Search Article Keyword:  



PubMed Submission Abstract PDF Feed Back  Click Count: 2977 DownLoad Count: 2396 



ISSN 1007-9327 CN 14-1219/R  World J Gastroenterol  2007 March 28;13(12):1770-1787


A comparative review of HLA associations with hepatitis B and C viral infections across global populations


Rashmi Singh, Rashmi Kaul, Anil Kaul, Khalid Khan





Rashmi Singh, Rashmi Kaul, Anil Kaul, Department of Biochemistry and Microbiology, Center of Health Sciences, Oklahoma State University, Tulsa, OK 74107, United States

Khalid Khan, Department of Pediatrics, Division of Gastroenterology, University of Minnesota, United States

Correspondence to: Rashmi Kaul, PhD, Assistant Professor of Immunology, Department of Biochemistry and Microbiology, Oklahoma States University-Center of Health sciences, 1111 W. 17th St. Tulsa, OK 74107,

United States.

Telephone: +1-918-5611231  Fax: +1-918-5618276

Received: 2006-12-25           Accepted: 2007-03-07



Hepatitis B (HBV) and hepatitis C (HCV) viral infection or co-infection leads to risk of development of chronic infection, cirrhosis and hepatocellular carcinoma (HCC). Immigration and globalization have added to the challenges of public health concerns regarding chronic HBV and HCV infections worldwide. The aim of this study is to review existing global literature across ethnic populations on HBV and HCV related human leukocyte antigen (HLA) associations in relation to susceptibility, viral persistence and treatment. Extensive literature search was conducted to explore the HLA associations in HBV and HCV infections reported across global populations over the past decade to understand the knowledge status, weaknesses and strengths of this information in different ethnic populations. HLA DR13 is consistently associated with HBV clearance globally. HLADRB1*11/*12 alleles and DQB1*0301 are associated with HBV persistence but with HCV clearance worldwide. Consistent association of DRB1*03 and *07 is observed with HCV susceptibility and non-responsiveness to HBV vaccination across the population. HLA DR13 is protective for vertical HBV and HCV transmission in Chinese and Italian neonates, but different alleles are associated with their susceptibility in these populations. HLA class molecule interactions with Killer cell immunoglobulin like receptors (KIR) of natural killer (NK) cells modulate HCV infection outcome via regulating immune regulatory cells and molecules. HLA associations with HBV vaccination, interferon therapy in HBV and HCV, and with extra hepatic manifestations of viral hepatitis are also discussed. Systematic studies in compliance with global regulatory standards are required to identify the HLA specific viral epitope, stage specific T cell populations interacting with different HLA alleles during disease progression and viral clearance of chronic HBV or HCV infections among different ethnic populations. These studies would facilitate stage specific therapeutic strategies for clearance of HBV and HCV infections or co-infections across global populations and aid in identification of HBV-HCV combined vaccine. HLA associations of chronic HBV or HCV development with confounding host factors including alcohol, drug abuse, insulin resistance, age and gender are lacking and warrant detailed investigation across global populations.


© 2007 The WJG Press. All rights reserved.


Key words: Human leukocyte antigen; HBV persistence; HCV persistence; Interferon response to HBV and HCV; HBV vaccination response


Singh R, Kaul R, Kaul A, Khan K. A comparative review of HLA associations with hepatitis B and C viral infections across global populations. World J Gastroenterol 2007; 13(12): 1770-1787



Hepatitis B (HBV) together with hepatitis C (HCV) accounts for 75% of liver diseases and are regarded a major threat to public health worldwide. Hepatitis B and C co-infections have raised major concern in HIV, transplant and other immunosuppressed patients. Intravenous drug abuse is currently the main risk but nosocomial infection is also of concern for HBV and HCV infection. Three independent factors seem to be associated with fibrosis: age, daily alcohol consumption and male gender. Over two billion people are expected to be infected with HBV during their lifetime and about 350 million are estimated to be chronic carriers[1]. Chronic carriers develop life-threatening liver cirrhosis or HCC. Hepatitis C infected patients have greater chances to develop chronic hepatitis and liver cancer. About 54% to 86% of infected individuals develop chronic manifestation, and females and children tend to have lower rate of chronicity. It is estimated that about 200 million people around the world are HCV infected. 4.1 million (1.6%) Americans have been infected with HCV, of whom 80% are chronically infected[2].

The mechanism of HBV and HCV pathogenesis remains elusive. Host genetic factors are proposed to be governing the pathology of disease progression or regression along with the viral and environmental factors. Interplay of HLA restricted T lymphocytes, antibody-secreting B-lymphocytes, NK cells and cytokines, conditions the immune response to viral infections. Effective presentation of viral antigens to CD4+ T cells and CD8+ T cells by HLA classⅡ and classmolecules respectively, is the key regulation of optimum immune response against viral infection, and further dictates viral clearance or persistence. Inconsistency is observed in response to HBV vaccination and interferon treatment following HBV and HCV infection. Varied response to vaccination is implicated to specific combinations of polymorphic HLA classⅡ alleles that influence the capacity of HLA classⅡ molecules to bind and present antigen to CD4+ cells that augment antibody production and cytotoxic T lymphocytes activation. Numerous clinical and laboratory investigations have identified several immunogenetic factors involved in conditioning viral hepatitis. Gene polymorphisms and heterozygosity at HLA loci enable HLA molecules to present a wide array of antigens and diversify the properties of HLA molecules with respect to antigen binding and presentation[3].

HLA associations with respect to HBV and HCV infection susceptibility, protection, disease severity, interferon treatment response and response to vaccination have been intensively investigated across the global populations. We have attempted to review the published literature on HLA associations with HBV and HCV infections with the purpose of identifying common HLA allele association with hepatitis B and C. Convergence of this information would provide but not be limited to (a) insight into the immunopathogenesis of HBV-HCV co-infections and superinfections, (b) identification of genetic markers to predict the course of infection/treatment response and (c) enable designing of combined vaccine strategies for viral hepatitis B and C.



Viral persistence and viral clearance

Viral clearance (acute infection) or persistence (chronic infection) is conditioned by immune response mechanisms regulated by HLA molecules. HLA associations with susceptibility and protection from persistent HBV infection, though robust, are inconsistent even within the same population. HLA allele associations with HBV clearance and persistence in global population are outlined in Table 1A and B.

HLA Classallele associations: susceptibility to HBV infection and chronicity is attributed to HLA A*0206 allele in Taiwanese, B35 in Chinese[4], B18, B35, B40, Cw3 allele in Russian, A3 and B18 in Kazakhs[5] B8-Cw-7 haplotype in Senegalese[6], and HLA A*01-B*08-DRB1*03, B-44-Cw1601 and B*44-Cw*0501 haplotype in American Caucasians[7] (Table 1A). Also, HLAB8 in European Caucasians is associated with non-response to HBV vaccination (Table 2A) indicating inefficient immune response against HBV antigen in HLA B8 carriers[7].

HLA B61 in Taiwanese[4], A*26 in Japanese[8] and A*0301 in American Caucasians[7] are protective (Table 1b). HLA A2 and A11 are protective alleles for HBV chronicity in Russians and Kazakhs respectively[5]. HLA A-24 and Cw1 are related to lower risk for chronic manifestations of HBV infection in Turkey[9].

HLA Classallele associations: HLA classalleles HLA DRB1*13 and HLA DRB1*11/*12 are consistently associated with viral clearance and viral persistence of HBV infection respectively in major populations (Table 1B). In contrast HLA DRB1*11/*12 alleles are associated with HBV clearance in Chinese[10,11] and HLA DRB1*13 is reported as a susceptibility gene for chronic HBV infection in Turkish populations[9]. HLA DR7 and DRB1*15 are also protective for HBV infection in Chinese but associated with chronic infection in Turkish and Indian populations respectively[9,12-14]. HLA DR15 is also reported to be associated with responsiveness to HBsAg vaccine in European Caucasian populations (Table 2B). These variations observed in HLA allele associations are confounding and suggest influence of other genes on the effect of these alleles on disease outcome.

HLA DR13 is associated with protection from vertical transmission of HBV and HCV in Chinese and Italian infants[15-17] and with HBV clearance across the population (Table 1B). The protectiveness of HLA DR13 is proposed to be either due to proficient antigen presentation by DR13 molecules or linked polymorphisms in neighboring immune regulatory gene.

Hepatitis B viral persistence and disease chronicity is associated with HLA DQA1*0501 and HLA DQB1*0301 in Chinese and African Americans[10,18] and with HLA DR9 in Chinese and Koreans[11,19]. In Chinese populations HLA DR3 is associated with HCV persistence and vertical transmission[10,15]. Pellegris et al studied HBV and HCV related HCC in Italian subjects, 73 with liver cirrhosis and 32 without liver cirrhosis. They have suggested the possibility of HLA DQ1 allele association with susceptibility to liver cell destruction and HLA DR3 with absence of cell destruction in HCC subjects showing liver cirrhosis and no cirrhosis respectively[20].

HLA ClassⅢ allele associations: Polymorphisms in cytokine genes influence outcome of HBV infection. In Chinese populations tumor necrosis factor-alpha (TNF)alpha-857GG is associated with self-limiting infection while TNF-alpha-857 CC and -238G/A polymorphism[21,22] with chronic HBV infection. Polymorphism at position -238 G/A in TNF alpha is associated with chronic HBV infection and defective viral clearance[23] in German Caucasians. The carriers of the -592A allele in IL-10 promoter and -308G/-238G haplotype homozygotes in the TNF-alpha promoter region have higher risk of persistent HBV infection in Koreans[24]. In Italian patients the genotype -308G/G and haplotype TCGG (-T1031, -C863, -G308, -G238) are associated with an unfavorable prognosis in those with chronic HBV infection[25]. TNF-alpha promoter polymorphism -308A is common in Iranian population but is not associated with hepatitis B disease chronicity[26]. IL18 polymorphism at position -137G is associated with chronic HBV infection while -137C is protective in Chinese. Polymorphism at position -137C may be associated with higher production of IL18 that augments IFN-gamma production and thus better immune response against HBV infection[27]. Genetic ability to produce low levels of IFN-gamma is related to susceptibility for chronic HBV infection[28]. Polymorphism of IL10 promoter at position -819T/C and -592A/C is related to chronic infection[29]. Decreased IL10 production owing to -819T and -592A allele contributes to the asymptomatic carrier state and thus is relevant for disease progression in Japanese[30]. Frodsham et al have identified an HLA classcytokine receptor gene cluster as a major susceptibility locus for HBV infection via genome analysis in Gambian populations. Polymorphism at the typeIFN receptor gene, IFN-AR2, and the IL-10RB gene is associated with viral clearance[31]. TNF-alpha polymorphism at position -244G/A is not present in American Caucasian and Egyptian hepatitis B patients but is present in Egyptian healthy individuals suggesting its protective role[32].


Response to HBV vaccination

Variegated antibody response following standard HBV vaccination in otherwise healthy individuals is observed, with 5%-10% showing no response. It is suggested that non-responsiveness may also be associated with antigen-specific HLA determined deficiency in the T cell repertoire and not only with defective antigen presentation or HLA classⅡ affinity for hepatitis surface antigen (HbsAg) derived peptide[33]. Clinical evidence suggests strong association of HLA genes with response to HBV vaccination in the global population, which is outlined in Table 2A-C. Martinetti et al explored HBV vaccination response in neonates to identify the genetic predisposing factors[34] influencing the response.

HLA classallele associations: HLA classand classⅡ molecules are synergistically involved in the immune response to recombinant HbsAg, with a stronger association of HLA DRB1 locus[35]. HLA classloci (A, B and C) association with vaccine responsiveness is not clear and is considered mainly due to its strong linkage disequilibrium with HLA DR locus. Non-responsiveness to HbsAg vaccination is reported to be associated with HLA A1, B15, and B40 in Indians of Asian origin, HLA A1, A2, B8, and B7 in Caucasians and HLA B54 in Chinese. Responsiveness is associated with HLA A11 in Indians of Asian origin and A10, A1 and B7 in Caucasians (Table 2A and B).

HLA class Ⅱ allele associations: HLA DR alleles in several populations are major determinants of response to HBV vaccination. Clinical studies have supported HLA DR3 and DR7 association with non-responsiveness to HBsAg vaccination (Table 2A). HLA haplotype Bw54CREG, C4RFLP (6.5 kb + 12.0 kb)-DR4-DRw53-DQw4, (DQA1*0301-DQB1*0401) is in increased frequency in Japanese non-responders (NR) while HLA groupDR1, DRw6, DQw1 are in low frequency in the non-responders[36] to HbsAg vaccine. HLA DR3, DR4, DR7, DR13 (DRB1*1302), DR14, DR16 is associated with non-responsiveness and HLA DR1, DR5, DR11, DR13 (DRB1*1301) and DR15 with responsiveness (Table 2A and B) to HBV vaccination across the population. HLA DR alleles associations were not reported in Indian (Asian) populations. Higher frequency of HLA DR4, DR7 and DR14 is associated with non-responsiveness and HLA DR1 with responsiveness in Japanese, Chinese and Caucasian populations (Table 2A and B). HLA DR10 and DR51 association with HBV vaccine responsiveness is reported only in Indian (Asian) population[37]. HLA DRB1*13 alleles carriers are hyper responsive to anti measles vaccine and HLA DR7 with non-responsiveness, resembling the pattern of response for recombinant HbsAg vaccine[38].

HLA DP alleles -DPB1*1101 with non-responsiveness, DPB1*0401 with responsiveness- are significant in determining the HBV vaccination response[39] in Belgian populations. HLA DQ2 (DQB1*02) is predominantly associated with non-responsiveness to HBV vaccine in Indian (Asian) and Caucasian populations (Table 2A). HLA DQB1*0202, DQB1*0502, DQB1*0604 and DQA1*0102 alleles are associated with non-responsiveness and DQB1*0301, DQB1*0501, DQB1*0603, DQA1*0101 and 0103 with responsiveness in different European populations to this vaccine. Despite robust association in wide population HLA DQ2 did not qualify to be a non-responder marker[40] for HBV vaccine in European populations. However it was suggested to be an indicator for sub-optimal response to HBV vaccination in homozygous subjects.

HLA classallele associations: HLA class Ⅲ complement allele C4AQ0 is strongly associated with non-responsiveness to anti HBV vaccination[41]. It may contribute to inefficient complement activation and thus failure of B cells to secrete anti-HB immunoglobulin[34,42]. Complement protein production is linked to HLA haplotype[43]. Other HLA class Ⅲ genes including BfF, Cw4, Cw2, and C4A6 are associated with responsiveness to HBV vaccination in the Caucasian population (Table 2B). Kramer et al studied the TCR/CD3 density in non-responders and responders following vaccination in end stage renal disease (ESRD) patients. In these patients lower density of TCR/CD3 was reported in responders carrying C4A*6 and BfF alleles in comparison to non-carriers. Low TCR/CD3 density is related with non-responsiveness and is found associated with HLA A1-B8-DR3 haplotype. The HLA DR3 (associated with HBV vaccine non responsiveness) positive responders lacked C4A*6 and BfF alleles. HLA A1, C4A*6 and Bf*F alleles are associated with non-responders as well as responders but occur within different haplotypes in non-responders and responders[44] for HBV vaccination.

Homozygous individuals for non-responder haplotype are strongly non-responsive to HBV vaccination when compared to the heterozygous state[45]. Homozygotes for HLA A1, B8, DR3, and DQ2 alleles are found exclusively in non-responders while heterozygotes are mostly non-responders[46] for HBV vaccination.

Non-uniformity observed in HLA association may be due to interaction between HLA factors within a haplotype. In Belgian populations HLA DPB1*0201 is associated with non-responsiveness to HBV vaccine when it occurs with haplotype DRB1*0701/DRB4*0101-DQB1*020*[39]. Also interaction with non-HLA genes in addition to HLA genes may influence responsiveness to HBV vaccination[47]. Presence of certain HLA genes in both responder and non-responder subjects suggests a role for other genes (cytokines, T cell receptors etc) in influencing the response to anti Hepatitis B vaccination and HLA alleles may be markers for such association[48]. Several susceptibility genes for immunoglobulin deficiency associated with haplotype HLA-B8, SC01, and DR3 are found in higher frequency in HBV vaccine non-responders[33,49]. Low levels of IL2 cause hypo-response to HBV vaccination[50]. IL10 ACC haplotype is associated with lower production of IL10 and thus favor strong humoral immune response to HbsAg[51].



Viral persistence and viral clearance

Activation of T helper (TH) 1 response is associated with self-resolving viral infection and that of TH2 with chronicity. The reactivation mechanism of T cells contributing to activation of particular TH CD4+ cells during HCV infection is not understood. Since negative finding by Vitte et al in Caucasians[52], several HLA alleles and haplotypes have been found associated with susceptibility and resistance to hepatitis C infection, progression to liver damage and cirrhosis, development of hepatocellular carcinoma and response to interferon therapy in several populations. These are outlined in Table 3A-C. Associations with HLA class Ⅱ genes are reported more often than HLA class. HLA classallelic diversity is suggested to have little influence on fibrosis and disease severity associated with chronic HCV infections[53].

HLA classallele associations: Susceptibility to HCV infections is associated with A*19 in Saudi people[54] and with HLA A*28, A*29, B*14, DR7 in Egyptians[55]. HLA A11-C*04 is associated with HCV persistence in Ireland[56]. HLA B-35 and B8 are strongly associated with chronic HCV infection, with HLA B-35 being positively related to chronic viral infection regardless of viral type[5,57]. In American whites, HCV persistence is associated with HLA Cw*04 and HLA B53, homozygosity of HLA Cw*04 have stronger effect on persistence than single copy of the allele[58].

Protection from HCV infection is associated with HLA-B51, -B52, -B55, -B56, -B61, B70, -Cw1, -Cw3, and -Cw4 in Japanese populations[59]. In Ireland HLA B27 and A*03 have strong association with self-resolving HCV infection[60]. Spontaneous HCV clearance is associated with HLA B-27 in German women cohorts[61] and HLA A*1101, B57 and Cw0102 are reported to be associated with viral clearance in American whites[58]. HLA C allele association with HCV clearance is found in Japanese (Cw1, Cw4)[59], Russian (Cw4)[5] and American populations (Cw0102)[58] (Table 3A). HLA Cw*0602 protects from vertical HCV transmission in infants while HLA CW*07 is the susceptibility allele[16] for HCV.

NK cells mediate direct killing of infected and transformed cells contributing to viral clearance and protection from tumor development. This killer activity is under the control of HLA classmolecule interaction with inhibitory and activation receptors-killer cell immunoglobulin like receptors (KIR) of NK cells. HLA C molecules interact with KIRs of NK cells and modulate their cell killer activity. Activation receptor KIRDL3 and HLA-C1C1 ligand interact directly to influence viral clearance in HCV infection[62]. KIRDL3 associated protection is not found in individuals lacking HLA-C1C1 allele[62]. HLA C2C2 interaction with NK cell receptor is associated with viral persistence in Spanish populations[63]. KIR3DS1-HLA Bw4180 genotype is associated with protection from development of HCC in HCV carriers[64]. HLA Cw7 inhibitory interaction with NK cells is proposed to be associated with HCC in Italian patients[20]. It is notable that HLA B8-Cw7 haplotype is associated with HBV associated liver cancer[6]. In an in vitro study, HLA E is shown to inhibit NK cell mediated lysis of HCV infected cells via interaction with NK cell receptor NKG2A, contributing to HCV persistence[65]. HLA E expression on hepatocytes is stabilized by recognition of HCV core protein by HLA A2 molecules[65]. Increased expression of inhibitory receptor CD94/NKG2A on NK cells was found in chronic hepatitis C patients and is suggested to contribute to immune resistance towards HCV infection and HCV mediated cellular transformation via modulating dendritic cell function and cytokine secretion[66,67].

HLA classⅡ allele associations: HLA DRB1*0405 and DQB1*0401/0402 alleles are associated with viral persistence and chronic HCV infection in Japanese[68-70]. Also, DRB1*0405-DQB1*0401/0402 haplotype[59] and HLA B54-DRB1*0405-DQB1*0401 haplotype are associated with HCV induced liver injury[68]. In Thailand and most European Caucasians HLA DRB1*0301, DQB1*0201 and DQA1*0201 are found associated with chronic HCV infection and HLA DRB1*0701 is associated with disease severity throughout the European populations (Table 3A). In Irish viremic females increased risk for HCV infection related disease severity and high viral load was associated with HLA DRB1*15-DQB1*0602[71]. In Italy HLA DQB1*0502 and DR14 and DR 17 are associated with risk to liver cirrhosis and progressive liver damage respectively (Table 3A).

HLA DRB1*11 alleles and DQB1*0301 is consistently associated with decreased disease severity of Hepatitis C worldwide (Table 3B)[72,73]. In French populations DQB1*0301 is associated with viral clearance in females and DRB1*11 with protection from disease progression in males[74,75] for hepatitis C infection. In contrast Reno et al found association of DRB1*11 with HCV clearance in the French female gender[76]. HLA DQB1*0301 is linked to HCV clearance in American populations showing stronger association with African-Americans[77]. Carriers of HLA DR11 and DQB1*0301 alleles may present the HCV epitopes more efficiently to CD4+T cells than others and thus show efficient viral clearance[73]. Viral clearance is associated with DRB1*0101 and DQB10501 in American Caucasians and with DRB1*0101 in Irish, Saudi, and Egyptian populations (Table 3B). HLA DRB1*0101 allele appears to have better HCV specific T cell response[78]. DRB1*0701-DQB1*02 haplotype is associated with low HCV viral load in Ireland[71]. HLA DR7 is associated with hepatitis C disease severity in several populations and also with HBV infection, except for in Thailand where it is associated with HCV viral clearance along with HLA DQA*0201. HLA DR13 is protective for vertical transmission in infants born to HCV+ ve Italian mothers[16,17]. In infants born to infected mothers HLA DRB1*1104 is associated with seroreversion and DRB1*1101 with viral persistence[79] for HCV infection. In Japanese and the DRB1*0901-DQB1*0303 haplotype is related to protection from cirrhosis in hepatitis C[70] and HLA B44-DRB1*1302-DQB1*0604 and DRB1*1302-DRB1*0604 with asymptomatic carrier phenotype[68].

HLA class Ⅲallele associations: HLA class and cytokine genes have been reported in influencing HCV infection outcome. HLA DR3/MICA-A*4, B*18 is increased in patients with HCC but absent in HCV carriers[64]. Single Nucleotide Polymorphism (SNP)-863A in TNF alpha gene is associated with HCV clearance in African American patients, while wild-type haplotype -863C/-308G is associated with viral persistence in the same[80]. TNF alpha-308 G is found associated with HBV persistent infection in Chinese and Koreans but its status with American populations for HBV is not known. IL10 ATA haplotype possibly influences HCV clearance in Italians[81]. Positive association is reported between TNF alpha 238.2 promoter variant and chronic active hepatitis B and C in Germans[23]. In Indian (Asian) populations the TNF-beta (A/A) allele is indicated to be associated with disease progression[82].



Interferon treatment is currently the most adopted therapy for chronic hepatitis patients. It upregulates the expression of HLA DR, CD80 and ICAM-molecules on dendritic cells and thus augmenting the immune response[83]. Interferon treatment for chronic HBV and HCV infection is successful only in one third of patients. HLA DR locus appears to be a prominent immunogenetic factor influencing interferon treatment response. HLA association in independent studies on Chinese populations has reported HLA DRB1*14 and DQA1*0501 and DQB1*0301 to be associated with responsiveness in chronic hepatitis B. DRB1*07 allele carriers are prevalent among chronic hepatitis B patients and associated with non-responsiveness to anti HBV vaccination and IFN-alpha treatment (Tables 1A, 2A and 4).

In Chinese populations DRB1*04 is associated with non-responsiveness to interferon therapy in HCV as well as HBV infected subjects (Table 4)[84,85]. HLA DRB1*04 is associated with male non-responders while HLADRB1*07 is reported for female responsiveness in Chinese patients with chronic HCV infection[84]. Japanese HLA allele associations with response to interferon treatment is inconsistent (Table 4) and involve HLA classand classalleles for hepatitis C. HLA A24-B54-DR4 haplotype and HLA B54 allele are predictors of poor response to IFN therapy in Japanese hepatitis C subjects[86]. High serum level of IL10 is also suspected to result in poor response to interferon treatment in chronic HCV cases[47]. Low serum levels of IL10 are associated with responsiveness to HBV vaccination[51].

In Spanish populations HLA B44 is associated with responsiveness to interferon + ribavirin therapy but not when interferon therapy is given alone in hepatitis C cases. Also, HLA class Ⅱ does not influence response to interferon treatment in this population[87]. HLA DRB1*0404 is associated with responsiveness in the HCV infected Caucasian population[88]. Piekarsha et al did not find any association of HLA DRB1* alleles with response to Interferon alpha 2b treatment of Polish HCV subjects[89], but in other populations these alleles are reported to influence the response (Table 4). HLA DRB1*07 is associated with non-responsiveness for HBV and for HCV infected subjects from France, but is associated with responsiveness in HCV cases from Poland and Germany and females subjects from China (Table 4).

HLA allele association with interferon treatment response seems to differ for chronic HBV and HCV infections in global populations. This can be attributed to differences in the antigenic determinants of these two different viruses and consequently differences in the HLA molecules involved. However associations of same HLA allele for hepatitis B as well as C with respect to therapeutic response or non-response, though in different population, warrants explanation. HLA typing for interferon treatment receiving cohorts in different population would give an insight towards the mechanism and immune interactions involved. Interferon therapy involves adverse effects; HLA studies will help identifying responder/no responder markers that would help select patients suitable for interferon therapy.



Vertical transmission from infected mothers is a major contributor to increased HCV and HBV infection. Genetic factors in neonates surely influence the outcome of vertical transmission. Liu et al reported HLA DR3 carriers to be at risk of vertical transmission of HBV and DR13 carriers to be resistant in Chinese populations[15]. In Italian subjects, HLA DR13 (DRB1*1302) and DRB1*1104 were reported to be protective in neonates for vertical transmission[16,17,79]. HLA DRB1*1104 is associated with seroreversion in infants born to infected mothers but DRB1*1101 is associated with viral persistence in such infants. The difference in association related to sub allelic differences could to be due to glycine/valine dimorphism at position 86 of the antigen binding sites of the DR B1* molecule. HLA DRB1*86GG was associated with HCV infected children while DRB1*86VV homozygotes were seroconverts[79]. HLA-DQB1*06, -G*0105N, -Cw*0602, DRB1*1104 and -DRB1*1302 alleles are protective while HLA-Cw*07, -G*010401, -DRB1*0701, -DRB1*1401 and homozygosity for HLA-G 14bp deletion are risk factors for HCV vertical transmission in Italian children[16].



HLA associations have been described for extra-hepatic co-morbidities triggered by HCV and HBV infection. HLA DQB1*0603 is associated with development of HBV associated membranous nephropathy in South African black children[90]. HLA DRB1*11 and HLA DRB1*1302, DQB1*0404, DQB1*0604 are associated with susceptibility and protection respectively to HBV related glomerulonephritis in Korea[91]. Sebastiani et al proposed involvement of HLA DR6 in extra hepatic manifestation of HCV related diseases[92]. HCV associated oral lichen planus was reported in HLA DR6 carriers (DRB1*13/*14 alleles)[93]. HLA DRB1*13 alleles are reported to be associated with disease severity in chronic HCV infection in European populations[94,95]. Chronic HCV infection also shows association between DQB1*11 and DR3 with formation of cryoglobulins[72]. HLA studies in this aspect would allow finding of HLA marker for extra hepatic manifestations of hepatic viral infections. Such studies may help prevent post transplantation associated liver damage in recipients. A recent study has suggested donor–recipient mismatch at HLA DRB1 locus and HLA B14 to be responsible for severe fibrosis development in the recipient[96]. The knowledge of HLA gene marker association with risk for HBV/HCV related disease progression/cirrhosis may be helpful while seeking donor-recipient HLA match before transplantation.

Czaja et al have suggested that genetic predisposition, facilitated by viral infection may trigger autoimmune hepatitis (AIH)[97]. Similarities in HLA associations in viral hepatitis and AIH are observed. In European and North American Caucasians HLA DRB1*0301 is strongly associated with AIH[97], and in most European population DRB1*0301 is associated with HCV persistence (Table 3A). HLA DRB1*0405 is a susceptible allele for AIHas well as HCV viral persistence in Japanese[68,70,97]. In Germans DRB1*07 is a risk factor for AIH Ⅱ, and is also found associated with HCV viral persistence[94,97]. Such associations require an extensive study of HLA association in AIH and viral hepatitis patients.



HLA restricted virus specific T cells play an essential role in Hepatitis A related hepatocellular injury, however limited information about the host HLA association in HAV infection is available. HLA-A9 was suggested to be the susceptibility factor in Brazil during an outbreak of hepatitis A infection[98]. HLA-B27[99] and HLA A1, B8, DR3[100] associations with fulminant hepatitis A infection in HCV infected patients is reported. Hepatitis A viral infection (HAV) is suspected to trigger AIH in genetically susceptible patients carrying HLA DRB1*0401[101]. Strong association of DRB1*1301 haplotype with protracted forms of HAV infection that further developed to AIH in pediatric patients is reported[102]. Extensive investigation of HAV infected individuals worldwide will contribute to the limited information regarding its HLA association and its relation to HLA associations of HBV and HCV infections.

HLA association with Hepatitis D and E is not known. Hepatitis E causes acute infections, and Hepatitis D is associated with Hepatitis B infection. A high risk of chronic delta (HDV) infection in Russians is associated with HLA-B8 and HLA-B35, and in Kazakhs with HLA-B35 and HLA-D40[5].



Extensive allele diversity is observed in HLA associations with susceptibility and protection regarding HCV and HBV infections and disease progression in different global ethnic populations. HLA loci diversity due to racial admixture, environment and selection pressure and by inherent polymorphic nature results in allelic variation in different ethnic groups, correspondingly we get different HLA associations with disease in different populations. Thus association of disease outcome with HLA alleles appears to depend upon the ethnicity of the infected individual and therefore is inconsistent across the populations despite being robust within an ethnic group.

The specific HLA associations with HBV and HCV infections are different, agreeing to their differences in viral properties and disease pathogenesis, with few exceptions where they share few HLA loci. This could be due to linkage disequilibrium of HLA alleles with disease-associated genes or shared HLA restricted HCV and HBV T cell viral epitopes. It is intriguing that HLA associations are oppositely directed and indicate interactions with other unidentified factors in influencing the HLA mediated immune signaling. It is also observed that HBV and HCV infections tend to suppress each other. HBV and HDV can suppress HCV infection and HCV and HDV can have negative effect on HBV. HCV super infection is seen to reduce HBsAg expression and promote its clearance[103].

HLA DR9 is protective for HCV infection in Japanese[69,70] but is a susceptible factor for chronic HBV in Koreans and Chinese[11,19] (Tables 1A and 3A). In a comparative study of HBV and HCV infected subjects, MICA (*) 015 is associated with viral clearance in case of HCV infection but with chronic infection in case of HBV[104]. HLA ClassⅡ HLA DRB1*11 and DQB1*0301 are protective for HCV infections, but are also associated with chronic HBV infection. Also, HLA DQB1*0301 is associated with responsiveness to interferon therapy in chronic HBV infection[85] and also to anti HBsAg vaccination[39]. Interferon treatment may activate antigen presentation by aiding generation of more DQB1*0301 responding cytototxic T lymphocytes and thus a protective response[85]. Constantini et al did not find any association between HCV clearance and alpha interferon therapy with IL1, IL10 and TNF alpha genes,[105]. This warrants further investigation with other HLA class Ⅲ genes to know the influence of interferon and a protective association of HLA DQB1*0301 allele in HCV clearance. Cytokine genes should also be investigated for any synergistic association with any of these HLA alleles in HBV infection. Involvement of the same alleles with different outcomes in response to viral infection in different population is intriguing. Collaborative studies involving well-characterized cohorts from different populations are needed.

The difference in influence of HLA DRB1*11 and DQB1*0303 in HCV and HBV infection outcome could be due to variation in viral specific antigen presentation and thus differences in immune responses. Investigating the molecular mechanisms involving HLA DR*11 and DQ*3 associated viral clearance in HCV would provide better understanding of this aspect. Identifying HLA DR*11 and DQ* 3 restricted viral HCV epitopes for CD8+ cells would allow finding or designing similar HBV specific epitopes. This can further be used therapeutically to enhance viral clearance in HLA DR*11 and DQ*3 carrying HBV infected subjects. Investigating involvement of shared epitopes for HBV/HCV may open up opportunities for generating combined HBV-HCV vaccine in the future.

Immunodominant antigenic epitopes have been identified in HCV and they could be investigated for HLA restricted stage specific presentation to develop HLA specific vaccine and peptide-based immunotherapies[106]. HLA B27 restricted HCV specific CD8+ epitope recovered from female subjects has been identified[61]. Such CD8+ specific HLA restricted peptides have been proposed as vaccine and have been shown effective against human metapneumovirus infection and disease in mice[107].

Since immunization at present is the most effective means of combating HBV infection, non-responders always remain at risk of getting infected. Identifying non-responding immunogenetic marker could help protect non-responders by giving them alternative protective therapy and would also permit avoiding administering vaccine to identified non-responding groups in a given population. Designing HLA restricted epitope based anti-HBV vaccine is an alternative for non-responding groups.

Association of HLA DR13 alleles is protective in both HCV and HBV infections in several populations (Tables 1B and 3B) and is proposed to be involved in enhancing immune response to various diseases[17]. In contrast HCV disease susceptibility and severity is linked to DR13 in German and Polish populations[94,95], though other reports from Germany suggest its protective role (Table 3B). It is also protective in vertical transmission of HBV and HCV infection (Tables 1B and 3B). Recognizing HLA DR13 restricted HBV and HCV T cell epitopes could lead to identification of similar/common antigenic determinants and open possibilities for designing a combined anti HBV-HCV vaccine.

HLA DRB1*07 is positively associated with severe disease outcome in both HBV and HCV infections (Tables 1A and 3A). This allele is related to non-responsiveness to anti-HBV vaccination and interferon treatment in subjects with chronic HBV and HCV infections (Table 4), but is reported with responsiveness to interferon treatment in individuals with chronic HCV infection from China and Poland[84,108]. HLA B35 and B40 is associated with chronic HBV and HCV infection in Russian populations[5,57], and the authors suggest chronic hepatitis to be associated with HLA B*35, independent of virus type. HLA B35 involvement is reported with viral persistence of HCV in Koreans[109], and of HBV in Han Chinese[4]. HLA B8 is associated with viral persistence and chronicity for both HBV and HCV infections in Caucasian populations (Tables 1A and 3A). HLA Cw*07 is a risk factor for vertical infection in Italians[16] and is associated with HBV related liver cancer in Senegalese[6]. Such associations suggest inability of these alleles to mount efficient immune responses for viral clearance irrespective of the viral type and warrants elaborate studies concentrating these alleles in several populations, to identify predisposing genetic markers for disease severity.

Studies focusing on viral hepatitis in the United States (US) in American populations have suggested differences in HLA allele association for Caucasians and African-Americans. HBV viral persistence is associated with HLA A*01-B*08-DRB1*03, B*44-Cw*1601 and B844-Cw*0501 haplotype in Caucasian Americans while HLA DQA1*0501, DQB1*0301 and DRB1*1102 haplotype in African Americans[7,18]. HLA A*0301 and HLA DRB1*1302 is associated with HBV clearance in Caucasian Americans, the later being associated with HBV viral clearance in Gambian populations[7,110]. HCV persistence is associated with HLA A*2301 in Caucasian Americans and with the HLA-Cw*04 allele in both Caucasian and African American populations. Also, two copies of HLA-Cw*04 showed stronger persistence than one copy of the allele[58]. Viral clearance showed stronger association with HLA A*1101 and B*57 alleles in both Caucasians and African Americans but HLA Cw*0102 showed stronger association with viral clearance only in Caucasians[58]. Another study by Thio et al reported HLA DQB1*0301 to be associated with viral clearance showing stronger associations in African Americans than Caucasian Americans. Also HLA DRB1*0101 and DQB1*0501 showed association with HCV viral clearance, but only in Caucasian Americans[77]. No information is available on HLA associations with interferon treatment response and racial differences in US American populations which needs investigation.

Variations in the immune response to viral insult appear to be genetically inherited. Reports on HLA gene associations with viral infections are inconsistent and contradictory. Several factors including (1) alteration in antigen binding affinity, (2) ineffective antigen presentation, (3) ineffective interaction of Ag-MHC and TCRs, (4) absence of specific T cells, (5) cytokine deficiency and (6) inadequate complement activation may contribute to defective/inefficient HLA mediated immune response mechanisms and various disease manifestations. Indirect associations of HLA in disease pathology have also been proposed. Circulating autoantibodies against HLA Classand classmolecules have been found, and may represent autoimmune response against HLA molecules that may induce HCV related chronic liver damage[111]. Complement abnormality has been associated with several liver diseases.

Polymorphism of TNF alpha and IL10 promoter has been implicated to influence HBV and HCV infections suggesting a vital role for cytokines in disease outcome. Genes outside the major histocompatibility complex also play a major role in determining the disease/treatment outcome of viral hepatitis. Altered expression of CD45 isoforms influence HCV outcome in humans and transgenic mice studies[112]. NK stimulating and inhibitory signaling receptor and HLA interaction influence viral persistence or clearance. Association of viral persistence and clearance is also reported with chemokine receptors[72].  

Due to (1) the highly polymorphic nature of HLA genes, (2) diversity observed in genetic interactions and (3) complexity of immune response, it has not been possible so far to “Tag” any allele or loci as a potential candidate for a particular disease or disease outcome. However clinical evidence vividly indicates such associations. Thus, it is prudent to argue that response to viral hepatitis infection is immunogenetically governed by multiple candidate genes (including HLA and non HLA genes) acting either independently or in association. HLA genes could be directly involved or may be closely linked to genetic markers for true susceptibility, protection and treatment response genes.



Racial diversity, variations in the study design, methodology and complex immune-regulatory mechanisms make it difficult to find consistent association of HLA alleles with a given HBV or HCV disease even in the same ethnic group of the global population.

The host-virus interaction resulting in acute or chronic viral infection depends on cellular immune responses that are regulated by the host’s HLA type and HLA restricted viral escape mutants. Much research is required for involving either the CD8 antigenic epitope or NK cell (involving KIR ligands) based HLA associations in individuals undergoing acute vs chronic infections in different ethnic populations. Thus, novel strategies are needed to combat the escape mechanisms utilized by viruses in different ethnic populations.

Limited numbers of studies across various ethnic populations have been conducted in relation to HBV vaccination outcome or various therapeutic outcomes against HBV or HCV infections. Thus, global network studies will be useful for HLA disease associations in different ethnic global populations in relation to various therapeutic or HBV vaccination outcome and resulting in viral clearance. Information on HLA association with disease outcome holds immense promise for designing host specific therapeutic strategies. HLA studies involving collaborative analysis of several immune regulatory host genes including T cell repertoire variables in cohorts from around the globe are needed to answer the puzzle regarding various host related immunogenetic factors in conditions resulting in varying outcomes of HBV or HCV hepatitis infection or their co-infections.



1       Rizzetto M. Hepatitis B vaccination: current status. Minerva Gastroenterol Dietol 1999; 45: 199-205   PubMed

2       Armstrong GL, Wasley A, Simard EP, McQuillan GM, Kuhnert WL, Alter MJ. The prevalence of hepatitis C virus        infection in the United States, 1999 through 2002. Ann Intern Med 2006; 144: 705-714   PubMed

3       Martin MP, Carrington M. Immunogenetics of viral infections. Curr Opin Immunol 2005; 17: 510-516   PubMed

4       Wu YF, Wang LY, Lee TD, Lin HH, Hu CT, Cheng ML, Lo SY. HLA phenotypes and outcomes of hepatitis B virus    infection in Taiwan. J Med Virol 2004; 72: 17-25   PubMed

5       Popov EA, Levitan BN, Alekseev LP, Pronina OA, Suchkov SV. Ter Arkh 2005; 77: 54-59   PubMed

6       Dieye A, Obami-Itou V, Barry MF, Raphenon G, Thiam A, Ndiaye R, Ndiaye M, Diaw ML, Diakhate L. Dakar Med   1999; 44: 166-170   PubMed

7       Thio CL, Thomas DL, Karacki P, Gao X, Marti D, Kaslow RA, Goedert JJ, Hilgartner M, Strathdee SA, Duggal P,    O'Brien SJ, Astemborski J, Carrington M. Comprehensive analysis of classand classⅡ HLA antigens and chronic     hepatitis B virus infection. J Virol 2003; 77: 12083-12087   PubMed

8        Zeniya M, Watanabe F, Aizawa Y, Toda G. Immunogenetic background of hepatitis B virus infection and     autoimmune hepatitis in Japan. Gastroenterol Jpn 1993; 28 Suppl 4: 69-75; discussion 76-80   PubMed

9        Karan MA, Tascioglu NE, Ozturk AO, Palanduz S, Carin M. The role of HLA antigens in chronic hepatitis B virus     infection. J Pak Med Assoc 2002; 52: 253-256   PubMed

10      Jiang YG, Wang YM, Liu TH, Liu J. Association between HLA classⅡ gene and susceptibility or resistance to     chronic hepatitis B. World J Gastroenterol 2003; 9: 2221-2225   PubMed

11      Meng XQ, Chen HG, Ma YL, Liu KZ. Influence of HLA class Ⅱ molecules on the outcome of hepatitis B virus     infection in population of Zhejiang Province in China. Hepatobiliary Pancreat Dis Int 2003; 2: 230-233   PubMed

12      Amarapurpar DN, Patel ND, Kankonkar SR. HLA classⅡ genotyping in chronic hepatitis B infection. J Assoc    Physicians India 2003; 51: 779-781   PubMed

13      Cheng YQ, Lin JS, Huang LH, Tian DY, Xiong P. Zhonghua Yixue Yichuanxue Zazhi 2003; 20: 247-249   PubMed

14      Han YN, Yang JL, Zheng SG, Tang Q, Zhu W. Relationship of human leukocyte antigen classⅡ genes with the    susceptibility to hepatitis B virus infection and the response to interferon in HBV-infected patients. World J    Gastroenterol 2005; 11: 5721-5724   PubMed

15      Liu HY, Kong BH, Luo X, Xu YP, Dai MS, Jiang S. Zhonghua Fuchanke Zazhi 2003; 38: 599-603   PubMed

16      Martinetti M, Pacati I, Cuccia M, Badulli C, Pasi A, Salvaneschi L, Minola E, De Silvestri A, Iannone AM,    Maccabruni A. Hierarchy of baby-linked immunogenetic risk factors in the vertical transmission of hepatitis C virus.    Int J Immunopathol Pharmacol 2006; 19: 369-378   PubMed

17      Bosi I, Ancora G, Mantovani W, Miniero R, Verucchi G, Attard L, Venturi V, Papa I, Sandri F, Dallacasa P, Salvioli    GP. HLA DR13 and HCV vertical infection. Pediatr Res 2002; 51: 746-749   PubMed

18      Thio CL, Carrington M, Marti D, O'Brien SJ, Vlahov D, Nelson KE, Astemborski J, Thomas DL. ClassⅡ HLA alleles    and hepatitis B virus persistence in African Americans. J Infect Dis 1999; 179: 1004-1006   PubMed

19      Ahn SH, Han KH, Park JY, Lee CK, Kang SW, Chon CY, Kim YS, Park K, Kim DK, Moon YM. Association between    hepatitis B virus infection and HLA-DR type in Korea. Hepatology 2000; 31: 1371-1373   PubMed

20      Pellegris G, Ravagnani F, Notti P, Fissi S, Lombardo C. B and C hepatitis viruses, HLA-DQ1 and -DR3 alleles and    autoimmunity in patients with hepatocellular carcinoma. J Hepatol 2002; 36: 521-526   PubMed

21      Li HQ, Li Z, Liu Y, Li JH, Dong JQ, Gao JR, Gou CY, Li H. Association of-238G/A and -857C/T polymorphisms of    tumor necrosis factor-alpha gene promoter region with outcomes of hepatitis B virus infection. Biomed Environ Sci    2006; 19: 133-136   PubMed

22      Lu LP, Li XW, Liu Y, Sun GC, Wang XP, Zhu XL, Hu QY, Li H. Association of -238G/A polymorphism of tumor    necrosis factor-alpha gene promoter region with outcomes of hepatitis B virus infection in Chinese Han population.    World J Gastroenterol 2004; 10: 1810-1814   PubMed

23      Hohler T, Kruger A, Gerken G, Schneider PM, Meyer zum Buschenefelde KH, Rittner C. A tumor necrosis factor-   alpha (TNF-alpha) promoter polymorphism is associated with chronic hepatitis B infection. Clin Exp Immunol 1998;    111: 579-582   PubMed

24      Cheong JY, Cho SW, Hwang IL, Yoon SK, Lee JH, Park CS, Lee JE, Hahm KB, Kim JH. Association between chronic    hepatitis B virus infection and interleukin-10, tumor necrosis factor-alpha gene promoter polymorphisms. J    Gastroenterol Hepatol 2006; 21: 1163-1169   PubMed

25      Niro GA, Fontana R, Gioffreda D, Valvano MR, Lacobellis A, Facciorusso D, Andriulli A. Tumor necrosis factor gene    polymorphisms and clearance or progression of hepatitis B virus infection. Liver Int 2005; 25: 1175-1181   PubMed

26      Somi MH, Najafi L, Noori BN, Alizadeh AH, Aghah MR, Shavakhi A, Ehsani MJ, Aghazadeh R, Masoodi M, Amini S,    Baladast M, Zali MR. Tumor necrosis factor-alpha gene promoter polymorphism in Iranian patients with chronic    hepatitis B. Indian J Gastroenterol 2006; 25: 14-15   PubMed

27      Zhang PA, Wu JM, Li Y, Yang XS. Association of polymorphisms of interleukin-18 gene promoter region with    chronic hepatitis B in Chinese Han population. World J Gastroenterol 2005; 11: 1594-1598   PubMed

28      Ben-Ari Z, Mor E, Papo O, Kfir B, Sulkes J, Tambur AR, Tur-Kaspa R, Klein T. Cytokine gene polymorphisms in    patients infected with hepatitis B virus. Am J Gastroenterol 2003; 98: 144-150   PubMed

29      Zhang PA, Li Y, Yang XS. Zhonghua Yixue Yichuanxue Zazhi 2006; 23: 410-414    PubMed

30      Miyazoe S, Hamasaki K, Nakata K, Kajiya Y, Kitajima K, Nakao K, Daikoku M, Yatsuhashi H, Koga M, Yano M, Eguchi     K. Influence of interleukin-10 gene promoter polymorphisms on disease progression in patients chronically infected    with hepatitis B virus. Am J Gastroenterol 2002; 97: 2086-2092   PubMed

31      Frodsham AJ, Zhang L, Dumpis U, Taib NA, Best S, Durham A, Hennig BJ, Hellier S, Knapp S, Wright M,    Chiaramonte M, Bell JI, Graves M, Whittle HC, Thomas HC, Thursz MR, Hill AV. ClassⅡ cytokine receptor gene    cluster is a major locus for hepatitis B persistence. Proc Natl Acad Sci USA 2006; 103: 9148-9153   PubMed

32      Zein NN, Germer JJ, El-Zayadi AR, Vidigal PG. Ethnic differences in polymorphisms of tumor necrosis factor-alpha,    interleukin-10, and transforming growth factor-beta1 genes in patients with chronic hepatitis C virus infection. Am J    Trop Med Hyg 2004; 70: 434-437   PubMed

33      Alper CA. The human immune response to hepatitis B surface antigen. Exp Clin Immunogenet 1995; 12: 171-181      PubMed

34      Martinetti M, De Silvestri A, Belloni C, Pasi A, Tinelli C, Pistorio A, Salvaneschi L, Rondini G, Avanzini MA, Cuccia     M. Humoral response to recombinant hepatitis B virus vaccine at birth: role of HLA and beyond. Clin Immunol 2000;    97: 234-240   PubMed

35      Mineta M, Tanimura M, Tana T, Yssel H, Kashiwagi S, Sasazuki T. Contribution of HLA classand classⅡ alleles    to the regulation of antibody production to hepatitis B surface antigen in humans. Int Immunol 1996; 8: 525-531      PubMed

36      Hatae K, Kimura A, Okubo R, Watanabe H, Erlich HA, Ueda K, Nishimura Y, Sasazuki T. Genetic control of    nonresponsiveness to hepatitis B virus vaccine by an extended HLA haplotype. Eur J Immunol 1992; 22: 1899-1905      PubMed

37      Das K, Gupta RK, Kumar V, Singh S, Kar P. Association of HLA phenotype with primary non-response to    recombinant hepatitis B vaccine: a study from north India. Trop Gastroenterol 2004; 25: 113-115   PubMed

38      Hayney MS, Poland GA, Jacobson RM, Schaid DJ, Lipsky JJ. The influence of the HLA-DRB1*13 allele on measles    vaccine response. J Investig Med 1996; 44: 261-263   PubMed

39      Desombere I, Willems A, Leroux-Roels G. Response to hepatitis B vaccine: multiple HLA genes are involved.    Tissue Antigens 1998; 51: 593-604   PubMed

40      Desombere I, Van der Wielen M, Van Damme P, Stoffel M, De Clercq N, Goilav C, Leroux-Roels G. Immune    response of HLA DQ2 positive subjects, vaccinated with HBsAg/AS04, a hepatitis B vaccine with a novel adjuvant.    Vaccine 2002; 20: 2597-2602   PubMed

41      De Silvestri A, Pasi A, Martinetti M, Belloni C, Tinelli C, Rondini G, Salvaneschi L, Cuccia M. Family study of non-   responsiveness to hepatitis B vaccine confirms the importance of HLA classⅢ C4A locus. Genes Immun 2001; 2:    367-372   PubMed

42      Hohler T, Stradmann-Bellinghausen B, Starke R, Sanger R, Victor A, Rittner C, Schneider PM. C4A deficiency and    nonresponse to hepatitis B vaccination. J Hepatol 2002; 37: 387-392   PubMed

43      Truedsson L, Awdeh Z, Yunis EJ, Mrose S, Moore B, Alper CA. Quantitative variation of C4 variant proteins    associated with many MHC haplotypes. Immunogenetics 1989; 30: 414-421   PubMed

44      Kramer J, Stachowski J, Barth C, Ujhelyi E, Tarjan V, Sulowicz W, Fust G, Baldamus CA. Genetic regulation of the    impaired immune response to hepatitis-B vaccine associated with low TCR density in end stage renal disease    patients: contribution of complement C4 and factor B alleles. Immunol Lett 1997; 59: 13-19   PubMed

45      McDermott AB, Cohen SB, Zuckerman JN, Madrigal JA. Human leukocyte antigens influence the immune response    to a pre-S/S hepatitis B vaccine. Vaccine 1999; 17: 330-339   PubMed

46      Stachowski J, Kramer J, Fust G, Maciejewski J, Baldamus CA, Petranyi GG. Relationship between the reactivity to    hepatitis B virus vaccination and the frequency of MHC class,Ⅱ and Ⅲ alleles in haemodialysis patients. Scand J    Immunol 1995; 42: 60-65   PubMed

47      Kuzushita N, Hayashi N, Katayama K, Kanto T, Oshita M, Hagiwara H, Kasahara A, Fusamoto H, Kamada T. High    levels of serum interleukin-10 are associated with a poor response to interferon treatment in patients with chronic    hepatitis C. Scand J Gastroenterol 1997; 32: 169-174   PubMed

48      Lango-Warensjo A, Cardell K, Lindblom B. Haplotypes comprising subtypes of the DQB1*06 allele direct the    antibody response after immunisation with hepatitis B surface antigen. Tissue Antigens 1998; 52: 374-380      PubMed

49      Alper CA, Kruskall MS, Marcus-Bagley D, Craven DE, Katz AJ, Brink SJ, Dienstag JL, Awdeh Z, Yunis EJ. Genetic     prediction of nonresponse to hepatitis B vaccine. N Engl J Med 1989; 321: 708-712   PubMed

50      Xie J, Wang X, Zhuang G, Xu H, Hao B, Tang X, Wu Q.  Zhonghua Ganzangbing Zazhi 2000; 8: 332-334   PubMed

51      Hohler T, Reuss E, Freitag CM, Schneider PM. A functional polymorphism in the IL-10 promoter influences the    response after vaccination with HBsAg and hepatitis A. Hepatology 2005; 42: 72-76   PubMed

52      Vitte RL, Fortier C, Richardet JP, Grimbert S, Trinchet JC, Beaugrand M, Lepage V, Raffoux C. HLA antigens in     patients with chronic hepatitis C. Tissue Antigens 1995; 45: 356-361   PubMed

53      Patel K, Norris S, Lebeck L, Feng A, Clare M, Pianko S, Portmann B, Blatt LM, Koziol J, Conrad A, McHutchison JG.    HLA classallelic diversity and progression of fibrosis in patients with chronic hepatitis C. Hepatology 2006; 43:    241-249   PubMed

54      Hadhoud A, Abdulaziz AM, Menawi LA, Shaheen FA, Abdulghaffar A, Abas FA, Al Mobrak MF. The relationship    between HLA typing and HCV infection and outcome of renal transplantation in HCV positive patients. Exp Clin    Transplant 2003; 1: 19-25   PubMed

55      Zekri AR, El-Mahallawy HA, Hassan A, El-Din NH, Kamel AM. HLA alleles in Egyptian HCV genotype-4 carriers.    Egypt J Immunol 2005; 12: 77-86   PubMed

56      Fanning LJ, Kenny-Walsh E, Shanahan F. Persistence of hepatitis C virus in a white population: associations with    human leukocyte antigen class 1. Hum Immunol 2004; 65: 745-751   PubMed

57      Bondarenko AL, Baramzina SV. Zh Mikrobiol Epidemiol Immunobiol 2002; : 55-57   PubMed

58      Thio CL, Gao X, Goedert JJ, Vlahov D, Nelson KE, Hilgartner MW, O'Brien SJ, Karacki P, Astemborski J, Carrington    M, Thomas DL. HLA-Cw*04 and hepatitis C virus persistence. J Virol 2002; 76: 4792-4797   PubMed

59      Kondo Y, Kobayashi K, Kobayashi T, Shiina M, Ueno Y, Satoh T, Shimosegawa T. Distribution of the HLA    classallele in chronic hepatitis C and its association with serum ALT level in chronic hepatitis C. Tohoku J Exp Med    2003; 201: 109-117   PubMed

60      McKiernan SM, Hagan R, Curry M, McDonald GS, Kelly A, Nolan N, Walsh A, Hegarty J, Lawlor E, Kelleher D.    Distinct MHC classandⅡ alleles are associated with hepatitis C viral clearance, originating from a single source.    Hepatology 2004; 40: 108-114   PubMed

61      Neumann-Haefelin C, McKiernan S, Ward S, Viazov S, Spangenberg HC, Killinger T, Baumert TF, Nazarova N,    Sheridan I, Pybus O, von Weizsacker F, Roggendorf M, Kelleher D, Klenerman P, Blum HE, Thimme R. Dominant    influence of an HLA-B27 restricted CD8+ T cell response in mediating HCV clearance and evolution. Hepatology    2006; 43: 563-572   PubMed

62      Khakoo SI, Thio CL, Martin MP, Brooks CR, Gao X, Astemborski J, Cheng J, Goedert JJ, Vlahov D, Hilgartner M, Cox    S, Little AM, Alexander GJ, Cramp ME, O'Brien SJ, Rosenberg WM, Thomas DL, Carrington M. HLA and NK cell    inhibitory receptor genes in resolving hepatitis C virus infection. Science 2004; 305: 872-874   PubMed

63      Montes-Cano MA, Caro-Oleas JL, Romero-Gomez M, Diago M, Andrade R, Carmona I, Aguilar Reina J, Nunez-   Roldan A, Gonzalez-Escribano MF. HLA-C and KIR genes in hepatitis C virus infection. Hum Immunol 2005; 66:    1106-1109   PubMed

64      Lopez-Vazquez A, Rodrigo L, Martinez-Borra J, Perez R, Rodriguez M, Fdez-Morera JL, Fuentes D, Rodriguez-   Rodero S, Gonzaez S, Lopez-Larrea C. Protective effect of the HLA-Bw4I80 epitope and the killer cell    immunoglobulin-like receptor 3DS1 gene against the development of hepatocellular carcinoma in patients with    hepatitis C virus infection. J Infect Dis 2005; 192: 162-165   PubMed

65      Nattermann J, Nischalke HD, Hofmeister V, Ahlenstiel G, Zimmermann H, Leifeld L, Weiss EH, Sauerbruch T,    Spengler U. The HLA-A2 restricted T cell epitope HCV core 35-44 stabilizes HLA-E expression and inhibits cytolysis    mediated by natural killer cells. Am J Pathol 2005; 166: 443-453   PubMed

66      Takehara T, Hayashi N. Natural killer cells in hepatitis C virus infection: from innate immunity to adaptive    immunity. Clin Gastroenterol Hepatol 2005; 3: S78-S81   PubMed

67      Jinushi M, Takehara T, Tatsumi T, Kanto T, Miyagi T, Suzuki T, Kanazawa Y, Hiramatsu N, Hayashi N. Negative    regulation of NK cell activities by inhibitory receptor CD94/NKG2A leads to altered NK cell-induced modulation of    dendritic cell functions in chronic hepatitis C virus infection. J Immunol 2004; 173: 6072-6081   PubMed

68      Kuzushita N, Hayashi N, Moribe T, Katayama K, Kanto T, Nakatani S, Kaneshige T, Tatsumi T, Ito A, Mochizuki K,    Sasaki Y, Kasahara A, Hori M. Influence of HLA haplotypes on the clinical courses of individuals infected with    hepatitis C virus. Hepatology 1998; 27: 240-244   PubMed

69      Higashi Y, Kamikawaji N, Suko H, Ando M. Analysis of HLA alleles in Japanese patients with cirrhosis due to    chronic hepatitis C. J Gastroenterol Hepatol 1996; 11: 241-246   PubMed

70      Aikawa T, Kojima M, Onishi H, Tamura R, Fukuda S, Suzuki T, Tsuda F, Okamoto H, Miyakawa Y, Mayumi M. HLA    DRB1 and DQB1 alleles and haplotypes influencing the progression of hepatitis C. J Med Virol 1996; 49: 274-278      PubMed

71      Fanning LJ, Levis J, Kenny-Walsh E, Whelton M, O'Sullivan K, Shanahan F. HLA classⅡ genes determine the    natural variance of hepatitis C viral load. Hepatology 2001; 33: 224-230   PubMed

72      Yee LJ. Host genetic determinants in hepatitis C virus infection. Genes Immun 2004; 5: 237-245   PubMed

73      Hong X, Yu RB, Sun NX, Wang B, Xu YC, Wu GL. Human leukocyte antigen classⅡ DQB1*0301, DRB1*1101 alleles    and spontaneous clearance of hepatitis C virus infection: a meta-analysis. World J Gastroenterol 2005; 11: 7302-   7307   PubMed

74      Alric L, Fort M, Izopet J, Vinel JP, Charlet JP, Selves J, Puel J, Pascal JP, Duffaut M, Abbal M. Genes of the major    histocompatibility complex classⅡ influence the outcome of hepatitis C virus infection. Gastroenterology 1997;    113: 1675-1681   PubMed

75      Alric L, Fort M, Izopet J, Vinel JP, Bureau C, Sandre K, Charlet JP, Beraud M, Abbal M, Duffaut M. Study of host-    and virus-related factors associated with spontaneous hepatitis C virus clearance. Tissue Antigens 2000; 56: 154-   158   PubMed

76      Renou C, Halfon P, Pol S, Cacoub P, Jouve E, Bronowicki JP, Arpurt JP, Rifflet H, Picon M, Causse X, Canva V,    Denis J, Tran A, Bourliere M, Ouzan D, Pariente A, Dantin S, Alric L, Cartier V, Reville M, Caillat-Zucman S.    Histological features and HLA classⅡ alleles in hepatitis C virus chronically infected patients with persistently    normal alanine aminotransferase levels. Gut 2002; 51: 585-590   PubMed

77      Thio CL, Thomas DL, Goedert JJ, Vlahov D, Nelson KE, Hilgartner MW, O'Brien SJ, Karacki P, Marti D, Astemborski    J, Carrington M. Racial differences in HLA classⅡ associations with hepatitis C virus outcomes. J Infect Dis 2001;    184: 16-21   PubMed

78      Barrett S, Ryan E, Crowe J. Association of the HLA-DRB1*01 allele with spontaneous viral clearance in an Irish    cohort infected with hepatitis C virus via contaminated anti-D immunoglobulin. J Hepatol 1999; 30: 979-983      PubMed

79      Martinetti M, Pacati I, Daielli C, Salvaneschi L, Maccabruni A. Critical role of Val/Gly86 HLA-DRB dimorphism in the    neonatal resistance or susceptibility to maternal hepatitis C virus infection. Pediatr Infect Dis J 1997; 16: 1001-   1002   PubMed

80      Thio CL, Goedert JJ, Mosbruger T, Vlahov D, Strathdee SA, O'Brien SJ, Astemborski J, Thomas DL. An analysis of    tumor necrosis factor alpha gene polymorphisms and haplotypes with natural clearance of hepatitis C virus    infection. Genes Immun 2004; 5: 294-300   PubMed

81      Mangia A, Santoro R, Piattelli M, Pazienza V, Grifa G, Iacobellis A, Andriulli A. IL-10 haplotypes as possible    predictors of spontaneous clearance of HCV infection. Cytokine 2004; 25: 103-109   PubMed

82      Goyal A, Kazim SN, Sakhuja P, Malhotra V, Arora N, Sarin SK. Association of TNF-beta polymorphism with disease    severity among patients infected with hepatitis C virus. J Med Virol 2004; 72: 60-65   PubMed

83      Yu YS, Tang ZH, Han JC, Xi M, Feng J, Zang GQ. Expression of ICAM-1, HLA-DR, and CD80 on peripheral    circulating CD1 alpha DCs induced in vivo by IFN-alpha in patients with chronic hepatitis B. World J Gastroenterol    2006; 12: 1447-1451   PubMed

84      Jiao J, Wang JB. Hepatitis C virus genotypes, HLA-DRB alleles and their response to interferon-   alpha and ribavirin in patients with chronic hepatitis C. Hepatobiliary Pancreat Dis Int 2005; 4: 80-   83   PubMed

85      Zang GQ, Xi M, Feng ML, Ji Y, Yu YS, Tang ZH. Curative effects of interferon-alpha and HLA-DRB1 -DQA1 and -   DQB1 alleles in chronic viral hepatitis B. World J Gastroenterol 2004; 10: 2116-2118   PubMed

86      Kikuchi I, Ueda A, Mihara K, Miyanaga O, Machidori H, Ishikawa E, Tamura K. The effect of HLA alleles on    response to interferon therapy in patients with chronic hepatitis C. Eur J Gastroenterol Hepatol 1998; 10: 859-863      PubMed

87      Romero-Gomez M, Gonzalez-Escribano MF, Torres B, Barroso N, Montes-Cano MA, Sanchez-Munoz D, Nunez-   Roldan A, Aguilar-Reina J. HLA classB44 is associated with sustained response to interferon + ribavirin therapy in    patients with chronic hepatitis C. Am J Gastroenterol 2003; 98: 1621-1626   PubMed

88      Sim H, Wojcik J, Margulies M, Wade JA, Heathcote J. Response to interferon therapy: influence of human leucocyte    antigen alleles in patients with chronic hepatitis C. J Viral Hepat 1998; 5: 249-253   PubMed

89      Piekarska A, Woszczek G, Sidorkiewicz M, Kuydowicz J. Przegl Epidemiol 2002; 56: 123-128   PubMed

90      Bhimma R, Hammond MG, Coovadia HM, Adhikari M, Connolly CA. HLA classandⅡ in black children with    hepatitis B virus-associated membranous nephropathy. Kidney Int 2002; 61: 1510-1515   PubMed

91      Park MH, Song EY, Ahn C, Oh KH, Yang J, Kang SJ, Lee HS. Two subtypes of hepatitis B virus-associated    glomerulonephritis are associated with different HLA-DR2 alleles in Koreans. Tissue Antigens 2003; 62: 505-511      PubMed

92      Sebastiani GD, Bellisai F, Caudai C, Rottoli P, Valensin PE, Pippi L, Morozzi G, Porciello G, Donvito A, Bilenchi R,    Giannini F, Galeazzi M. Association of extrahepatic manifestations with HLA classⅡ alleles and with virus genotype    in HCV infected patients. J Biol Regul Homeost Agents 2005; 19: 17-22   PubMed

93      Carrozzo M, Francia Di Celle P, Gandolfo S, Carbone M, Conrotto D, Fasano ME, Roggero S, Rendine S, Ghisetti V.    Increased frequency of HLA-DR6 allele in Italian patients with hepatitis C virus-associated oral lichen planus. Br J    Dermatol 2001; 144: 803-808   PubMed

94      Kallinowski B, Scherer S, Mehrabi A, Theilmann L, Stremmel W. Clinical impact of HLA DR B1 genotypes in chronic    hepatitis C virus infection. Transplant Proc 1999; 31: 3346-3349   PubMed

95      Kryczka W, Brojer E, Kalinska A, Urbaniak A, Zarebska-Michaluk D. DRB1 alleles in relation to severity of liver    disease in patients with chronic hepatitis C. Med Sci Monit 2001; 7 Suppl 1: 217-220   PubMed

96      Belli LS, Burra P, Poli F, Battista Alberti A, Silini E, Zavaglia C, Fagiuoli S, Prando D, Espadas de Arias A,    Boninsegna S, Tinelli C, Scalamogna M, de Carlis L, Pinzello G. HLA-DRB1 donor-recipient mismatch affects the    outcome of hepatitis C disease recurrence after liver transplantation. Gastroenterology 2006; 130: 695-702      PubMed

97      Czaja AJ, Doherty DG, Donaldson PT. Genetic bases of autoimmune hepatitis. Dig Dis Sci 2002; 47: 2139-2150       PubMed

98      Arce-Gomez B, Moliterno RA, Rodrigues AL, Barbosa J, deOliveira MR, Abreu JC, SpeckdoNascimento VA, Sasaki    MG. Association of viral hepatitis A with HLA-A9. Hum Immunol 1987; 18: 205-209   PubMed

99      Brncic N, Matic-Glazar D, Viskovic I, Grzetic M, Racki S. Acute renal failure complicating nonfulminant hepatitis a in    HLA-B27 positive patient. Ren Fail 2000; 22: 635-640   PubMed

100   Vento S. Fulminant hepatitis associated with hepatitis A virus superinfection in patients with chronic hepatitis C. J   Viral Hepat 2000; 7 Suppl 1: 7-8   PubMed

101   Hilzenrat N, Zilberman D, Klein T, Zur B, Sikuler E. Autoimmune hepatitis in a genetically susceptible patient: is it   triggered by acute viral hepatitis A? Dig Dis Sci 1999; 44: 1950-1952   PubMed

102   Fainboim L, Canero Velasco MC, Marcos CY, Ciocca M, Roy A, Theiler G, Capucchio M, Nuncifora S, Sala L, Zelazko   M. Protracted, but not acute, hepatitis A virus infection is strongly associated with HLA-DRB*1301, a marker for   pediatric autoimmune hepatitis. Hepatology 2001; 33: 1512-1517   PubMed

103   Liaw YF. Role of hepatitis C virus in dual and triple hepatitis virus infection. Hepatology 1995; 22: 1101-1108     PubMed

104   Karacki PS, Gao X, Thio CL, Thomas DL, Goedert JJ, Vlahov D, Kaslow RA, Strathdee S, Hilgartner MW, O'Brien SJ,   Carrington M. MICA and recovery from hepatitis C virus and hepatitis B virus infections. Genes Immun 2004; 5: 261-  266   PubMed

105   Constantini PK, Wawrzynowicz-Syczewska M, Clare M, Boron-Kaczmarska A, McFarlane IG, Cramp ME, Donaldson   PT. Interleukin-1, interleukin-10 and tumour necrosis factor-alpha gene polymorphisms in hepatitis C virus infection:   an investigation of the relationships with spontaneous viral clearance and response to alpha-interferon therapy. Liver   2002; 22: 404-412   PubMed

106   Gerlach JT, Ulsenheimer A, Gruner NH, Jung MC, Schraut W, Schirren CA, Heeg M, Scholz S, Witter K, Zahn R,   Vogler A, Zachoval R, Pape GR, Diepolder HM. Minimal T-cell-stimulatory sequences and spectrum of HLA restriction   of immunodominant CD4+ T-cell epitopes within hepatitis C virus NS3 and NS4 proteins. J Virol 2005; 79: 12425-  12433   PubMed

107   Herd KA, Mahalingam S, Mackay IM, Nissen M, Sloots TP, Tindle RW. Cytotoxic T-lymphocyte epitope vaccination   protects against human metapneumovirus infection and disease in mice. J Virol 2006; 80: 2034-2044   PubMed

108   Wawrzynowicz-Syczewska M, Underhill JA, Clare MA, Boron-Kaczmarska A, McFarlane IG, Donaldson PT. HLA   classⅡ genotypes associated with chronic hepatitis C virus infection and response to alpha-interferon treatment in   Poland. Liver 2000; 20: 234-239   PubMed

109   Yoon SK, Han JY, Pyo CW, Yang JM, Jang JW, Kim CW, Chang UI, Bae SH, Choi JY, Chung KW, Sun HS, Choi HB,   Kim TG. Association between human leukocytes antigen alleles and chronic hepatitis C virus infection in the Korean   population. Liver Int 2005; 25: 1122-1127   PubMed

110   Thursz MR, Kwiatkowski D, Allsopp CE, Greenwood BM, Thomas HC, Hill AV. Association between an MHC   classⅡ allele and clearance of hepatitis B virus in the Gambia. N Engl J Med 1995; 332: 1065-1069   PubMed

111   El Aggan HA, Sidkey F, El Gezery DA, Ghoneim E. Circulating anti-HLA antibodies in patients with chronic hepatitis   C: relation to disease activity. Egypt J Immunol 2004; 11: 71-79   PubMed

112   Dawes R, Hennig B, Irving W, Petrova S, Boxall S, Ward V, Wallace D, Macallan DC, Thursz M, Hill A, Bodmer W,   Beverley PC, Tchilian EZ. Altered CD45 expression in C77G carriers influences immune function and outcome of   hepatitis C infection. J Med Genet 2006; 43: 678-684   PubMed

113   Lu LP, Liu Y, Li XW, Sun GC, Zhu XL, Wu YZ, Hu QY, Li H. Zhongguo Yixue Kexueyuan Xuebao 2006; 28: 134-142     PubMed

114   Wu JF, Chen CH, Hsieh RP, Shih HH, Chen YH, Li CR, Chiang CY, Shau WY, Ni YH, Chen HL, Hsu HY, Chang MH. HLA   typing associated with hepatitis B E antigen seroconversion in children with chronic hepatitis B virus infection: a long-  term prospective sibling cohort study in Taiwan. J Pediatr 2006; 148: 647-651   PubMed

115   Cotrina M, Buti M, Jardi R, Rodriguez-Frias F, Campins M, Esteban R, Guardia J. Gastroenterol Hepatol 1997; 20:   115-118   PubMed

116   Hohler T, Gerken G, Notghi A, Lubjuhn R, Taheri H, Protzer U, Lohr HF, Schneider PM, Meyer zum Buschenfelde KH,   Rittner C. HLA-DRB1*1301 and *1302 protect against chronic hepatitis B. J Hepatol 1997; 26: 503-507   PubMed

117   Diepolder HM, Jung MC, Keller E, Schraut W, Gerlach JT, Gruner N, Zachoval R, Hoffmann RM, Schirren CA, Scholz   S, Pape GR. A vigorous virus-specific CD4+ T cell response may contribute to the association of HLA-DR13 with viral   clearance in hepatitis B. Clin Exp Immunol 1998; 113: 244-251   PubMed

118   Liu P, Xu H, Wang X, Li H, Zhuang G, Wu Z, Zhang K. Chin Med J (Engl) 2000; 113: 547-550   PubMed

119   Durupinar B, Okten G. HLA tissue types in nonresponders to hepatitis B vaccine. Indian J Pediatr 1996; 63: 369-  373   PubMed

120   Vingerhoets J, Goilav C, Vanham G, Kestens L, Muylle L, Kegels E, Van Hoof J, Piot P, Gigase P. Non-response to a   recombinant pre-S2-containing hepatitis B vaccine: association with the HLA-system. Ann Soc Belg Med Trop 1995;   75: 125-129   PubMed

121   Peces R, de la Torre M, Alcazar R, Urra JM. Prospective analysis of the factors influencing the antibody response to   hepatitis B vaccine in hemodialysis patients. Am J Kidney Dis 1997; 29: 239-245   PubMed

122   Qian Y, Zhang L, Liang XM, Hou JL, Luo KX. Association of immune response to hepatitis B vaccine with HLA-  DRB1*02, 07, 09 genes in the population of Han nationality in Guangdong Province. Diyi Junyidaxue Xuebao 2002;   22: 67-69   PubMed

123   Hsu HY, Chang MH, Ho HN, Hsieh RP, Lee SD, Chen DS, Lee CY, Hsieh KH. Association of HLA-DR14-DR52 with low   responsiveness to hepatitis B vaccine in Chinese residents in Taiwan. Vaccine 1993; 11: 1437-1440   PubMed

124   Caillat-Zucman S, Gimenez JJ, Wambergue F, Albouze G, Lebkiri B, Naret C, Moynot A, Jungers P, Bach JF. Distinct   HLA classⅡ alleles determine antibody response to vaccination with hepatitis B surface antigen. Kidney Int 1998;   53: 1626-1630   PubMed

125   McDermott AB, Zuckerman JN, Sabin CA, Marsh SG, Madrigal JA. Contribution of human leukocyte antigens to the   antibody response to hepatitis B vaccination. Tissue Antigens 1997; 50: 8-14   PubMed

126   Vidan-Jeras B, Brinovec V, Jurca B, Levicnik Steyinar S, Jeras M, Bohinjec M. The contribution of HLA-  ClassⅡ antigens in humoral non-response and delayed response to HBsAG vaccination. Pflugers Arch 2000; 440:   R188-R189   PubMed

127   Hohler T, Meyer CU, Notghi A, Stradmann-Bellinghausen B, Schneider PM, Starke R, Zepp F, Sanger R, Clemens R,   Meyer zum Buschenfelde KH, Rittner C. The influence of major histocompatibility complex classⅡ genes and T-cell   Vbeta repertoire on response to immunization with HBsAg. Hum Immunol 1998; 59: 212-218   PubMed

128   Wang C, Tang J, Song W, Lobashevsky E, Wilson CM, Kaslow RA. HLA and cytokine gene polymorphisms are   independently associated with responses to hepatitis B vaccination. Hepatology 2004; 39: 978-988   PubMed

129   Li M, Li R, Huang S, Gong J, Zeng X, Li Y, Lu M, Li H. The relationship between nonresponse to hepatitis B vaccine   and HLA genotype/haplotype. Zhonghua Yufangyixue Zazhi 2002; 36: 180-183   PubMed

130   Zavaglia C, Bortolon C, Ferrioli G, Rho A, Mondazzi L, Bottelli R, Ghessi A, Gelosa F, Iamoni G, Ideo G. HLA typing in   chronic type B, D and C hepatitis. J Hepatol 1996; 24: 658-665   PubMed

131   Lopez-Vazquez A, Rodrigo L, Mina-Blanco A, Martinez-Borra J, Fuentes D, Rodriguez M, Perez R,   Gonzalez S, Lopez-Larrea C. Extended human leukocyte antigen haplotype EH18.1 influences   progression to hepatocellular carcinoma in patients with hepatitis C virus infection. J Infect Dis   2004; 189: 957-963   PubMed

132   Yoshizawa K, Ota M, Saito S, Maruyama A, Yamaura T, Rokuhara A, Orii K, Ichijo T, Matsumoto A, Tanaka E,   Kiyosawa K. Long-term follow-up of hepatitis C virus infection: HLA classⅡ loci influences the natural history of the   disease. Tissue Antigens 2003; 61: 159-165   PubMed

133   Vejbaesya S, Songsivilai S, Tanwandee T, Rachaibun S, Chantangpol R, Dharakul T. HLA association with hepatitis   C virus infection. Hum Immunol 2000; 61: 348-353   PubMed

134   Hamed NA, Hano AF, Raouf HA, Gamal M, Eissa M. Relationship between HLA-DRB1*0101, DRB1*0301 alleles and   interleukin-12 in haemophilic patients and hepatitis C virus positive hepatocellular carcinoma patients. Egypt J   Immunol 2003; 10: 17-26   PubMed

135   Thursz M, Yallop R, Goldin R, Trepo C, Thomas HC. Influence of MHC classⅡ genotype on outcome of infection   with hepatitis C virus. The HENCORE group. Hepatitis C European Network for Cooperative Research. Lancet 1999;   354: 2119-2124   PubMed

136   Fanning LJ, Levis J, Kenny-Walsh E, Wynne F, Whelton M, Shanahan F. Viral clearance in hepatitis C (1b) infection:   relationship with human leukocyte antigen classⅡ in a homogeneous population. Hepatology 2000; 31: 1334-1337     PubMed

137   Asti M, Martinetti M, Zavaglia C, Cuccia MC, Gusberti L, Tinelli C, Cividini A, Bruno S, Salvaneschi L, Ideo G,   Mondelli MU, Silini EM. Human leukocyte antigen classⅡ andⅢ alleles and severity of hepatitis C virus-related   chronic liver disease. Hepatology 1999; 29: 1272-1279   PubMed

138   Mangia A, Gentile R, Cascavilla I, Margaglione M, Villani MR, Stella F, Modola G, Agostiano V, Gaudiano C, Andriulli   A. HLA classⅡ favors clearance of HCV infection and progression of the chronic liver damage. J Hepatol 1999; 30:   984-989   PubMed

139   Scotto G, Fazio V, D'Alessandro G, Monno L, Saracino A, Palumbo E, Angarano G. Association between HLA   classⅡ antigens and hepatitis C virus infection. J Biol Regul Homeost Agents 2003; 17: 316-321   PubMed

140   Hohler T, Gerken G, Notghi A, Knolle P, Lubjuhn R, Taheri H, Schneider PM, Meyer zum Buschenfelde KH, Rittner C.   MHC classⅡ genes influence the susceptibility to chronic active hepatitis C. J Hepatol 1997; 27: 259-264   PubMed

141   Hue S, Cacoub P, Renou C, Halfon P, Thibault V, Charlotte F, Picon M, Rifflet H, Piette JC, Pol S, Caillat-Zucman S.   Human leukocyte antigen classⅡ alleles may contribute to the severity of hepatitis C virus-related liver disease. J   Infect Dis 2002; 186: 106-109   PubMed

142   Wang LY, Lin HH, Lee TD, Wu YF, Hu CT, Cheng ML, Lo SY. Human leukocyte antigen phenotypes and hepatitis C   viral load. J Clin Virol 2005; 32: 144-150   PubMed

143   Yenigun A, Durupinar B. Decreased frequency of the HLA-DRB1*11 allele in patients with chronic hepatitis C virus   infection. J Virol 2002; 76: 1787-1789   PubMed

144   Tibbs C, Donaldson P, Underhill J, Thomson L, Manabe K, Williams R. Evidence that the HLA DQA1*03 allele confers   protection from chronic HCV-infection in Northern European Caucasoids. Hepatology 1996; 24: 1342-1345   PubMed

145   Cramp ME, Carucci P, Underhill J, Naoumov NV, Williams R, Donaldson PT. Association between HLA   classⅡ genotype and spontaneous clearance of hepatitis C viraemia. J Hepatol 1998; 29: 207-213   PubMed

146   Barrett S, Sweeney M, Crowe J. Host immune responses in hepatitis C virus clearance. Eur J Gastroenterol Hepatol   2005; 17: 1089-1097   PubMed

147   Congia M, Clemente MG, Dessi C, Cucca F, Mazzoleni AP, Frau F, Lampis R, Cao A, Lai ME, De Virgiliis S. HLA   classⅡ genes in chronic hepatitis C virus-infection and associated immunological disorders. Hepatology 1996; 24:   1338-1341   PubMed

148   De Re V, Caggiari L, Talamini R, Crovatto M, De Vita S, Mazzaro C, Cannizzaro R, Dolcetti R, Boiocchi M. Hepatitis C   virus-related hepatocellular carcinoma and B-cell lymphoma patients show a different profile of major   histocompatibility complex classⅡ alleles. Hum Immunol 2004; 65: 1397-1404   PubMed

149   Lechmann M, Schneider EM, Giers G, Kaiser R, Dumoulin FL, Sauerbruch T, Spengler U. Increased frequency of the   HLA-DR15 (B1*15011) allele in German patients with self-limited hepatitis C virus infection. Eur J Clin Invest 1999;   29: 337-343   PubMed

150   Tillmann HL, Chen DF, Trautwein C, Kliem V, Grundey A, Berning-Haag A, Boker K, Kubicka S, Pastucha L, Stangel   W, Manns MP. Low frequency of HLA-DRB1*11 in hepatitis C virus induced end stage liver disease. Gut 2001; 48:   714-718   PubMed

151   Zavaglia C, Martinetti M, Silini E, Bottelli R, Daielli C, Asti M, Airoldi A, Salvaneschi L, Mondelli MU, Ideo G.   Association between HLA classⅡ alleles and protection from or susceptibility to chronic hepatitis C. J Hepatol 1998;   28: 1-7   PubMed

152   Chu RH, Ma LX, Wang G, Shao LH. Influence of HLA-DRB1 alleles and HBV genotypes on interferon-alpha therapy   for chronic hepatitis B. World J Gastroenterol 2005; 11: 4753-4757   PubMed

153   Korenaga M, Hino K, Okita K. Nippon Rinsho 2001; 59: 1345-1350   PubMed

154   Muto H, Tanaka E, Matsumoto A, Yoshizawa K, Kiyosawa K. Types of human leukocyte antigen and decrease in   HCV core antigen in serum for predicting efficacy of interferon-Alpha in patients with chronic hepatitis C: analysis by   a prospective study. J Gastroenterol 2004; 39: 674-680   PubMed

155   Dincer D, Besisik F, Oguz F, Sever MS, Kaymakoglu S, Cakaloglu Y, Demir K, Turkoglu S, Carin M, Okten A. Genes   of major histocompatibility complex classⅡ  influence chronic C hepatitis treatment with interferon in hemodialysis   patients. Int J Artif Organs 2001; 24: 212-214   PubMed

156   Alric L, Fort M, Izopet J, Vinel JP, Bureau C, Sandre K, Charlet JP, Beraud M, Abbal M, Duffaut M. Study of host- and   virus-related factors associated with spontaneous hepatitis C virus clearance. Tissue Antigens 2000; 56: 154-158     PubMed

157   Miyaguchi S, Saito H, Ebinuma H, Morizane T, Ishii H. Possible association between HLA antigens and the response   to interferon in Japanese patients with chronic hepatitis C. Tissue Antigens 1997; 49: 605-611   PubMed

158   Nishiguchi S, Kaneshiro S, Tanaka M, Enomoto M, Akihiro T, Habu D, Takeda T, Fujino K, Tanaka T, Yano Y,   Shiomi S. Association of HLA alleles with response (especially biochemical response) to interferon therapy in   apanese patients with chronic hepatitis C. J Interferon Cytokine Res 2003; 23: 135-141   PubMed

159   Almarri A, El Dwick N, Al Kabi S, Sleem K, Rashed A, Ritter MA, Batchelor JR. Interferon-alpha therapy in HCV   hepatitis: HLA phenotype and cirrhosis are independent predictors of clinical outcome. Hum Immunol 1998; 59: 239-  242   PubMed


                                                                                               S- Editor  Liu Y    L- Editor  Alpini GD    E- Editor  Che YB





Reviews Add


Related Articles:
Establishment of a simple assay in vitro for hepatitis C virus NS3 serine protease based on recombinant substrate and single-chain protease
Genetic evolution of structural region of hepatitis C virus in primary infection
Full-length core sequence dependent complex-type glycosylation of hep atitis C virus E2 glycoprotein
A shield against a monster: Hepatitis C in hemodialysis patients
Positional effect of mutations in 5'UTR of hepatitis C virus 4a on patients' response to therapy