Impact of host gene polymorphisms on susceptibility to chronic hepatitis B virus infection

Infection, Genetics and Evolution 44 (2016) 94–105

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Infection, Genetics and Evolution journal homepage: www.elsevier.com/locate/meegid

Review

Impact of host gene polymorphisms on susceptibility to chronic hepatitis B virus infection Bita Moudi, Zahra Heidari ⁎, Hamidreza Mahmoudzadeh-Sagheb a b

Infectious Diseases and Tropical Medicine Research Center, Zahedan University of Medical Sciences, Zahedan, Iran Department of Histology, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran

a r t i c l e

i n f o

Article history: Received 6 April 2016 Received in revised form 21 June 2016 Accepted 22 June 2016 Available online 23 June 2016 Keywords: Hepatitis B virus Cytokine Genetic Polymorphism

a b s t r a c t Hepatitis B virus (HBV) infection can result in a number of different clinical conditions, including asymptomatic HBV carriers to chronic hepatitis and primary hepatocellular carcinoma. Variations in cytokine genes have been discussed to affect the natural history of HBV infection. These cytokines may involve in the viral binding to the cells, modulating the host immune response to infection and pathological changes in the liver, and affecting the antiviral therapies. Various studies reveal that SNPs play an important role in pathogenesis of HBV. On the other hand, various outcomes of infection cannot be completely shown by genetic factors because these studies have inconsistent results with regard to the possible impacts of host genetic polymorphisms on susceptibility to infection. Therefore, to identify the real effects of host genetic factors in HBV susceptibility and natural history of the disease, studies with large sample size will be needed. In addition, due to the complex interactions of genetic factors it is better to identify synergies of several SNPs. Such studies can provide better insights into the novel methods of diagnosis and treatment. Current review will discuss significant genetic variations in cytokine genes that may affect the susceptibility to the chronic HBV infection. © 2016 Elsevier B.V. All rights reserved.

Contents 1. 2.

Introduction . . . . . . . . . . . . . . . . . . . . . Genetic factors affecting the susceptibility to HBV infection 2.1. Cytokines . . . . . . . . . . . . . . . . . . . 2.1.1. IL-6 . . . . . . . . . . . . . . . . . . 2.1.2. IL-10 . . . . . . . . . . . . . . . . . 2.1.3. IL-28B . . . . . . . . . . . . . . . . . 2.1.4. TGF-β . . . . . . . . . . . . . . . . . 2.1.5. IFN-γ . . . . . . . . . . . . . . . . . 2.1.6. TNF-α. . . . . . . . . . . . . . . . . 2.1.7. MIF . . . . . . . . . . . . . . . . . . 2.2. HLA . . . . . . . . . . . . . . . . . . . . . . 2.3. Other candidate genes . . . . . . . . . . . . . 2.3.1. Chemokines . . . . . . . . . . . . . . 2.3.2. Vitamin D . . . . . . . . . . . . . . . 3. Summary. . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . . . . . .

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Abbreviations: HBV, hepatitis B virus; MHC, major histocompatibility complex; SNP, single nucleotide polymorphism; IFN-γ, interferon gamma; IL-6, interleukin 6; IL-10, interleukin10; IL-28B, interleukin 28B; TGF-β, Transforming growth factor beta; TNFα, tumor necrosis factor alpha; MIF, macrophage migration inhibitory factor; HLA, human leukocyte antigen. ⁎ Corresponding author at: Department of Histology, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran. E-mail addresses: [email protected] (B. Moudi), [email protected] (Z. Heidari), [email protected] (H. Mahmoudzadeh-Sagheb).

http://dx.doi.org/10.1016/j.meegid.2016.06.043 1567-1348/© 2016 Elsevier B.V. All rights reserved.

B. Moudi et al. / Infection, Genetics and Evolution 44 (2016) 94–105

1. Introduction Hepatitis B virus (HBV) is one of the most dangerous pathogens in the world. HBV infection has a dichotomous outcome; it may be acute, or persistent. Chronic hepatitis B virus (HBV) infection is an important infection that leads to major chronic liver diseases such as liver cirrhosis and hepatocellular carcinoma (HCC). Usually, in 5% of HBV infected patients, acute HBV infection can go on to develop chronic infection. This common severe illness is the reason of high mortality in the year worldwide (more than one million deaths). It is estimated that there are more than 200 millions people with chronic HBV infection in the world and 75% of them are from Asia. It is estimated that more than 25% of chronic HBV infected patients in Asia will die because of the HBV related chronic diseases. Chronic HBV infection is a major public health problem and an endemic disease in developing countries (Lavanchy, 2004). Transmission routes of hepatitis B are different in various parts of the world. In areas with high prevalence, HBV is transmitted mainly from mother to infant at birth via vertical transmission. The rate of vertical transmission is more than 90%. The most important route of transmission in areas with medium prevalence is transmission from an infected person during childhood and adolescence by horizontal transmission. In regions with low prevalence, unsafe sexual contact and injecting the drug with unsterilized needles are the most important routes of transmission in adults. Hepatitis B virus can survive outside of the body for a long time. Therefore, exposure to contaminated things such as toothbrushes, razors, toys and body fluids can increase the risk of HBV infection. Blood transfusion and contact with infected blood are also important ways in HBV transmission. The chance of infection transmission through the blood and blood products is about 6 to 8%. The outcomes of HBV infection vary among different infected subjects and not yet completely known. HBV can lead to different clinical manifestations and/ or no infection (Iino, 2002; Rantala and Van de Laar, 2008; Schweitzer et al., 2015). It seems there are three factors which can determine different natural history of HBV infection in infected subjects (Abel and Dessein, 1997; Ferrari, 1995; Guidotti and Chisari, 2001; McNicholl, 1998; McNicholl and Cuenco, 1999; Thursz, 2000). First of all is virological factors such as viral load, genotype and genetic variability in HBV virus genome. These pathogen-related factors can affect the host immune responses. The second is environmental factors such as immunological factors, treatment and nutrition. These parameters can change the outcome of HBV infection and host susceptibility to HBV infection. Finally, it is believed that the host genetic factors are the third agent which can change the outcomes of HBV infection. Although the effects of virological and environmental factors on HBV infection have been well known but the influence of the host genetic factors on susceptibility to HBV infection is not clearly understood (Dean et al., 2002; Grünhage and Nattermann, 2010; Hill, 1998a; Hill, 1998b; Mackay, 2006; McNicholl et al., 2000; Thursz, 1997; Thursz et al., 2011). Studies on identical twins reveals that host genetic factors can alter the natural history of HBV infection (Lin et al., 1989). The major histocompatibility complex (MHC) class I and class II, vitamin D receptor, cytokine, chemokine and their receptor genes are important compounds which have been studied for the relationship between the polymorphisms such as single nucleotide polymorphism (SNP) and the susceptibility to HBV infection. These polymorphisms, especially those one in the promoter region of genes, can affect the function and levels of the proteins. These events can increase or reduce the susceptibility to infectious diseases (de Andrade, 2004). Therefore, the focus of current article is to review the relationship between human genetic alleles and susceptibility to HBV infection. 2. Genetic factors affecting the susceptibility to HBV infection 2.1. Cytokines Cytokines are small proteins (approximately 5–20 kDa) that have important roles in cell signaling. They are produced by various cells

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such as macrophages, lymphocytes, mast cells, endothelial cells, fibroblasts, and stromal cells. Cytokines regulate host immune responses against infection, inflammation, trauma and cancer through their receptors (Dinarello, 2007). Type 1 cytokines such as interleukin-2 (IL-2), interleukin-12 (IL-12), interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α) are produced by helper T 1 (Th1) lymphocytes and enhance cellular immune responses. On the other side, type 2 cytokines such as Transforming growth factor beta (TGF-β), interleukin-4 (IL-4), interleukin-10 (IL-10), interleukin-13 (IL-13) and interleukin-28 (IL-28) are produced by T helper 2 (Th2) lymphocytes and regulate humoral immune responses. Some cytokines are cross-regulatory factors, it means that IFN-γ can decrease the levels of type 2 cytokines while IL-10 can decrease the levels of type 1 cytokines (Daniel et al., 1996). Inflammatory cytokines are induced by oxidative stress. Some cytokines can control the release of other cytokines. This event leads to increased oxidative stress in chronic inflammations (Chokkalingam et al., 2013; David et al., 2007; Vlahopoulos et al., 1999). A number of cytokines have been associated with chronic hepatitis B infection (Table 1.). Some of them have polymorphisms in their genes which have influenced the susceptibility to other chronic inflammations such as periodontal diseases (Heidari, 2014; Heidari et al., 2015a; Heidari et al., 2014a; Heidari et al., 2013; Heidari et al., 2015b; Heidari et al., 2014b; Sanchooli et al., 2012; Solhjoo et al., 2014). A number of cytokines such as IL-28 (Heidari et al., 2016), IL10 (Moudi et al., 2016) have changed natural history of HBV infection. Although, the key role of these T cell derived compounds in the pathogenesis of hepatitis B infection is unknown (McNicholl et al., 2000; Thursz, 1997). The relationship between chronic HBV infection and polymorphisms of genes encoding more important cytokines is reviewed in the following. 2.1.1. IL-6 Interleukin 6 (IL-6) is a pro-inflammatory and anti-inflammatory cytokine. IL-6 is secreted by T cells and macrophages after tissue damages leading to inflammation and is responsible for fever in infectious diseases, either acute or chronic. IL-6 can also improve osteoclast differentiation and bone absorptive process (Sanchooli et al., 2012; Scheller et al., 2011). It is involved in the pathogenesis of HBV infection and HBV-related clinical progression (Palumbo et al., 2015). During infection, T cells and macrophages produce IL-6 to regulate immune responses (Scheller et al., 2011). IL-6 cytokine stimulates the immune responses against hepatitis B virus infection. It seems that the level of IL-6 expression is associated to the susceptibility to chronic HBV infection (Dinarello, 1996; Song et al., 2000). It can regulate the biological function of several cells, such as hepatocytes. Increased levels of IL-6 have been reported in patients with chronic HBV, cirrhosis and HCC. It has been found that hepatitis B virus replication could be suppressed by IL-6, which leads to reduced the accumulation of HBV covalently closed circular DNA (cccDNA) in hepatocytes (Kuo et al., 2009; Palumbo et al., 2015). In addition, HBV infection is largely recognized by liver macrophages such as Kupffer cells. Induced Kupffer cells activate the nuclear factor kappa B (NF-kappaB) and secret IL-6 cytokine. Subsequently, IL-6 affect HBV gene expression and replication in hepatocytes (Hösel et al., 2009). Thus, it is suggested that IL-6 can be a diagnostic marker of chronic HBV infection. The IL-6 is encoded by the IL-6 gene localized on chromosome 7p21. Some studies demonstrated that polymorphisms of this gene can affect the concentration of IL-6 in serum (Erciyas et al., 2010; Mesa et al., 2014). Polymorphisms in promoter region of IL-6 gene affect transcription and expression of IL-6 in individuals. There are three SNPs in the IL6 promoter region (−597G/A, −572C/G and −174G/C), that have been reported in chronic HBV patients. These SNPs control the up-regulation of IL-6 levels. However, studies conducted by Ben-Ari et al. (2003), Park et al. (2003) and Giannitrapani et al. (2013) have been reported no

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Table 1 Cytokines polymorphisms involved in hepatitis B virus infection risk. Cytokine gens

SNP analyzed

Disease association Ref NS/RISK/PROTECTION

IL-6

−174G/C −597G/A, −572C/G, −174G/C −597G/A, −572C/G −597G/A, −572C/G, −174G/C −1082 A/G −819 T/C −1082 A/G −1082 A/G −592 A/C −592 A/C −1082 A/G, −819 T/C, −592 A/C −819 T/C, −592 A/C rs12979860C/T, rs8099917G/T

NS NS RISK RISK RISK RISK PROTECTION RISK PROTECTION RISK RISK RISK NS

rs12979860C/T

NS

rs12979860, rs12980275 and rs8099917 rs12979860, rs12980275 and rs8099917 rs12979860C/T, rs8099917G/T rs8099917G/T rs12979860C/T rs12979860, rs12980275, rs8105790 rs12979860C/T rs8099917G/T −509C/T, +915G/C −509C/T, −800G/A, −988C/A −509C/T −800GNA, −509CNT, Leu10Pro and Arg25Pro +874A/T +874A/T +874A/T, +2109A/G IFN-γ +874 and IFNGR-1 (−56 and −611) −308 G/A, −238 G/A −238 G/A −863C/A −857C/T −857C/T, −308 G/A −238 G/A, −308 G/A rs361525, rs1800629, rs1799724, rs1800630 and rs1799964 −1031TNC, −863CNA, −857CNT, −376GNA, −308GNA, −238GNA and −163GNA −238G/A, −308G/A, −857C/T, −863C/A, −1031T/C −308G/A MIF-173 G/C DRB1 DQA1, DQB1 DPA1 and DPB1 DPA1 and DPB1 DR13 HLA-B35, HLA-CW4, HLA-DQ2, and HLA-DQ8 HLA (A, B, DRB1) HLA-C, HLA-DP and HLA-DQ. CCR5-D32 CCR5-D 32 VDR Apa1 Codon 352

PROTECTION NS PROTECTION PROTECTION PROTECTION PROTECTION RISK RISK NS NS PROTECTION RISK RISK NS RISK RISK RISK RISK RISK PROTECTION PROTECTION RISK RISK RISK/PROTECTION

(Cheong et al., 2006a; Tseng et al., 2006) (Miyazoe et al., 2002; Peng et al., 2006; Shin et al., 2003a (Saxena et al., 2014a) (Da Silva Conde et al., 2014; De Niet et al., 2012; Heidari et al., 2016; Martin-Carbonero et al., 2012) (Holmes et al., 2013; Kandemir et al., 2013; Martin et al., 2010; Peng et al., 2012; Sonneveld et al., 2012; Zhang et al., 2014a) (Li et al., 2011) (Kim et al., 2013; Lee et al., 2013) (Seto et al., 2013) (Wu et al., 2012) (Lampertico et al., 2013) (Al-Qahtani et al., 2014) (Chen et al., 2012) (Li et al., 2012) (Hosseini Razavi et al., 2014) (Yang et al., 2005) (Kim et al., 2003a; Qi et al., 2009; Saxena et al., 2014b) (Falleti et al., 2008) (Ben-Ari et al., 2003; Saxena et al., 2014c) (Cheong et al., 2006b) (Liu et al., 2006a) (Korachi et al., 2013) (Zhang et al., 2011a) (HOHLER et al., 1998a; Lu et al., 2004; Zheng et al., 2012) (Kummee et al., 2007) (Shi et al., 2012) (Zhang et al., 2014b) (Cheong et al., 2006a) (Fletcher et al., 2011) (Kim et al., 2003b)

RISK/PROTECTION NS RISK PROTECTION PROTECTION RISK/PROTECTION PROTECTION PROTECTION RISK/PROTECTION RISK/PROTECTION PROTECTION RISK NS RISK PROTECTION

(Du et al., 2006) (Somi et al., 2006) (Zhang et al., 2013) (Hohler et al., 1997; Thio et al., 2003; Thursz et al., 1995) (Thio et al., 1999) (Guo et al., 2011; Kamatani et al., 2009) (Nishida et al., 2012) (Diepolder et al., 1998) (Albayrak et al., 2011) (Wu et al., 2004) (Hu et al., 2013) (Suneetha et al., 2006) (Ahn et al., 2006; Chang et al., 2005) (Suneetha et al., 2006) (Bellamy and Hill, 1998; Bellamy et al., 1999)

0IL-10

IL-28B

TGF-β

IFN-γ

TNF-α

MIF HLA

Chemokines Vitamin D Receptor

significant associations between IL-6 promoter variants and disease outcome in chronic HBV. In these studies, it has been reported that there was no significant difference between individuals with at least one IL6-572-G allele, compared to the CC genotype in regard to the occurrence of HBV-related HCC and cirrhosis. Moreover, there was a significant negative association between HBV-related HCC and IL-6-597 GA genotype. There was also no statistically significant difference in the genetic ability to produce IL-6 at position −174G/C. On the other hand, analysis the relationship between IL-6 (− 572C/G) genotypes and risk of HBVrelated HCC showed that there was a significant negative association for HCC development in individuals with GC genotype. While it seems that the CC genotype is an important protective factor for HBV-related cirrhosis development (Saxena et al., 2014d). Although, the studies in Spanish population reported that IL-6-597G allele is related to the

(Ben-Ari et al., 2003; Giannitrapani et al., 2013) (Park et al., 2003) (Saxena et al., 2014d) (Villuendas et al., 2002) (Moudi et al., 2016; Wu et al., 2011) (Ren et al., 2015) (Zhu et al., 2005) (Zhang et al., 2011b)

increased levels of IL-6 in serum, but there was no significant relationship between IL-6-572 and IL-6-597 genotypes and IL-6 levels (Villuendas et al., 2002). 2.1.2. IL-10 Interleukin-10 (IL-10) is an anti-inflammatory cytokine which produced by monocytes mainly T cells. It is a type 2 cytokine also known as human cytokine synthesis inhibitory factor (CSIF). Interleukin-10 is encoded by the IL-10 gene, which is located on chromosome 1q31– q32. IL-10 has pleiotropic effects on inflammation. It can regulate the expression of Th1 cytokines and MHC class II antigens and enhances the Janus kinase-Signal Transducer and Activator of Transcription (JAK-STAT) signaling pathway (Levings et al., 2001; Mosser and Zhang, 2008; Moudi et al., 2016).

B. Moudi et al. / Infection, Genetics and Evolution 44 (2016) 94–105

IL-10 can suppress the host Th1 immune response by inhibiting the expression of pro-inflammatory cytokines such as IL-2, TNF-alpha and IFN-gamma in Th1 cells (Pestka et al., 2004). In addition, during a viral infection, cytotoxic T-cells can inhibit the action of natural killer cells by releasing IL-10 (Eskdale et al., 1997). Therefore, IL-10 is an important immunoregulatory factor in the host immune system. It has been shown that polymorphisms in the IL-10 gene were related to the increased susceptibility to infectious and chronic diseases such as chronic periodontitis (unpublished data) HBV and HIV (Kallas et al., 2015; Ren et al., 2015). The expression of IL-10 protein is controlled at the transcriptional and post-transcriptional level. In patients with chronic hepatitis, the production of inappropriate amounts of IL-10, was reported to be associated with infection clearance (Fonseca et al., 2007; Yang et al., 2003). Low levels of IL-10 have been reported in patients with Multiple Sclerosis. Decrease in IL-10 levels leads to increased TNF-α levels. High amounts of TNF-α result in inflammation and chronic diseases (Fionula et al., 2008; Nakahara et al., 2012; OZENCI et al., 1999). A number of SNPs have been reported in the IL-10 gene which could influence the biological function of interleukin-10 (Hurme et al., 1998). The promoter region of IL-10 gene contains three SNPs at position −1082 (A/G), −819 (T/C), and −592 (A/C), which may have an effect on susceptibility to HBV infection. Increased levels of IL-10 have protective effects against HBV infection. Moreover, the existence of IL-10-1082 G allele is related to the hepatitis B virus clearance during intrauterine HBV infection (Zhu et al., 2005) and IL-10-1082 GG genotype is associated with reduced HBV viral load in children with chronic HBV infection (Wu et al., 2011). However, there are conflicting results in some studies on the polymorphism of IL-10 and HBV infection. Recently, we showed that IL-101082 G allele significantly more represented in HBV patients in comparison to healthy group (Moudi et al., 2016). We found higher frequencies of AG and GG genotypes at IL-10-1082 in HBV patients compared to the healthy controls. These genotypes were associated with increased susceptibility to HBV. None of the IL-10 − 592 A/C and − 819 T/C alleles or genotypes was associated with susceptibility to HBV. In a meta-analysis, Zhang et al. (2011b) reported that IL-10 − 1082AG polymorphism might affect susceptibility to HBV infection. On the other hand, IL-10 − 592 A/C SNP could improve the clearance of HBV (Zhang et al., 2011b). Individuals with −592A allele have an increased risk to HBV infection (Cheong et al., 2006a). In another study, Miyazoe et al. (2002) found that the −819T and −592A wild-type alleles were significantly more frequent in asymptomatic carriers than in patients with chronic progressive liver diseases. It means that these SNPs are inherited together and may affect progression of disease due to reduced IL-10 expression. Moreover, IL-10 SNPs are associated with higher risk of HBV-related HCC in some populations (Shin et al., 2003c; Tseng et al., 2006; Wang et al., 2006). Further, as reported by Saxena et al. (2014a) and Saxena and Kaur (2015), the CC/TA genotype of − 592 A/C and − 819 T/C to be in a significant positive association with HBV-related HCC and disease development. While Nieters et al. (2005) showed that the wild and heterozygous genotypes had no significant association with HCC. Moreover, combination of different alleles of the IL-10 SNPs (−592 A/C, − 819 T/C, − 1082 A/G) revealed that CCG haplotype was significantly more frequent in HBV group in comparison to control group and appeared to be associated with susceptibility to HBV (Moudi et al., 2016). In previous studies, the CCG haplotype was associated with increased IL-10 production compared with the ATA and CCA haplotypes (Turner et al., 1997). In addition, Afzal et al. (2011), showed that there were significant differences between HBV patients and controls in regard to ATG and CCA haplotypes. Haplotype analysis in Japanese and Chinese populations also revealed that IL-10 haplotype ATA was related to the persistent of HBV infection (Miyazoe et al., 2002; Peng et al., 2006). However, according to some data from Caucasian, Italy and Japan, there is no association between IL-10 haplotypes and chronic

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HBV infection (Kusumoto et al., 2006; Mangia et al., 2004; Shin et al., 2003b). These data suggest that the role of IL-10 cytokine in host immune system is complex and will need further elucidation.

2.1.3. IL-28B Interleukin 28B (IL-28B), also named as interferon-λ 3, is a class II cytokine that is encoded by the IL-28B gene (Heidari et al., 2016). It is related to type I interferon family. IL-28A, IL-28B and IL-29 genes are related cytokine genes that located on chromosome 19q13 and produce a cytokine gene cluster. Viral infection can induce the expression of this gene cluster (Sheppard et al., 2003). Studies have showed that treatment of mononuclear cells with viral infection induced production of IL-28 and IL-29 which led to protection against virus infection. Studies about luciferase revealed that IL-28 and IL-29 could induce immune responses through IFN-related cascades. On the other hand, IL-28 could bind to IL-28RA (IFNLR1) receptor that is contributed to the IL-10RB receptor. It means that IL-28 makes a relationship between type I IFNs and IL-10 family (Sheppard et al., 2003). Studies have been shown that some polymorphisms near the IL-28B gene can improve the clinical situations of chronic hepatitis C infected patients who treated with interferon and ribavirin (Ge et al., 2009). It seems that IL-28B protein is part of the host immune responses to protect against hepatitis C infection. Therefore, variations of the IL-28B gene may lead to appropriate immune response. These variations induce clearing the hepatitis C virus in the acute and/or chronic phase. IL-28B as a potential treatment for viral hepatitis, can reduce HBV replication in hepatocyte cell lines (Robek et al., 2005). Based on these facts, it seems that IL-28B might have an important role in patients with chronic hepatitis B infection. Several analyses of IL-28B SNPs in chronic hepatitis B patients yielded conflicting results. Some studies did not find significant relationship between IL-28B SNPs and HBV susceptibility (Da Silva Conde et al., 2014; De Niet et al., 2012; Heidari et al., 2016; Holmes et al., 2013; Kandemir et al., 2013; Kim et al., 2013; Lee et al., 2013; Li et al., 2011; Martin-Carbonero et al., 2012; Martin et al., 2010; Ochi et al., 2011; Seto et al., 2013; Tseng et al., 2011; Zhang et al., 2014a). In contrast, other studies showed some favorable genotypes that can predict virological and serological responses in HBeAg-negative and/or positive patients (Lampertico et al., 2013; Seto et al., 2013; Sonneveld et al., 2012; Wu et al., 2012). Some SNPs in IL-28B gene are related to the sustained viral response and spontaneous viral clearance in patients with chronic HBV infection. Al-Qahtani et al. (2014) showed that IL-28B polymorphisms were associated with HBV clearance. Also, IL-28B SNPs might be a good predicting factor for HBV infection recurrence and hepatic dysfunction after liver transplantation (Chen et al., 2012; Li et al., 2012). Seto et al. (2013) showed that IL-28B SNPs were associated with HBsAg seroconversions. Holmes et al. (2013) reported that IL-28B SNPs might not related to the HBeAg and HBsAg seroconversions to interferon treatment in Asian population but not in other populations (Lampertico et al., 2013; Sonneveld et al., 2012). In addition, it was reported that there were no associations between IL-28B SNPs and clearance of HBV in patient with persistent infection compared to the patients recovered from infection(Peng et al., 2012). Moreover, recently we analyzed IL-28B SNPs in chronic HBVinfected patients and controls. Our findings revealed that there were no differences in allele and genotype frequencies of the genetic variants of IL-28B between chronic HBV-infected patients and control (Heidari et al., 2016). The best explanations for these conflicting results in chronic HBV are different genetic backgrounds, the heterogeneity between the study populations, different sample size and type of treatment regimens. Based on abovementioned studies, it seems that IL-28B polymorphisms have lower importance in chronic HBV risk compared to the HCV. Therefore, to estimate the possible role of IL-28B SNPs in HBV

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infection, it must be combined with a number of factors such as other cytokines and viral genotypes.

and ethnic origin could be the reasons for the conflicting results on the effects of TGF-β1 gene polymorphisms in chronic HBV susceptibility.

2.1.4. TGF-β Transforming growth factor beta (TGF-β) is a multifunctional cytokine that controls proliferation, cellular differentiation, apoptosis, angiogenesis, and immune reactions. TGF-β is secreted by various inflammatory cells such as macrophages during tissue injury and regulates the synthesis of connective tissue components and matrix proteins in fibroblasts and other cell types via chemotactic mechanisms (Hanafy and Ado, 2011; Heidari et al., 2015b). This cytokine exists in three isoforms: TGF-β1, TGF-β2 and TGF-β3 that have been expressed in high levels in most tissues. TGF-β can induce the differentiation of fibroblasts at sites of inflammation to improve the lesions. In addition, it seems that induction of TGF-β secretion leads to increased eradication of inflammation through apoptotic mechanisms (Heidari et al., 2015b; Xiao et al., 2008). TGF-β1, as the product of host responses to inflammation, play an important role in the defense against viral infections. This cytokine, as the most common TGF-β isoform, can regulate the immune system of the host that leads to the suppression of the HBV replication via the reduction of the hepatocyte nuclear factor-4-alpha (HNF4A) (Hong et al., 2012). The gene encoding TGF-β1 is located on chromosome 19q13.1 and has several functional polymorphisms that can affect the expression and production of TGF-β1 among individuals (Buckova et al., 2001). It has been reported that TGF-β1 gene polymorphisms were related to the increased risk for some chronic infections and disease progression including periodontal diseases (Heidari et al., 2013; Heidari et al., 2015b; Heidari et al., 2014b) and hepatitis B and C (Hosseini Razavi et al., 2014; Liberek et al., 2009; Pereira et al., 2008; Romani et al., 2011; Suzuki et al., 2003). TGF-β1can control the production of extracellular matrix proteins therefore this cytokine has an important role in the pathogenesis and development of liver fibrosis (Gressner et al., 2002). Many polymorphism such as − 988C/A, − 800G/A, and − 509C/T SNPs in exon 1, an insertion/deletion at position +72 have been reported in the TGF-β1 gene that have effects on gene expression (Wang et al., 2005). Among these polymorphisms, − 509C/T SNP is associated with increased levels of TGF-β1. Yang et al. (2005) showed that TGF-β1509C/T polymorphism could change the expression of TGF-β1 and development of cirrhosis but they did not find any association between TGF-β1-509C/T polymorphism and cirrhosis. Saxena et al. (2014b) analyzed the relationship between TGF-β1-509C/T polymorphism and HBVrelated HCC risk in Indian population. They revealed that individuals with at least one T allele have an increased risk for HCC. On the other hand, C allele reported as a protective factor for HBV-related cirrhosis and HCC in inactive carriers. Kim et al. (2003a) reported that risk of HCC reduced in individuals with CT or TT genotypes compare to the CC genotype. In addition, Qi et al. (2009) showed significantly reduced risk of HCC in patients with TT genotype compared to the wild CC genotype. In Italian population both homozygotes genotypes were risk factors for cirrhosis (Falleti et al., 2008). Other studies have been revealed that TGF-β1-509C allele can increase HCV clearance rates (Kimura et al., 2006). In Chinese population it was revealed that T allele was significantly related to the reduced colorectal cancer risk (Zhang et al., 2009). Grainger et al. (1999)have showed that TGF-β1-509T allele can increase the production of TGF-β1. But the studies conducted by Saxena et al. (2014b) and Qi et al. (2009) did not show statistically significant differences in TGF-β1 levels among patients or healthy controls in regard to the TGF-β1-509C/T gene polymorphism. Similarly, in other study Heidari et al. (2013) did not find significant association between chronic periodontitis and − 509 C/T variants of the TGF-β1 gene. But they showed that TGF-β1-509C/T was strongly associated with quantitative parameters of connective tissue constituents of interdental papilla in chronic periodontitis patients (Heidari et al., 2015b). Geography

2.1.5. IFN-γ Interferon gamma (IFN-γ) is a soluble cytokine. It is a member of the type II class of interferons. In humans, the IFN-γ protein is encoded by the IFNG gene that is located on chromosome 12q24. IFN-γ is produced by various cells such as natural killer (NK) cells, Th1 and cytotoxic T lymphocyte cells (Heidari et al., 2015a). IFNγ, can regulate innate and adaptive immunity against viral infections through the following mechanisms: the activation of the macrophages and increasing the expression of Class II MHC molecule. It has antiviral and anti-tumor functions. Inadequate level of IFN-γ is related to the inflammatory diseases due to its inhibitory effects on viral replication (Schoenborn and Wilson, 2007). Interferon gamma receptor 1 (IFNGR1) and Interferon gamma receptor 2 (IFNGR 2) produce a heterodimeric receptor for IFN-γ. Combination of IFN-γ and this receptor induces the JAK-STAT signaling pathway. The function of the IFN-γ is inhibited by binding IFN-γ to the glycosaminoglycan heparan sulfate at the cell surface (Sadir et al., 1998). The polymorphisms in the regulatory regions and introns of IFN-γ and its receptor genes can change the expression of IFN-γ in patients with acute HBV infection and chronic HBV carriers. It means that polymorphisms in the IFN-γ and its receptor genes can increase the risk of hepatitis developing (Ben-Ari et al., 2003; Penna et al., 1997; Pravica et al., 2000; Rizvi et al., 2012). A number of polymorphisms within IFN-γ (+874 A/T, −179 T/G, CA repeat microsatellite) and its receptor (−611A/G, +189T/G and +95C/T) genes have been participated in chronic inflammatory diseases (Bream et al., 2000; Heidari et al., 2015a; Huang et al., 2007; Pravica et al., 1999). In our previous study, the association analysis conducted between the IFN-γ (+874 A/T) and IFN-γR1 (−611A/G, +189T/G and +95C/T) gene polymorphisms and chronic periodontitis risk in an Iranian population, showed that the IFN-γ (+ 874 A/T) was significantly in positive association with chronic periodontitis (Heidari et al., 2015a). IFN-γ gene polymorphism at position + 874 in first intron of the IFN-γ gene can modulate HBV infection risk through the nuclear factor κB binding area (Pravica et al., 2000). Saxena et al. (2014c) analyzed the association between IFN-γ (+ 874 A/T) genotypes and HBV-related HCC risk in Indian population. They showed that there was a significant negative association between TA + AA genotypes and hepatitis and HCC development. In contrast, Cheong et al. (2006b) did not find significant association between the IFN-γ (+ 874 A/T) and susceptibility to HBV infection. Moreover, a Chinese study has been reported that combination genotype of − 874 and − 2109 SNPs produce AG haplotype might be a risk factor for susceptibility to HBV infection (Liu et al., 2006a). Forte et al. (2009), Colakogullari et al. (2008) and Farhat et al. (2008) reported increased frequencies of individuals with wild genotype compared to TA genotype in different populations. A Turkish study revealed that + 874AA genotype is associated to the viral load and chronic HBV infection (Korachi et al., 2013). In another study Huang et al. (2007) revealed a significant association between the IFN-γ polymorphism at position − 764 and spontaneous recovery of HBV. They showed that − 764G allele could increase the promoter activity of the gene compared to the C allele. Ben-Ari et al. (2003) reported that IFN-γ + 879 polymorphism lead to reduced serum levels of IFN-γ in chronic HBV infected patients compared to a control group. They reported a negative relationship between fibrosis scores and IFN-γ production in HBV infected patients. Recently, in an investigation, we found that there was a significant relationship between the IFN-γ (+ 874 T/A) polymorphism and the risk of HBV infection in Iranian population. In this study, statistical analysis indicated a significant difference in the frequency of AA genotype between HBV infected patients and control groups. In addition, allele A had a higher frequency among HBV infected patients compared with control. There were no significant

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differences in IFN- γ R1 (− 611A/G), IFN- γ R1 (+ 189T/G), IFN- γ R1 (+95C/T) (unpublished data). 2.1.6. TNF-α Tumor necrosis factor alpha (TNF-α) is a pro-inflammatory cytokine involved in inflammation. It is produced by many cell types mainly macrophages. TNF-α control the apoptotic cell death and inflammation and inhibit viral replication through the regulation of immune cells (Heidari et al., 2014a; Locksley et al., 2001; Solhjoo et al., 2014). Insufficient TNFα production causes various diseases such as cancer, psoriasis and inflammatory bowel disease (Brynskov et al., 2002; Locksley et al., 2001; Victor and Gottlieb, 2002). The human TNF-α gene is located on chromosome 6p21.3. This gene has an AU-rich element in the 3' UTR region that is a polymorphic site (Heidari et al., 2014a; Nedwin et al., 1985; Solhjoo et al., 2014). TNF-α has two receptors: TNFR1 and TNFR2. TNFR1 is found in various cells, but TNFR2 is expressed only in immune cells. When TNF-α binds to its receptors, can inhibit the replication of viruses such as herpes simplex virus type 1, mouse cytomegalovirus and hepatitis B virus (Guidotti and Chisari, 2001; Herbein and O'Brien, 2000). Increments of expression of TNF-α and its receptors were reported in patients with HBV infection and proposed that TNFα gene polymorphisms could affect the natural history of chronic HBV infection (Sheron et al., 1991; Zhang et al., 2011a). TNF-α as a Th1 cytokine contributes in the viral clearance and the host immune response to HBV through noncytotoxic antiviral mechanisms (Fiorentino et al., 1991). There are five polymorphisms in promoter region of TNF-α gene at positions − 1031(T/C), − 863(C/A), − 857(C/T), − 308(G/A) and − 238(G/A) which can influence the transcriptional function of this gene (Knight and Kwiatkowski, 1999). However, Mekinian et al. (2011) showed that −308(G/A) SNP did not change TNF-α expression in healthy people, but it is pointed out that TNF-α − 308(G/A) and − 238(G/A) SNPs may affect the level of TNF-α secretion (D’Alfonso and Richiardi, 1994; Wilson et al., 1993). These SNPs may increase transcription and serum level of TNF-α (Abraham and Kroeger, 1999). It has been shown that −308(G/A) SNP has a weak effect on susceptibility to persistent HBV in the Gambian population but −238(G/A) SNP has an influence on the HBV outcome in European population. In this study, association between −238(G/A) alleles and HBV clearance was related to the higher TNF-α secretion in German patients (HOHLER et al., 1998a). In addition, −238(G/A) polymorphism have been associated with spontaneous elimination of HCV infection (Hohler et al., 1998b). In this regard, meta-analysis studies reported that − 863C and − 857T alleles were associated with HBV clearance in Thais (Kummee et al., 2007) and Asians (Shi et al., 2012) populations, respectively. Also, − 308G and −238A alleles were related to the HBV persistent infection in Chinese (Zhang et al., 2014b) and European (Zheng et al., 2012) populations. Other studies in Korean and South Indian populations have revealed that a number of haplotypes such as − 308G/− 238G and − 1031C/863A/− 857C/− 308G/− 238G are associated with persistent HBV infection (Cheong et al., 2006a; Fletcher et al., 2011). Moreover, other functional haplotypes from − 1031(T/C), − 863(C/A) and −857(C/T) SNPs have been reported to be associated with HBV clearance in Koreans (Kim et al., 2003b), Thais (Kummee et al., 2007) and Chinese population (Du et al., 2006). In contrast, Miyazoe et al. (2002) showed that TNF-α polymorphisms were not related to the HBV infection in Japanese carriers. Similarly, an Iranian study did not report any significant association between TNF-α polymorphisms and HBV pathogenesis (Somi et al., 2006). On the contrary, there was not significant relationship between TNF-α polymorphisms and rheumatoid arthritis (Chen et al., 2007; Cuenca et al., 2003; Vikram et al., 2011) and chronic periodontitis (Heidari, 2014; Heidari et al., 2014a; Solhjoo et al., 2014) as inflammatory diseases. Although, it seems that TNF-α polymorphisms can block the HBV gene expression via alteration the expression of TNF-α but conflicting data will need further evaluation to show the real effect of TNF-α polymorphisms in HBV infection.

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2.1.7. MIF Macrophage migration inhibitory factor is a pleiotropic cytokine that produce innate and adaptive immunity and control the host immunity responses against the chronic diseases such as HBV infection (Calandra and Roger, 2003; Grieb et al., 2010). MIF was originally discovered as a lymphokine involved in various macrophage functions (phagocytosis, spreading, tumoricidal activity and etc.). MIF is a T-cellderived pro-inflammatory cytokine that mainly expresses at sites of inflammation. It has an important role in cell-mediated immunity and inflammation. It means that MIF can regulate the biological function of macrophages through the inhibition of anti-inflammatory effects of glucocorticoids. Some cytokines such as IFN-γ and TNF-α stimulate the expression of MIF in macrophages (Nishihira, 2000). Usually, serum MIF level is increased in inflammatory autoimmune diseases (Calandra and Roger, 2003; Kozak et al., 1995; Weiser et al., 1989). The gene encoding the MIF protein is located on chromosome 22q11.23. The SNPs in the MIF gene can influence the susceptibility to chronic infectious diseases. It is due to changing the level of MIF protein expression in the host (Calandra and Roger, 2003; Donn et al., 2002). There are four polymorphisms in human MIF gene: rs2096525 and rs2070766 are mapped in introns and rs755622 and 2794 (Aldinucci et al., 2008) are located in promoter of MIF gene. These variations have biological effects on transcription activity of MIF specially those one in promoter region (Donn et al., 2002; Donn et al., 2001). Moreover, it has been investigated that these polymorphisms could implicate in existence of chronic inflammatory diseases such as rheumatoid arthritis (Radstake et al., 2005), inflammatory bowel disease (de Jong et al., 2001), psoriasis (Donn et al., 2004) and hepatitis B (Zhang et al., 2013). Studies have shown that serum levels of MIF were significantly higher in individuals with MIF −173C allele (Donn et al., 2002). Baugh et al. (2002) found CATT tetra nucleotide repeat polymorphism at position −794 had effects on the activity of the MIF promoter. They showed that the 5-CATT allele has the lowest level of promoter activity in vitro, which associated with reduced disease severity in chronic inflammatory conditions. Recently, our finding suggested that MIF −173 G/C variant increased the risk of chronic periodontitis and HBV in Iranian population. Our results showed that carriers of the MIF −173C allele were at significantly higher risk of chronic inflammation than carriers of the MIF −173-G allele (unpublished data). These facts support the hypothesis that the MIF −173C allele increases risk for chronic inflammations. 2.2. HLA The human leukocyte antigen (HLA) is the genes that encode a number of proteins which are responsible for stimulation of the immune responses. These genes are located on chromosome 6 and encode antigenpresenting proteins on the surface of cells that are essential for immune function. HLAs have three classes: 1- MHC class I (A, B, and C); 2- MHC class II (DP, DM, DOA, DOB, DQ, and DR); 3- MHC class III. When a cell is encounter to an infectious pathogen, MHC I present peptides of the virus from inside the cell to the surface of the cell and bring them to the killer T-cells that destroy cells. killer T-cells induce lysis or apoptosis of the infected hepatocytes. MHC class II present fragments of the virus from outside the cell and bring them to T-lymphocytes that regulate the functions of T-helper cells and B-cells. MHC class III produces compounds that cooperate in above mentioned systems. In a patient infected with a virus, antigen-presenting cells can phagocyte the pathogen, then deliver the pathogen peptides to T cells which lead to elimination of the pathogen. Therefore, mutations in HLAs can cause autoimmune and infectious diseases (Mack et al., 2013). The biological role of MHC class II polymorphisms in clearing the pathogenesis of HBV is the principal majority of recent studies. In Gambia, Thursz (1997) and Thursz et al. (1995) found that the allele HLA-DRB1*1302 was associated with spontaneous elimination of HBV infection. Similarly, such association was found in European and Caucasians population by Hohler et al. (1997) and Thio et al. (2003). They

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confirmed that existence of DRB1*1302 polymorphism could clear the HBV infection in vivo. In addition, Thio et al. (1999) showed a significant association between haplotype cluster of DQA1*0501DQB1*0301DQB1*1102 and viral persistence. Moreover, it is identified that the alleles DRB1*1101 and DQB1*0301 are associated with spontaneous elimination of HCV (Alric et al., 1997; Minton et al., 1998; Thursz et al., 1999). In contrast, Zavaglia et al. (1996) did not show any association between HLA phenotypes and clearance of HBV or HCV virus. Two GWAS studies revealed that HLA-DPA1 and DPB1 were related to the viral clearance in the Japanese (Kamatani et al., 2009) and Korea (Nishida et al., 2012) population. Furthermore, HLA-DPA1 A allele and HLA-DPB1 genotype were associated with protective responses against progression of HBV and HCC development in Asian individuals (Guo et al., 2011; Hu et al., 2012; Kamatani et al., 2009; Nishida et al., 2012). The studies have shown that HLA-DR13 allele is higher in healthy controls than in patients with chronic hepatitis B (Diepolder et al., 1998). These studies found that HLA-DR13 could improve CD+ T cell response to HBV core antigen during HBV infection. The effective function of HLA-DR13 allele on the pathogenesis of HBV also may be the result of linked polymorphisms in a closing immunoregulatory gene. Therefore, these facts revealed convincing association between self-limiting of HBV infection and the HLA class II allele DR13. More study in Qatar showed an association between HLA-DR2 and DR7 and clearance and persistence of the hepatitis B virus, respectively (Almarri and Batchelor, 1994). In this regard, convincing studies about association between MHC class I and HBV persistence are rare. However, Albayrak et al. (2011) showed that HLA-B35 and HLA-CW4 were important risk factors in Turkey population. Chinese reports showed that HLA-B*4001 was not related to the HBV clearance but had an effect in Taiwan populations (Wu et al., 2004). Hu et al. (2013) investigated the relationship between HLA-C (rs3130542A) and persistence of HBV in Chinese population. Further studies are suggested to investigate the immunoregulatory function of HLA polymorphisms in the immune response against HBV infection. 2.3. Other candidate genes 2.3.1. Chemokines Chemokines are chemotactic small cytokines, which form a subfamily of the cell signaling molecules. Various cells, such as CD8+ T cells, that influence the immune system can produce chemokines in nearby cells to induce chemotaxis. Some of them are pro-inflammatory cytokines and produced during an immune response. Others are homeostatic cytokines and cooperate in migration of cells such as leukocyte. These chemo attractant cytokines stimulate cell migration from blood into tissue and vice versa through chemotaxis process. In addition chemokines can regulate T-cell differentiation and tumor cell metastasis (Graves and Jiang, 1995). Chemokines have four groups: CXC, CC, CX3C and XC. These proteins binds to chemokine receptors and induce their functions. Studies have shown that chemokines have power to control immune responses in vivo and in vitro against infections such as HIV (Cocchi et al., 1995; Garzino-Demo et al., 1999). The CCR5 is a receptor for chemokines and mediate cell activation during innate and adaptive immune response (Strieter et al., 1996). Studies have shown that CCR5-D32 mutation could affect susceptibility to HCV infection (Liu et al., 2006b). Moreover, an increased frequency of CCR5 Wt/mt allele have been reported in chronic HBV patients compared to the healthy subjects (Suneetha et al., 2006). In addition, the CCR5-59029G and CCR5-59353T variations have viral clearance functions in HBV infection. However, CCR5 D 32 or RANTES were not associated with HBV clearance (Ahn et al., 2006; Chang et al., 2005). In contrast, heterozygosity of CCR5 D 32 increases the risk of HBV infection in Indian population that is evidence for HBV-related liver disease (Suneetha et al., 2006). Chang et al. (2005) showed that CCR5 59029A

and 59029G alleles were related to the increased risk of HBV infection and spontaneous HBV clearance, respectively. In regard to the other chronic infections such as HIV, it has been reported that CCR2 V64I SNP might be associated with a delay in progression to AIDS (Smith et al., 1997). According to studies, the role of chemokines and their receptors in HBV infection has not been completely clarified. Further studies are recommended in examining association between chemokines and their receptors and HBV infection. 2.3.2. Vitamin D The biological active form of vitamin D can modulate cell growth, immune functions and apoptosis. Vitamin D can reduce the inflammation by stimulating the genes that encoding immunomodulatory factors. Vitamin D binds to vitamin D receptor (VDR) that is expressed on the surface of monocytes and lymphocytes. This binding activates the innate immunity systems and improves the immune responses through inhibiting the Th1 cell functions and activating the Th2 cells responses (Beard et al., 2011; Hewison, 2011). Low levels of vitamin D are associated to the viral infections (Cannell et al., 2006; Luong and Nguyen, 2011; Nnoaham and Clarke, 2008; Spector, 2011). The vitamin D receptor is expressed on the surface of monocytes and lymphocytes. In a Gambian study, Bellamy and Hill (1998) and Bellamy et al. (1999) analyzed the association between vitamin D receptor gene polymorphisms. These polymorphisms appear to influence transcription efficiency of this gene and susceptibility to HBV infection. They showed positive association between vitamin D receptor gene polymorphisms and viral clearance. Further, Bellamy showed that homozygotes genotype tt for a polymorphism at codon 352 were significantly lower among those with persistent hepatitis B infection compared to the other genotypes. Gutierrez et al. (2011) reported that vitamin D improve immune responses of the host against infection with HCV. On the other hand, Garcıa-Martın et al. (2013) showed that rs2228570TC polymorphism in vitamin D receptor gene is a good predictor of the outcome of PEGIFN/RBV therapy in HCV patients. In this study, subjects with T allele had a higher probability of obtaining SVR. Suneetha et al. (2006) showed that the frequency of VDR a/a allele was higher in patients with higher HBV DNA suffered from HBV-related liver disease. These results affirm the vital role of vitamin D receptor gene polymorphisms in the pathogenesis of chronic HBV infection. 3. Summary Host immunity and genetic factors play important roles during infections. The aim of our research is to provide diagnostic markers for the susceptibility to HBV infection. It is believed that host genetic factors can change the transcriptional levels of immune factors that lead to the alteration of the immune responses against viral infection and liver disease progression. There are a large number of host genetic factors recognized with advanced technologies that are believed to be associated with HBV susceptibility and related-liver diseases. A large number of host genetic factors that contributed in HBV infection have been discovered with GWAS technology. Due to the complexity of the host genetic interactions, it is likely that single allelic variants are responsible for HBV susceptibility or resistance. The most successful example is the identification of several SNPs or haplotypes in cytokines, MHC class II and a number of chemokines genes in HBV infection. Some of these SNPs are associated with HBV clearance or persistent infection and contribute to the outcomes of HBV infection. Some cytokine genotypes such as IL-10 and IL-28B are suggested to predict the response to treatments because of its function in reducing the hepatic inflammation (Sonneveld et al., 2012). Therefore, it can be a gene therapy target for HBV infection. It is suggested that polymorphisms of Type 1 cytokines such as interleukin-2, 4, 12 and 13 can predict the immune response to HBV vaccination (Pan et al., 2012). On the other hand, various MHC alleles such as DRB1*1302, A*0301, DR2, DR6 and DR13 have been identified that are associated with favorable outcomes in HBV infection. The

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variants in the HLA class II region such as HLA-DP, HLA-DQ and HLA-DR are also considered to be important in determining the risk of HBV infection. Moreover, some cytokines such as TNF-α and vitamin D have polymorphisms that can be used in recognizing the susceptibility to HBV in mother and child because these cytokines are contributed in mechanisms by which disease occurs (Chatzidaki et al., 2012). Most of these genetic alterations might be affect the signaling pathways of Wnt/b-catenin, p53 and JAK/STAT and believed to induce HBV infection or resistance to disease. Some of these different mutational profiles is believed to modulate the host immune system and are considered as useful biomarkers for determining HBV. Due to the ethnic variability of the findings, it is not easy to accredit these results in different populations, so, further studies in larger patient cohorts and in different stages of liver disease progression, with high reproducibility in different study populations are needed to confirm the real effects of genotypes in HBV infections. These studies will be useful in the appropriate therapeutic strategies for HBV infection. Such studies will provide far better insights into HBV pathogenesis. Additionally, the use of advanced technology could enable the identification of other candidate genes in regard to the HBV infection. Numerous studies have reported the host genetic factors associated with HBV susceptibility and related-liver diseases. However, there are inconsistent results in understanding the clinical roles of these factors in the field of the understanding the host and disease interactions. In addition, the host genetics alone cannot explain the different individual susceptibility and ethnic differences in response to HBV infection. Therefore, answers to the dichotomous findings about susceptibility to the infection will be provided by further analysis of other host genetic and environment factors. The application of novel technologies will answer to these complicated problems and provided therapeutic and preventive strategies for HBV infection. With this view we will understand mechanisms of liver pathogenesis. Acknowledgements Financial support: None. Declaration of interest: The authors report no declarations of interest. References Abel, L., Dessein, A.J., 1997. The impact of host genetics on susceptibility to human infectious diseases. Curr. Opin. Immunol. 9, 509–516. Abraham, L.J., Kroeger, K.M., 1999. Impact of the -308 TNF promoterpolymorphism on the transcriptional regulation of the TNF gene: relevance to disease. J. Leukoc. Biol. 66, 562–566. Afzal, M.S., Tahir, S., Salman, A., Baig, T.A., 2011. Analysis of interleukin-10 gene polymorphisms and hepatitis C susceptibility in Pakistan. J. Infect. Dev. Ctries. 5, 473–479. Ahn, S.H., Kim do, Y., Chang, H.Y., 2006. Association of genetic variations in CCR5 and its ligand, RANTES with clearance of hepatitis B virus in Korea. J. Med. Virol. 78, 1564–1571. Al-Qahtani, A.A., Al-Anazi, M.R., Abdo, A.A., Sanai, F.M., AlHamoudi, W.K., Alswat, K.A., AlAshgar, H.I., Khalaf, N.Z., Viswan, N.A., Al Ahdal, M.N., 2014. Genetic variation in interleukin 28B and correlation with chronic hepatitis B virus infection in Saudi Arabian patients. Liver Int. 34, 208–216. Albayrak, A., Ertek, M., Tasyaran, M.A., Pirim, I., 2011. Role of HLA allele polymorphism in chronic hepatitis B virus infection and HBV vaccine sensitivity in patients from eastern Turkey. Biochem. Genet. 49, 258–269. Aldinucci, D., Lorenzon, D., Cattaruzza, L., Pinto, A., Gloghini, A., Carbone, A., Colombatti, A., 2008. Expression of CCR5 receptors on Reed-Sternberg cells and Hodgkin lymphoma cell lines: involvement of CCL5/Rantes in tumor cell growth and microenvironmental interactions. Int. J. Cancer 122, 769–776. Almarri, A., Batchelor, J.R., 1994. HLA and hepatitis B infection. Lancet 344, 1194–1195. Alric, L., Fort, M., Izopet, J., Vinel, J.P., Charlet, J.P., Selves, J., Puel, J., Pascal, J.P., Duffaut, M., Abbal, M., 1997. Genes of the major histocompatibility complex class II influence the outcome of hepatitis C virus infection. Gastroenterology 113, 1675–1681. Baugh, J.A., Chitnis, S., Donnelly, S.C., Monteiro, J., Lin, X., Plant, B.J., Wolfe, F., Gregersen, P.K., Bucala, R., 2002. A functional promoter polymorphism in the macrophage migration inhibitory factor (MIF) gene associated with disease severity in rheumatoid arthritis. Genes Immun. 3, 170–176. Beard, J.A., Bearden, A., Striker, R., 2011. Vitamin D and the anti-viral state. J. Clin. Virol. 50, 194–200.

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