HEPATOLOGY ELSEWHERE EDITORSKris Kowdley, Seattle, WAGeoffrey McCaughan, Newtown, AustraliaChristian Trautwein, Aachen, Germany

Reviving Pegylated Interferon as aTherapeutic Agent for Hepatitis D:No More Room for Nucleos(t)ides?

Wedemeyer H, Yurdaydın C, Dalekos GN, Erhardt A,Cakaloglu Y, Degertekin H, et al.; for HIDIT StudyGroup. Peginterferon plus adefovir versus either drugalone for hepatitis delta. N Engl J Med 2011;364:322-331. (Reprinted with permission.)

Abstract

BACKGROUND: Chronic infection with hepatitis B virus andhepatitis delta virus (HDV) results in the most severe form of viralhepatitis. There is no currently approved treatment. We investi-gated the safety and efficacy of 48 weeks of treatment with peginter-feron alfa-2a plus adefovir dipivoxil, peginterferon alfa-2a alone,and adefovir dipivoxil alone. METHODS: We conducted arandomized trial in which 31 patients with HDV infection receivedtreatment with 180 lg of peginterferon alfa-2a weekly plus 10 mgof adefovir daily, 29 received 180 lg of peginterferon alfa-2aweekly plus placebo, and 30 received 10 mg of adefovir aloneweekly for 48 weeks. Follow-up was conducted for an additional24 weeks. Efficacy end points included clearance of HDV RNA,normalization of alanine aminotransferase levels, and a decline inlevels of hepatitis B surface antigen (HBsAg). RESULTS: The pri-mary end point—normalization of alanine aminotransferase levelsand clearance of HDV RNA at week 48—was achieved in twopatients in the group receiving peginterferon alfa-2a plus adefovirand two patients in the group receiving peginterferon alfa-2a plusplacebo but in none of the patients in the group receiving adefoviralone. At week 48, the test for HDV RNA was negative in 23% ofpatients in the first group, 24% of patients in the second, and noneof those in the third (P¼0.006 for the comparison of the first andthird groups; P¼0.004 for the comparison of the second andthird). The efficacy of peginterferon alfa-2a was sustained for 24weeks after treatment, with 28% of the patients receiving peginter-feron alfa-2a plus adefovir or peginterferon alfa-2a alone havingnegative results on HDV-RNA tests; none of the patients receivingadefovir alone had negative results. A decline in HBsAg levels ofmore than 1 log10 IU per milliliter from baseline to week 48 wasobserved in 10 patients in the first group, 2 in the second, andnone in the third (P<0.001 for the comparison of the firstand third groups and P¼0.01 for the comparison of the firstand second). CONCLUSIONS: Treatment with peginterferon alfa-2a for 48 weeks, with or without adefovir, resulted in sustainedHDV RNA clearance in about one quarter of patients with HDVinfection.

Comment

Since its discovery in 1977 by Rizzetto et al., hepatitisdelta virus (HDV) has been known as a special and

incomplete virus with an extraordinarily small RNAgenome (1.7 kb) encoding two hepatitis D antigens(HDAgs): a small, 24-kDa HDAg and a bigger, 27-kDaHDAg.1 Viral replication is possible only in hepatitis Bvirus (HBV)–infected cells because hepatitis B surfaceantigen (HBsAg) is needed as a lipid layer around theprotein-RNA complex of HDV. Because of this uniquemethod of replication, HDV has obtained its own genus(Deltavirus). Five percent of all HBV-positive patientsare expected to be HDV-positive, although we shouldkeep in mind that there are significant regional differen-ces in prevalence. Chronic delta hepatitis can cause themost severe form of viral hepatitis known to date,2 anda standard therapy regimen has not been established yet.Two paths of infection and two subsequent courses of

disease are possible: a coinfection with hepatitis B (witha high risk of fulminant hepatitis and a 95% chance ofthe clearance of both viruses) and a superinfection withpreexisting hepatitis B (with the possibility of fulminanthepatitis and/or severe chronic disease). Patients withchronic hepatitis B who acquire an HDV superinfectionhave a high risk of developing liver cirrhosis.3,4

For Hep-Net International Delta Hepatitis Interven-tion Trial I (HIDIT-I), Wedemeyer et al.5 recruited 90patients with chronic hepatitis B and D coinfectionsfrom multiple centers in Germany, Greece, and Turkeyand compared three different therapy regimens: pegy-lated interferon alfa-2a (PEG-IFNa2a) and a placebo(n ¼ 29), PEG-IFNa2a and adefovir (ADV; n ¼ 32),and ADV alone (n ¼ 30) for 48 weeks. Eighty patientscompleted the study (89%), and follow-up was per-formed for another 24 weeks. Among others, the pri-mary and secondary endpoints were the normalizationof alanine aminotransferase levels, the clearance ofHDV RNA, and a significant decline in HBsAg levels.Wedemeyer et al.5 found that 48 weeks of therapy with

PEG-IFNa2a, alone or in combination with ADV, signifi-cantly reduced HDV RNA levels, with 28% of the patientsclearing the virus within 24 weeks of the end of therapy.Treatment with ADV alone had no significant effect onHDV clearance after 24 weeks, although the suppressionof HBV DNA under therapy was best in the ADV group.These results are consistent with earlier studies evaluatingPEG-IFN as an effective therapeutic agent.6,7

HDV has (at least) eight different genotypes. Theseeight different clades have specific distributions in

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different regions of the world.8 In all patients of thisstudy, genotype 1 was detected. Genotype 1 is character-istic for Caucasian patients from Europe and can causesevere chronic disease. Different pathological effects de-pendent on the different genotypes have been discussedin the past (see Fig. 1 for further details). Because theclinical course of the disease can differ with the geno-type,9 we do not know whether positive data on theeffects of PEG-IFNa2a treatment can be assigned to theother genotypes. Furthermore, with the influence ofeight different HBV genotypes known to date10 (30patients of the study population were tested for theirHBV genotype, and all had genotype D), this study canprovide reliable results only about coinfections with

HBV genotype D and HDV genotype 1. More studiesneed to be conducted to obtain more information aboutvariations in therapy and efficacy for differentgenotypes.Several different treatment regimens for treating

patients with hepatitis D have been evaluated in thepast.11 Nucleosides and nucleotides were ineffective forHDV infections in multiple studies. For genotypes 1and 2, Aslan et al.12 previously postulated a primaryimmune-mediated disease with elevated levels of CD4þ

T cells, and this makes an immunomodulatory com-pound such as interferon a reasonable therapeuticchoice. In 1991, the first 12-month interferon treatmentstudy was published by Rizzetto’s group; a biochemical

Fig. 1. Different therapeutic agents have been evaluated over the last 20 years for delta hepatitis. Interferon (pegylated or not pegylated) hasbeen used as a therapeutic agent since 1991, and there have been promising results in multiple studies over the last years. On the other hand,although nucleos(t)ides are the standard therapy for hepatitis B, efforts to prove their therapeutic effect for HDV infections have failed. Studieswith more potent nucleos(t)ides are currently under way, and a possibly positive effect of combination therapy has to be evaluated. Prenylationinhibitors might become therapeutic options in the future,19 and after promising preclinical results with the HBV/HDV entry inhibitor Myrcludex B(indicated by asterisks in the figure), we are awaiting the first clinical data. In addition, this figure illustrates the different interactions of HDVwith hepatocytes and HBV. To date, delta hepatitis is considered an immune-mediated disease involving hepatocytes as MHC class II presentingcells and cytotoxic CD4þ T cells.12,21 Cytopathic effects have been discussed in the past, but they do not seem to be the main pathologicalmechanisms of HDV infection. The inhibition of IFN-a signaling seems to be an important factor not only in the persistence of chronic diseasebut also in successful resistance against interferon therapy.22 With clusterin activation23 and NF-jB activation,24 more mechanisms are known tobe involved in hepatic inflammation and hepatocellular carcinoma development caused by HDV infection. Abbreviations: Enh, enhancer; IFN-a,interferon-a; IFNAR, interferon-a/b receptor; JAK1, Janus kinase 1; MHC, major histocompatibility complex; NF-jB, nuclear factor kappa B; 2,5-OAS, 20,50-oligoadenylate synthetase; PKR, protein kinase R; STAT, signal transducer and activator of transcription; Tyk2, tyrosine kinase 2.

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response was found, although a virological response wasnot achieved.13 In 2006, the first data for a small group(n ¼ 16) treated with PEG-IFNa2b were presented,6

and a sustained virological response was shown in 43%of the patients. Wedemeyer et al.5 have now put hepati-tis D therapy with PEG-IFN back into the limelight.Their data demonstrate that PEG-IFN is at present theonly reasonable therapeutic option for HDV infection.What is the Remaining Significance of Nucleos

(t)ide Therapy? HDV coinfection leads to hepatitis B eseroconversion and low HBV DNA levels, which are typi-cal signs of delta hepatitis dominating an HBV infec-tion.14 This constellation can cause severe hepatitis with ahigh risk of decompensating end-stage liver disease or he-patocellular carcinoma development, and this makes opti-mal treatment necessary. In light of the current results andprevious studies already showing the ineffectiveness ofnucleos(t)ide therapy, we are faced with the questionwhether there is any role for these compounds in treatingpatients chronically coinfected with hepatitis B and hepa-titis D. ADV has lost its role as a first-line therapy forchronic hepatitis B over the last years, and to date, thereare no available data addressing the prognosis of treatmentwith entecavir or tenofovir in these cases. Anyway,although no significant suppression of HBsAg was noticedin the PEG-IFN–alone group, HDV RNA clearance wasachieved to the same degree found in the PEG-IFN andADV group. In addition, HBsAg levels could be furtherreduced with combination therapy. In this cohort, HDVreplication correlated with serum HBsAg levels.15 HBsAgreduction might be a prognostic factor for possible clear-ance in the future because HDV needs HBsAg as an enve-lope protein. Thus, is there a reasonable indication forcombination therapy? With respect to HBsAg levels, thistherapeutic scheme had the most profound effect. Becausean HBsAg decline is a positive predictor of successful ther-apy in hepatitis B e antigen–positive patients with chronichepatitis B monoinfections,16 combination therapy mightalso be favorable in HBV/HDV-coinfected patients withhepatitis B e antigen and/or a high viral load. A positiveeffect provided by combination therapy in these patientsmust be evaluated in future studies. An ongoing Hep-Netstudy (HIDIT-II) is evaluating a possible regimen involv-ing tenofovir and PEG-IFNa2a.Who Should Be Treated? Taking into consideration

the present study as well as future studies, we believe thatall patients with HDV infections and without contraindi-cations should be evaluated for PEG-IFN therapy.Because patients undergoing interferon therapy are athigh risk for adverse events and long treatment intervalsare needed with a probable effectiveness of only 25%, it isimportant to identify prognostic factors to determine

treatment outcomes. In 2007, Wedemeyer17 evaluateddifferent cytokine patterns in patients participating in thisstudy. He showed that differences in the T cell responsediscriminated between responders and nonresponders.Also, as mentioned before, an HBsAg decline might be aprognostic factor of the virological response. Reliable pa-rameters are needed to provide valuable predictions oftherapeutic success early during treatment and to deter-mine the necessary duration of therapy.Perspective. Future studies should be performed to

determine whether combination therapy is an optionin patients with chronic hepatitis B and D coinfec-tions. Currently, HIDIT-II is recruiting patients tocompare PEG-IFN plus tenofovir to PEG-IFN plus aplacebo. Because an earlier trial achieved promisingresults in patients coinfected with human immunodefi-ciency virus, HBV, and HDV,18 we are looking for-ward to discovering whether the therapy response canbe improved, although the treatment duration was sig-nificantly longer in that study (median ¼ 6 years).Because a decline in HBsAg levels during therapy is apotential prognostic parameter for these patients, lon-ger treatment intervals have to be considered.Finally, novel treatment options include prenylation

inhibitors19 and HBV entry inhibitors, which are cur-rently in early clinical development. They might be treat-ment options in the future. HBV/HDV entry inhibitors(e.g., Myrcludex B) have been successfully tested in pre-clinical studies, and clinical trials have to be conducted todetermine whether these novel compounds can be success-fully used.20 Because 15 to 20 million people are infectedwith HDV worldwide and immigration from areas ofhigh endemicity mainly to Europe is a growing problem,successful therapeutic regimens are desperately needed.

HOLGER H. LUTZ, M.D.CHRISTIAN TRAUTWEIN, M.D.Department of Medicine IIIUniversity Hospital AachenAachen, Germany

References1. Handa H, Yamaguchi Y. Hepatitis Delta Virus. New York, NY:

Springer; 2006.

2. Nakano T, Shapiro CN, Hadler SC, Casey JL, Mizokami M, Orito E,et al. Characterization of hepatitis D virus genotype III among YucpaIndians in Venezuela. J Gen Virol 2001;82(pt 9):2183-2189.

3. Niro GA, Smedile A, Ippolito AM, Ciancio A, Fontana R, Olivero A,et al. Outcome of chronic delta hepatitis in Italy: a long-term cohortstudy. J Hepatol 2010;53:834-840.

4. Romeo R, Del Ninno E, Rumi M, Russo A, Sangiovanni A, de Fran-chis R, et al. A 28-year study of the course of hepatitis delta infection:a risk factor for cirrhosis and hepatocellular carcinoma. Gastroenterol-ogy 2009;136:1629-1638.

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5. Wedemeyer H, Yurdaydın C, Dalekos GN, Erhardt A, Cakaloglu Y,Degertekin H, et al.; for HIDIT Study Group. Peginterferon plus ade-fovir versus either drug alone for hepatitis delta. N Engl J Med 2011;364:322-331.

6. Castelnau C, Le Gal F, Ripault MP, Gordien E, Martinot-Peignoux M,Boyer N, et al. Efficacy of peginterferon alpha-2b in chronic hepatitisdelta: relevance of quantitative RT-PCR for follow-up. HEPATOLOGY

2006;44:728-735.

7. Niro GA, Ciancio A, Gaeta GB, Smedile A, Marrone A, Olivero A,et al. Pegylated interferon alpha-2b as monotherapy or in combina-tion with ribavirin in chronic hepatitis delta. HEPATOLOGY 2006;44:713-720.

8. Le Gal F, Gault E, Ripault MP, Serpaggi J, Trinchet JC, Gordien E,et al. Eighth major clade for hepatitis delta virus. Emerg Infect Dis2006;12:1447-1450.

9. Su CW, Huang YH, Huo TI, Shih HH, Sheen IJ, Chen SW, et al. Ge-notypes and viremia of hepatitis B and D viruses are associated withoutcomes of chronic hepatitis D patients. Gastroenterology 2006;130:1625-1635.

10. Kiesslich D, Crispim MA, Santos C, Ferreira Fde L, Fraiji NA, Komni-nakis SV, et al. Influence of hepatitis B virus (HBV) genotype on theclinical course of disease in patients coinfected with HBV and hepatitisdelta virus. J Infect Dis 2009;199:1608-1611.

11. Wedemeyer H, Manns MP. Epidemiology, pathogenesis and manage-ment of hepatitis D: update and challenges ahead. Nat Rev Gastroen-terol Hepatol 2010;7:31-40.

12. Aslan N, Yurdaydin C, Wiegand J, Greten T, Ciner A, Meyer MF, et al.Cytotoxic CD4 T cells in viral hepatitis. J Viral Hepat 2006;13:505-514.

13. Rosina F, Pintus C, Meschievitz C, Rizzetto M. A randomized con-trolled trial of a 12-month course of recombinant human interferon-alpha in chronic delta (type D) hepatitis: a multicenter Italian study.HEPATOLOGY 1991;13:1052-1056.

14. Williams V, Brichler S, Radjef N, Lebon P, Goffard A, Hober D, et al.Hepatitis delta virus proteins repress hepatitis B virus enhancers andactivate the alpha/beta interferon-inducible MxA gene. J Gen Virol2009;90(pt 11):2759-2767.

15. Zachou K, Yurdaydin C, Drebber U, Dalekos GN, Erhardt A, Cakalo-glu Y, et al. Quantitative HBsAg and HDV-RNA levels in chronic deltahepatitis. Liver Int 2010;30:430-437.

16. Sonneveld MJ, Rijckborst V, Boucher CA, Hansen BE, Janssen HL.Prediction of sustained response to peginterferon alfa-2b for hepatitis Be antigen-positive chronic hepatitis B using on-treatment hepatitis Bsurface antigen decline. HEPATOLOGY 2010;52:1251-1257.

17. Wedemeyer H. Differential cytokine pattern of HDV-specific cellularimmune responses distinguishes treatment responder and nonresponderto peg-IFN alpha-2a treatment: results from the HEP-NET/interna-tional HIDIT-1 study. J Hepatol 2007;46(Suppl):S13-S14.

18. Sheldon J, Ramos B, Toro C, Rios P, Martinez-Alarcon J, BottecchiaM, et al. Does treatment of hepatitis B virus (HBV) infection reducehepatitis delta virus (HDV) replication in HIV-HBV-HDV-coinfectedpatients? Antivir Ther 2008;13:97-102.

19. Bordier BB, Ohkanda J, Liu P, Lee SY, Salazar FH, Marion PL, et al.In vivo antiviral efficacy of prenylation inhibitors against hepatitis deltavirus. J Clin Invest 2003;112:407-414.

20. Engelke M, Mills K, Seitz S, Simon P, Gripon P, Schnolzer M, et al.Characterization of a hepatitis B and hepatitis delta virus receptor bind-ing site. HEPATOLOGY 2006;43:750-760.

21. Herkel J, Jagemann B, Wiegard C, Lazaro JF, Lueth S, Kanzler S, et al.MHC class II-expressing hepatocytes function as antigen-presentingcells and activate specific CD4 T lymphocytes. HEPATOLOGY 2003;37:1079-1085.

22. Pugnale P, Pazienza V, Guilloux K, Negro F. Hepatitis delta virus inhib-its alpha interferon signaling. HEPATOLOGY 2009;49:398-406.

23. Liao FT, Lee YJ, Ko JL, Tsai CC, Tseng CJ, Sheu GT. Hepatitis deltavirus epigenetically enhances clusterin expression via histone acetylationin human hepatocellular carcinoma cells. J Gen Virol 2009;90(pt 5):1124-1134.

24. Park CY, Oh SH, Kang SM, Lim YS, Hwang SB. Hepatitis delta viruslarge antigen sensitizes to TNF-alpha-induced NF-kappaB signaling.Mol Cells 2009;28:49-55.

CopyrightVC 2011 by the American Association for the Study of Liver Diseases.View this article online at wileyonlinelibrary.com.DOI 10.1002/hep.24311Potential conflict of interest: Nothing to report.

Genome-Wide Association Studies inPrimary Sclerosing Cholangitis: Still MoreQuestions Than Answers?

Melum E, Franke A, Schramm C, Weismuller TJ,Gotthardt DN, Offner FA, et al. Genome-wide associa-tion analysis in primary sclerosing cholangitis identifiestwo non-HLA susceptibility loci. Nat Genet 2011;43:17-19. (Reprinted with permission.)

Abstract

Primary sclerosing cholangitis (PSC) is a chronic bile duct dis-ease affecting 2.4-7.5% of individuals with inflammatory boweldisease. We performed a genome-wide association analysis of2,466,182 SNPs in 715 individuals with PSC and 2,962 con-trols, followed by replication in 1,025 PSC cases and 2,174controls. We detected non-HLA associations at rs3197999 inMST1 and rs6720394 near BCL2L11 (combined P ¼ 1.1 �10�16 and P ¼ 4.1 � 10�8, respectively).

Comment

The etiopathogenesis of primary sclerosing chol-angitis (PSC) remains unknown, although it is nowaccepted that genetic factors play a major role inthe development of the disease.1 First-degree rela-tives have an 80-fold–increased risk of developingPSC.2 Moreover, studies that were first carried out30 years ago established that there are close associa-tions with the human leukocyte antigen (HLA)complex on chromosome 6p21.3 Surprisingly, theexact gene or genes responsible for the associationin this highly polymorphic region have not beenidentified.1,2 The heritability of PSC has an esti-mated relative sibling risk of approximately 10,which is in the range of other HLA-associated con-ditions.2 PSC is likely to be a complex disease inwhich different environmental factors interact withmultiple genetic factors and contribute to both thepathogenesis and progression of this chronic choles-tatic biliary disease.PSC is characterized by a close association with

inflammatory bowel disease and particularly ulcerativecolitis, which coexists in approximately three-quarters

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of Northern European patients with PSC.3 In addi-tion, approximately 5% to 10% of patients with totalulcerative colitis will have or will develop PSC duringthe course of their illness. Intriguingly, the clinicalphenotype of ulcerative colitis associated with PSC(inflammatory bowel disease with PSC) exhibits sig-nificant differences with the ulcerative colitis pheno-type without PSC,4 and this raises the possibility ofsignificant genotypic differences between the patientgroups.A recent meta-analysis of six genome-wide associa-

tion study (GWAS) data sets for ulcerative colitiscompared 6687 ulcerative colitis patients with 19,718controls.5 The report identified 29 additional risk locinot previously identified for ulcerative colitis andthereby increased the number of ulcerative colitis–associated loci to 47. The authors documented thatthe number of confirmed risk loci in inflammatorybowel disease is 99; this number includes at least 28association signals shared by ulcerative colitis andCrohn’s disease.In contrast, GWASs of liver disease in general and

PSC in particular are in their infancy.6 A recentGWAS in Northern European patients with PSC fromthe Norwegian PSC group confirmed that the strong-est associations are on chromosome 6p21, which isclosest to the HLA-B region.7 These HLA associationsappear to be specific to PSC.For PSC, just as for the majority of HLA-associ-

ated diseases, significant associations have been dem-onstrated outside the HLA complex with a genepresent on chromosome 13q31. However, this geneis not specific to PSC because significant associationsat this locus have been found for ulcerative colitisand multiple sclerosis. This suggests that the genemay be involved in the pathogenesis of inflamma-tion rather than specific disease susceptibility. Furthersignificant associations that were also previouslyestablished as ulcerative colitis susceptibility loci weredetected on chromosomes 2q35 and 3p21.7 Theauthors suggested G-protein–coupled bile acid recep-tor 1 and macrophage stimulating 1 (MST1), respec-tively, as the likely genes involved in the diseaseprocess.In the latest study,8 the same group repeated and

extended the GWAS by increasing the size of the Scan-dinavian and German study population and thereplication cohort to 715 and 1025 PSC patients,respectively, although the numbers of patients includedin the study are still relatively small in comparisonwith the much larger numbers included in GWASs ofinflammatory bowel disease.

In agreement with the original study, the strongestassociations were detected in the HLA complex. Ananalysis revealed a complex association signal in theclass II region and confirmed the strong associationwith the HLA-B*08 locus in the class I region. Thissuggests multiple causative loci within the region.Clear differences were found in the HLA complex incomparison with ulcerative colitis (for which the asso-ciation signal is less extensive), and associated single-nucleotide polymorphisms (SNPs) were observed nearthe HLA class II region. This is a potentially impor-tant observation that requires further study in thesearch for the elusive PSC susceptibility gene or genesin this region.Outside the HLA complex, the findings of the first

study were confirmed and extended. Multiple SNPsin strong linkage equilibrium at chromosome 3p21were associated at a genome-wide significance level.8

Further analysis using the replication cohort demon-strated the most prominent association at MST1. Theamino acid change at this locus, which is now associ-ated with PSC and was previously demonstrated inpatients with ulcerative colitis and Crohn’s disease,9

has been proposed to affect the MST1 receptor inter-action. MST1 is known to encode macrophage stimu-lating protein, which regulates innate immuneresponses to bacterial ligands. The variant(rs3197999, R689C) identified in this study and pre-viously in patients with inflammatory bowel disease9

has been predicted to interfere with the binding ofmacrophage stimulating protein to its receptor. TheMST1 protein is known to be expressed at high lev-els in gallbladder epithelium; it is possible, therefore,that the disease-associated variant may influence bili-ary and intestinal inflammation in these diseases.This potentially important finding clearly warrantsfurther study.In addition, a replicated associated signal outside

the HLA complex was demonstrated on chromosome2q13 by multiple SNPs encompassing the B celllymphoma 2–like 11 (BCL2L11) locus. BCL2L11 isknown to encode the B cell lymphoma 2 interactingprotein (Bim), which has a major influence on themaintenance of immune tolerance.10 Bim is a mem-ber of an apoptotic subgroup of proteins calledBH3-only proteins, which are critical to the initia-tion of apoptosis in response to many death stim-uli.10,11 The protein induces tolerance by the regula-tion of the negative selection of B lymphocytes inthe bone marrow and by the induction of the apo-ptosis of autoreactive T lymphocytes and the dele-tion of activated T lymphocytes after an immune

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response in both the thymus and the periphery.10,11

Mice lacking Bim may develop a systemic lupus ery-thematosus–like autoimmune disease.11 Preliminarystudies in Bcl2l11�/� mice demonstrated the infiltra-tion of mononuclear cell around some intrahepaticbile ducts, which were not seen in wild-type mice.8

The potentially important role of this regulatoryprotein in the immune response of the liver andbiliary system in patients with PSC remains to beestablished.Although it was not significantly replicated, a highly

significant association was shown at the interleukin-2receptor alpha locus for several SNPs that were previ-ously shown to influence the risk of developing type 1diabetes and multiple sclerosis.What does the future hold for GWASs of PSC?

The evidence from the GWAS results for inflamma-tory bowel disease has shown that ‘‘one GWAS isnever enough.’’6 At least two larger GWASs of PSCare currently in progress in the United Kingdom andUnited States, and they may detect unsuspected lociand confirm previous findings. However, it nowseems unlikely that the specific disease susceptibilitygene or genes for PSC will be detected by GWASs.The strength of GWASs lies in the detection ofgenetic variants commonly found in the general pop-ulation (>5%); these can be used to detect generaldisease genes influencing, for example, the immuneresponse and carcinogenesis and hence can providepotentially important insights into the pathogenesisof disease.After 3 decades of research, the region of the HLA

complex on chromosome 6p21 still appears to be themost likely site of genetic susceptibility. Other techni-ques that are designed to detect uncommon genes andto explore the HLA complex in more detail, such asexome sequencing, may prove to more rewarding inthe future.

ROGER CHAPMAN, M.D.Department of Translational GastroenterologyJohn Radcliffe HospitalHeadington, OxfordUnited Kingdom OX3 9DU

References1. Maggs JR, Chapman RW. An update on primary sclerosing cholangitis.

Curr Opin Gastroenterol 2008;24:377-383.2. Karlsen TH, Schrumpf E, Boberg KM. Genetic epidemiology of pri-

mary sclerosing cholangitis. World J Gastroenterol 2007;13:5421-5431.3. Chapman RW, Varghese Z, Gaul R, Kokkinon N, Sherlock S. Associa-

tion of primary sclerosing cholangitis with HLA-B8. Gut 1983;24:38-41.

4. Loftus EV Jr, Harewood GC, Loftus CG, Tremaine WJ, Harmsen WS,Zinsmeister AR, et al. PSC-IBD: a unique form of inflammatory boweldisease associated with primary sclerosing cholangitis. Gut 2005;54:91-96.

5. Anderson CA, Boucher G, Lees CW, Franke A, D’Amato M, Taylor

KD, et al. Meta-analysis identifies 29 additional ulcerative colitis risk

loci increasing the number of confirmed associations to 47. Nat Genet

2011;43:246-252.6. Karlsen TH, Melum E, Franke A. The utility of genome-wide associa-

tion studies in hepatology. HEPATOLOGY 2010;51:1833-1842.7. Karlsen TH, Franke A, Melum E, Kaser A, Hov JR, Balschun T, et al.

Genome-wide analysis in primary sclerosing cholangitis. Gastroenterol-

ogy 2010;138:1102-1111.8. Melum E, Franke A, Schramm C, Weismuller TJ, Gotthardt DN, Off-

ner FA, et al. Genome-wide association analysis in primary sclerosing

cholangitis identifies two non-HLA susceptibility loci. Nat Genet 2011;

43:17-19.9. Goyette P, Lefebvre C, Ng A, Brant SR, Cho JH, Duerr RH, et al.

Gene-centric association mapping of chromosome 3p implicates MST1in pathogenesis. Mucosal Immunol 2008;11:131-138.

10. Strasser A. The role of BH3-only proteins in the immune system. NatRev Immunol 2005;5:189-200.

11. Hughes P, Bouillet P, Strasser A. Role of Bim and other Bcl-2 familymembers in autoimmune and degenerative diseases. Curr Dir Auto-immun 2006;9:74-94.

CopyrightVC 2011 by the American Association for the Study of Liver Diseases.View this article online at wileyonlinelibrary.com.DOI 10.1002/hep.24333Potential conflict of interest: Nothing to report.

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