitis B infection: lessons learned from a single centre experience,” Hepatitis Research and Treatment, vol. 2011, Article ID 524027, 5 pages, 2011.

T. Andus, J. Bauer, and W. Gerok, “Effects of cytokines on the liver,” Hepatology, vol. 13, no. 2, pp. 364–375, 1991.

R. Gonzalez-Amaro, C. Garcia-Monzon, L. Garcia-Buey et al., “Induction of tumor necrosis factor α production by human hepatocytes in chronic viral hepatitis,” Journal of Experimental Medicine, vol. 179, no. 3, pp. 841–848, 1994.

M. Koulentaki, G. Notas, E. Petinaki et al., “Nitric oxide and pro-inflammatory cytokines in acute hepatitis B,” European Journal of Internal Medicine, vol. 15, no. 1, pp. 35–38, 2004.

J. Vingerhoets, P. Michielsen, G. Vanham et al., “HBV-specific lymphoproliferative and cytokine responses in patients with chronic hepatitis B,” Journal of Hepatology, vol. 28, no. 1, pp. 8–16, 1998.

R. Puro and R. J. Schneider, “Tumor necrosis factor activates a conserved innate antiviral response to hepatitis B virus that destabilizes nucleocapsids and reduces nuclear viral DNA,” Journal of Virology, vol. 81, no. 14, pp. 7351–7362, 2007.

M. C. Navas, I. Suarez, A. Carreno, D. Uribe, W. A. Rios, F. Cortes-Mancera, et al., “Hepatitis B and hepatitis C infection biomarkers and TP53 mutations in hepatocellular carcinomas from colombia,” Hepatitis Research and Treatment, vol. 2011, Article ID 582945, 10 pages, 2011.

R. F. Schwabe and D. A. Brenner, “Mechanisms of liver injury. I. TNF-α-induced liver injury: role of IKK, JNK, and ROS pathways,” American Journal of Physiology—Gastrointestinal and Liver Physiology, vol. 290, no. 4, pp. G583–G589, 2006.

A. Mohamadkhani, K. Sayemiri, R. Ghanbari, E. Elahi, H. Poustchi, and G. Montazeri, “The inverse association of serum HBV DNA level with HDL and adiponectin in chronic hepatitis B infection,” Virology Journal, vol. 7, p. 228, 2010.

M. Biermer, R. Puro, and R. J. Schneider, “Tumor necrosis factor alpha inhibition of hepatitis B virus replication involves disruption of capsid integrity through activation of NF-κB,” Journal of Virology, vol. 77, no. 7, pp. 4033–4042, 2003.

P. C. Kao, J. F. Wu, Y. H. Ni et al., “Tumour necrosis factor-α promoter region polymorphisms affect the course of spontaneous HBsAg clearance,” Liver International, vol. 30, no. 10, pp. 1448–1453, 2010.

D. Q. Chen, Y. Zeng, J. Zhou et al., “Association of candidate susceptible loci with chronic infection with hepatitis B virus in a Chinese population,” Journal of Medical Virology, vol. 82, no. 3, pp. 371–378, 2010.

J. E. Jeng, H. R. Tsai, L. Y. Chuang et al., “Independent and additive interactive effects among tumor necrosis factor-α polymorphisms, substance use habits, and chronic hepatitis b and hepatitis C virus infection on risk for hepatocellular carcinoma,” Medicine, vol. 88, no. 6, pp. 349–357, 2009.

H. Y. Xie, W. L. Wang, M. Y. Yao, S. F. Yu, X. N. Feng, J. Jin, et al., “Polymorphisms in cytokine genes and their association with acute rejection and recurrence of hepatitis B in Chinese liver transplant recipients,” Archives of Medical Research, vol. 39, no. 4, pp. 420–428, 2008.

B. Basturk, Z. Karasu, M. Kilic, S. Ulukaya, S. Boyacioglu, and B. Oral, “Association of TNF-α -308 polymorphism with the outcome of hepatitis B virus infection in Turkey,” Infection, Genetics and Evolution, vol. 8, no. 1, pp. 20–25, 2008.

D. S. Tao, YX, and Q. Guo, “Study of the genetic polymorphisms of TNF-α promoter and the infection of HBV,” Journal of Kunming Medical University, vol. 29, pp. 45–50, 2008.

P. Kummee, P. Tangkijvanich, Y. Poovorawan, and N. Hirankarn, “Association of HLA-DRB1*13 and TNF-α gene polymorphisms with clearance of chronic hepatitis B infection and risk of hepatocellular carcinoma in Thai population,” Journal of Viral Hepatitis, vol. 14, no. 12, pp. 841–848, 2007.

P. X. Xing, M. J. Zou, Q. T. Xing, H. C. Wang, and Y. S. Wang, “Relationship between proinflammatory cytokine gene polymorphisms and diseases of HBV infection,” Journal of Shandong University, vol. 45, pp. 1229–1233, 2007.

P. V. Suneetha, S. K. Sarin, A. Goyal, G. T. Kumar, D. K. Shukla, and S. Hissar, “Association between vitamin D receptor, CCR5, TNF-α and TNF-β gene polymorphisms and HBV infection and severity of liver disease,” Journal of Hepatology, vol. 44, no. 5, pp. 856–863, 2006.

M. H. Somi, L. Najafi, B. Noori N et al., “Tumor necrosis factor-alpha gene promoter polymorphism in Iranian patients with chronic hepatitis B,” Indian Journal of Gastroenterology, vol. 25, no. 1, pp. 14–15, 2006.

C. Li, C. Zhi-Xin, Z. Li-Juan, P. Chen, and W. Xiao-Zhong, “The association between cytokine gene polymorphisms and the outcomes of chronic HBV infection,” Hepatology Research, vol. 36, no. 3, pp. 158–166, 2006.

J. Y. Cheong, S. W. Cho, I. L. Hwang et al., “Association between chronic hepatitis B virus infection and interleukin-10, tumor necrosis factor-α gene promoter polymorphisms,” Journal of Gastroenterology and Hepatology, vol. 21, no. 7, pp. 1163–1169, 2006.

T. Du, X. H. Guo, X. L. Zhu et al., “Association of TNF-α promoter polymorphisms with the outcomes of hepatitis B virus infection in Chinese Han population,” Journal of Viral Hepatitis, vol. 13, no. 9, pp. 618–624, 2006.

P. A. Zhang, WJ, Y. Li, and P. X. Xiang, “Association of tumor necrosis factor-α gene promoter polymorphisms with susceptibility of hepatitis B virus infection,” Chinese Journal of Microcirculation, vol. 15, pp. 76–79, 2005.

G. A. Niro, R. Fontana, D. Gioffreda et al., “Tumor necrosis factor gene polymorphisms and clearance or progression of hepatitis B virus infection,” Liver International, vol. 25, no. 6, pp. 1175–1181, 2005.

X. W. Xu, M. H. Lu, and D. M. Tan, “Association between tumour necrosis factor gene polymorphisms and the clinical types of patients with chronic hepatitis B virus infection,” Clinical Microbiology and Infection, vol. 11, no. 1, pp. 52–56, 2005.

Y. Liu, X. Guo, T. Du, J. H. Li, X. L. Zhu, and J. R. Gao, “Association of TNF-α polymorphisms with the outcomes of HBV infection,” Chinese Journal of Medical Genetics, vol. 22, pp. 406–410, 2005.

Y. S. Zhou, F. S. Wang, M. X. Liu, L. Jin, and W. G. Hong, “Relationship between susceptibility of hepatitis B virus and gene polymorphism of tumor necrosis factor-α,” World Chinese Journal of Digestology, vol. 13, no. 2, pp. 207–210, 2005.

Y. Liu, X. Gou, T. Du, J. H. Li, X. L. Zhu, and J. R. Gao, “Association of TNF-α polymorphisms with the outcomes of HBV infection,” Chinese Journal of Medical Genetics, vol. 22, pp. 406–410, 2005.

P. A. Zhang, Y. Li, P. X. Xiang, and J. M. Wu, “Association of TNF-α gene promoter polymorphisms with outcome of hepatitis B virus infection,” World Chinese Journal of Digestology, vol. 12, no. 9, pp. 2086–2090, 2004.

Y. J. Kim, H. S. Lee, J. H. Yoon et al., “Association of TNF-α promoter polymorphisms with the clearance of hepatitis B virus infection,” Human Molecular Genetics, vol. 12, no. 19, pp. 2541–2546, 2003.

S. Miyazoe, K. Hamasaki, K. Nakata et al., “Influence of interleukin-10 gene promoter polymorphisms on disease progression in patients chronically infected with hepatitis B virus,” American Journal of Gastroenterology, vol. 97, no. 8, pp. 2086–2092, 2002.

J. Lin, Y. Cheng, D. Tian et al., “Tumor necrosis factor alpha HLA-DRB(1) gene polymorphism and genetic susceptibility to cirrhosis,” Zhonghua nei ke za zhi, vol. 41, no. 12, pp. 818–821, 2002.

T. Heise, L. G. Guidotti, and F. V. Chisari, “La autoantigen specifically recognizes a predicted stem-loop in hepatitis B virus RNA,” Journal of Virology, vol. 73, no. 7, pp. 5767–5776, 1999.

M. D. Robek, S. F. Wieland, and F. V. Chisari, “Inhibition of hepatitis B virus replication by interferon requires proteasome activity,” Journal of Virology, vol. 76, no. 7, pp. 3570–3574, 2002.

E. Lara-Pezzi, P. L. Majano, M. Gómez-Gonzalo et al., “The hepatitis B virus X protein up-regulates tumor necrosis factor α gene expression in hepatocytes,” Hepatology, vol. 28, no. 4 I, pp. 1013–1021, 1998.

M. H. Zheng, D. D. Xiao, X. F. Lin, S. J. Wu, M. M. Peng, X. Y. Yu, et al., “The tumour necrosis factor-alpha-238A allele increases the risk of chronic HBV infection in European populations,” Journal of Viral Hepatitis, vol. 19, no. 2, pp. e11–e17, 2012.

P. Zhou, G. Q. Lv, J. Z. Wang et al., “The TNF-α-238 polymorphism and cancer risk: a meta-analysis,” PLoS ONE, vol. 6, no. 7, Article ID e22092, 2011.

Y. Y. Li, “Tumor necrosis factor-alpha g308alpha gene polymorphism and essential hypertension: a meta-analysis involving 2244 participants,” PLoS ONE, vol. 7, no. 4, Article ID e35408, 2012.

L. Liu, X. Yang, X. Chen, T. Kan, Y. Shen, Z. Chen, et al., “Association between TNF-α polymorphisms and cervical cancer risk: a meta-analysis,” Molecular Biology Reports, vol. 39, no. 3, pp. 2683–2688, 2012.

Y. Wei, F. Liu, B. Li et al., “Polymorphisms of tumor necrosis factor-alpha and hepatocellular carcinoma risk: a HuGE systematic review and meta-analysis,” Digestive Diseases and Sciences, vol. 56, no. 8, pp. 2227–2236, 2011.

J. Li, C. F. Hao, W. Yao, Y. X. Yun, B. Gao, and Y. X. Wang, “A meta-analysis of susceptibility to pneumoconiosis and polymorphism of tumor necrosis factor-alpha 308 and 238 locus,” Chinese Journal of Preventive Medicine, vol. 45, no. 6, pp. 547–552, 2011.

B. Zhang, T. Liu, and Z. Wang, “Association of tumor necrosis factor-alpha gene promoter polymorphisms (-308G/A, -238G/A) with recurrent spontaneous abortion: a meta-analysis,” Human Immunology, vol. 73, no. 5, pp. 574–579, 2012.

Z. Yang, X. Qi, Q. Wu, A. Li, P. Xu, and D. Fan, “Lack of association between TNF-α gene promoter polymorphisms and pancreatitis: a meta-analysis,” Gene, vol. 503, no. 2, pp. 229–234, 2012.

C. Xie, X. F. Liu, and M. S. Yang, “A meta-analysis on the association between three promoter variants of TNF-α and Crohn's disease,” Molecular Biology Reports, vol. 39, no. 2, pp. 1575–1583, 2012.

J. He, X. Pei, W. Xu, C. Wang, X. Zhang, J. Wu, et al., “The relationship between tumor necrosis factor-alpha polymorphisms and hepatitis C virus infection: a systematic review and meta-analysis,” Renal Failure, vol. 33, no. 9, pp. 915–922, 2011.

L. Y. Wu, Y. Zhou, C. Qin, and B. L. Hu, “The effect of TNF-α, FcgammaR and CD1 polymorphisms on Guillain-Barre syndrome risk: evidences from a meta-analysis,” Journal of Neuroimmunology, vol. 243, no. 1-2, pp. 18–24, 2012.

Q. Wang, P. Zhan, L. X. Qiu, Q. Qian, and L. K. Yu, “TNF-308 gene polymorphism and tuberculosis susceptibility: a meta-analysis involving 18 studies,” Molecular Biology Reports, vol. 39, no. 4, pp. 3393–3400, 2012.

Y. H. Lee, S. J. Choi, J. D. Ji, and G. G. Song, “CTLA-4 and TNF-α promoter-308 A/G polymorphisms and ANCA-associated vasculitis susceptibility: a meta-analysis,” Molecular Biology Reports, vol. 39, no. 1, pp. 319–326, 2012.

A. Baena, J. Y. Leung, A. D. Sullivan et al., “TNF-α promoter single nucleotide polymorphisms are markers of human ancestry,” Genes and Immunity, vol. 3, no. 8, pp. 482–487, 2002.

M. H. Zheng, L. X. Qiu, Y. N. Xin, H. F. Pan, K. Q. Shi, and Y. P. Chen, “Tumor necrosis factor-α-308A allele may have a protective effect for chronic hepatitis B virus infection in Mongoloid populations,” International Journal of Infectious Diseases, vol. 14, no. 7, pp. e580–e585, 2010.

L. G. Guidotti, P. Borrow, M. V. Hobbs et al., “Viral cross talk: intracellular inactivation of the hepatitis B virus during an unrelated viral infection of the liver,” Proceedings of the National Academy of Sciences of the United States of America, vol. 93, no. 10, pp. 4589–4594, 1996.

L. G. Guidotti, T. Ishikawa, M. V. Hobbs, B. Matzke, R. Schreiber, and F. V. Chisari, “Intracellular inactivation of the hepatitis B virus by cytotoxic T lymphocytes,” Immunity, vol. 4, no. 1, pp. 25–36, 1996.

M. R. Thursz, D. Kwiatkowski, C. E. M. Allsopp, B. M. Greenwood, H. C. Thomas, and A. V. S. Hill, “Association between an MHC class II allele and clearance of hepatitis B virus in the gambia,” The New England Journal of Medicine, vol. 332, no. 16, pp. 1065–1069, 1995.

S. H. Ahn, K. H. Han, J. Y. Park, et al., “Association between hepatitis B virus infection and HLA-DR type in Korea,” Hepatology, vol. 31, no. 6, pp. 1371–1373, 2000.

P. Juszczynski, E. Kalinka, J. Bienvenu et al., “Human leukocyte antigens class II and tumor necrosis factor genetic polymorphisms are independent predictors of non-Hodgkin lymphoma outcome,” Blood, vol. 100, no. 8, pp. 3037–3040, 2002.

K. Negoro, Y. Kinouchi, N. Hiwatashi et al., “Crohn's disease is associated with novel polymorphisms in the 5'- flanking region of the tumor necrosis factor gene,” Gastroenterology, vol. 117, no. 5, pp. 1062–1068, 1999.

T. Higuchi, N. Seki, S. Kamizono et al., “Polymorphism of the 5'-flanking region of the human tumor necrosis factor (TNF)-α gene in Japanese,” Tissue Antigens, vol. 51, no. 6, pp. 605–612, 1998.

K. M. Kroeger, K. S. Carville, and L. J. Abraham, “The -308 tumor necrosis factor-α promoter polymorphism effects transcription,” Molecular Immunology, vol. 34, no. 5, pp. 391–399, 1997.

A. G. Wilson, J. A. Symons, T. L. McDowell, H. O. McDevitt, and G. W. Duff, “Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 7, pp. 3195–3199, 1997.

H. H. Fidder, R. Heijmans, Y. Chowers et al., “TNF-857 polymorphism in Israeli Jewish patients with inflammatory bowel disease,” International Journal of Immunogenetics, vol. 33, no. 2, pp. 81–85, 2006.

M. C. Warlé, A. Farhan, H. J. Metselaar et al., “Are cytokine gene polymorphisms related to in vitro cytokine production profiles?” Liver Transplantation, vol. 9, no. 2, pp. 170–181, 2003.

C. E. Murcray, J. P. Lewinger, D. V. Conti, D. C. Thomas, and W. J. Gauderman, “Sample size requirements to detect gene-environment interactions in genome-wide association studies,” Genetic Epidemiology, vol. 35, no. 3, pp. 201–210, 2011.

S. H. Jung, “Sample size and power calculation for molecular biology studies,” Methods in Molecular Biology, vol. 620, pp. 203–218, 2010.

Y. Yang, E. F. Remmers, C. B. Ogunwole, D. L. Kastner, P. K. Gregersen, and W. Li, “Effective sample size: quick estimation of the effect of related samples in genetic case-control association analyses,” Computational Biology and Chemistry, vol. 35, no. 1, pp. 40–49, 2011.

K. Kubota and A. Wakana, “Sample-size formula for case-cohort studies,” Epidemiology, vol. 22, no. 2, p. 279, 2011.

L. M. Chen, J. G. Ibrahim, and H. Chu, “Sample size and power determination in joint modeling of longitudinal and survival data,” Statistics in Medicine, vol. 30, no. 18, pp. 2295–2309, 2011.

S. L. West, G. Gartlehner, A. J. Mansfield, et al., “Comparative effectiveness review methods: clinical heterogeneity,” Tech. Rep. 10-EHC070-EF, Agency for Healthcare Research and Quality (US), Rockville, Md, USA, 2010, AHRQ Methods for Effective Health Care.

E. W. Steyerberg and M. J. C. Eijkemans, “Heterogeneity bias: the difference between adjusted and unadjusted effects,” Medical Decision Making, vol. 24, no. 1, pp. 102–104, 2004.

K. M. Kuntz and S. J. Goldie, “Assessing the sensitivity of decision-analytic results to unobserved markers of risk: defining the effects of heterogeneity bias,” Medical Decision Making, vol. 22, no. 3, pp. 218–227, 2002.

H. Sato, A. Watanabe, T. Tanaka et al., “Regulation of the human tumor necrosis factor-α promoter by angiotensin II and lipopolysaccharide in cardiac fibroblasts: different cis-acting promoter sequences and transcriptional factors,” Journal of Molecular and Cellular Cardiology, vol. 35, no. 10, pp. 1197–1205, 2003.