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Semin Liver Dis 2011; 31(4): 375-386
DOI: 10.1055/s-0031-1297926
© Thieme Medical Publishers

The Impact of Human Gene Polymorphisms on HCV Infection and Disease Outcome

Esperance A.K. Schaefer1 , Raymond T. Chung1
  • 1GI Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
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Publication History

Publication Date:
21 December 2011 (online)

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ABSTRACT

In recent years, some genome-wide association studies have identified several single nucleotide polymorphisms (SNPs) associated with hepatitis C viral containment, treatment response, and disease progression. IL28B is a gene on chromosome 19, coding for interferon-λ3, and two polymorphisms upstream of this the gene have been strongly associated with clinical outcomes after treatment for the hepatitis C virus (HCV). The IL28B polymorphisms have additionally been associated with spontaneous clearance. The mechanism has yet to be clearly defined, but appears to involve differential responsiveness to interferon signaling between the favorable and unfavorable genotypes. ITPA is a gene on chromosome 20, coding for inosine triphosphatase, and polymorphisms on this gene have been associated with ribavirin-induced hemolytic anemia. Functional variants of ITPA have been identified that have decreased enzymatic activity, which appear to protect against anemia. Finally, PNPLA3 polymorphisms were initially described as predictors of nonalcoholic fatty liver disease, but have recently been associated with disease progression in HCV.

KEYWORDS

Hepatitis C - IL28B - IFNλ - PNPLA3 - ITPA

REFERENCES

  • 1 Seeff L B. Natural history of chronic hepatitis C.  Hepatology. 2002;  36 (5, Suppl 1) S35-S46
    Google Scholar
  • 2 Hayashi N, Takehara T. Antiviral therapy for chronic hepatitis C: past, present, and future.  J Gastroenterol. 2006;  41 (1) 17-27
    Google Scholar
  • 3 Muir A J, Bornstein J D, Killenberg P G. Atlantic Coast Hepatitis Treatment Group . Peginterferon alfa-2b and ribavirin for the treatment of chronic hepatitis C in blacks and non-Hispanic whites.  N Engl J Med. 2004;  350 (22) 2265-2271
    Google Scholar
  • 4 Ge D, Fellay J, Thompson A J et al.. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance.  Nature. 2009;  461 (7262) 399-401
    Google Scholar
  • 5 Thomas D L, Thio C L, Martin M P et al.. Genetic variation in IL28B and spontaneous clearance of hepatitis C virus.  Nature. 2009;  461 (7265) 798-801
    Google Scholar
  • 6 McCarthy J J, Li J H, Thompson A et al.. Replicated association between an IL28B gene variant and a sustained response to pegylated interferon and ribavirin.  Gastroenterology. 2010;  138 (7) 2307-2314
    Google Scholar
  • 7 Tanaka Y, Nishida N, Sugiyama M et al.. Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C.  Nat Genet. 2009;  41 (10) 1105-1109
    Google Scholar
  • 8 Suppiah V, Moldovan M, Ahlenstiel G et al.. IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy.  Nat Genet. 2009;  41 (10) 1100-1104
    Google Scholar
  • 9 Rauch A, Kutalik Z, Descombes P Swiss Hepatitis C Cohort Study et al. Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure: a genome-wide association study.  Gastroenterology. 2010;  138 (4) 1338-1345 1345 e1-e7
    Google Scholar
  • 10 Page K, Hahn J A, Evans J et al.. Acute hepatitis C virus infection in young adult injection drug users: a prospective study of incident infection, resolution, and reinfection.  J Infect Dis. 2009;  200 (8) 1216-1226
    Google Scholar
  • 11 Wang C C, Krantz E, Klarquist J et al.. Acute hepatitis C in a contemporary US cohort: modes of acquisition and factors influencing viral clearance.  J Infect Dis. 2007;  196 (10) 1474-1482
    Google Scholar
  • 12 Thomas D L, Astemborski J, Rai R M et al.. The natural history of hepatitis C virus infection: host, viral, and environmental factors.  JAMA. 2000;  284 (4) 450-456
    Google Scholar
  • 13 Tillmann H L, Thompson A J, Patel K German Anti-D Study Group et al. A polymorphism near IL28B is associated with spontaneous clearance of acute hepatitis C virus and jaundice.  Gastroenterology. 2010;  139 (5) 1586-1592 1592 e1
    Google Scholar
  • 14 Knapp S, Warshow U, Ho K M et al.. A polymorphism in IL28B distinguishes exposed, uninfected individuals from spontaneous resolvers of HCV infection.  Gastroenterology. 2011;  141 (1) 320-325 325 e1-e2
    Google Scholar
  • 15 Ruiz-Extremera A, Muñoz-Gámez J A, Salmerón-Ruiz M A et al.. Genetic variation in interleukin 28B with respect to vertical transmission of hepatitis C virus and spontaneous clearance in HCV-infected children.  Hepatology. 2011;  53 (6) 1830-1838
    Google Scholar
  • 16 Montes-Cano M A, García-Lozano J R, Abad-Molina C et al.. Interleukin-28B genetic variants and hepatitis virus infection by different viral genotypes.  Hepatology. 2010;  52 (1) 33-37
    Google Scholar
  • 17 Neumann A U, Lam N P, Dahari H et al.. Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-alpha therapy.  Science. 1998;  282 (5386) 103-107
    Google Scholar
  • 18 Layden-Almer J E, Cotler S J, Layden T J. Viral kinetics in the treatment of chronic hepatitis C.  J Viral Hepat. 2006;  13 (8) 499-504
    Google Scholar
  • 19 Scott J, Holte S, Urban T et al.. IL28B genotype effects during early treatment with peginterferon and ribavirin in difficult-to-treat hepatitis C virus infection.  J Infect Dis. 2011;  204 (3) 419-425
    Google Scholar
  • 20 Lindh M, Lagging M, Arnholm B et al.. IL28B polymorphisms determine early viral kinetics and treatment outcome in patients receiving peginterferon/ribavirin for chronic hepatitis C genotype 1.  J Viral Hepat. 2011;  18 (7) e325-e331
    Google Scholar
  • 21 Thompson A J, Muir A J, Sulkowski M S et al.. Interleukin-28B polymorphism improves viral kinetics and is the strongest pretreatment predictor of sustained virologic response in genotype 1 hepatitis C virus.  Gastroenterology. 2010;  139 (1) 120-129 e18
    Google Scholar
  • 22 Shiffman M L, Suter F, Bacon B R ACCELERATE Investigators et al. Peginterferon alfa-2a and ribavirin for 16 or 24 weeks in HCV genotype 2 or 3.  N Engl J Med. 2007;  357 (2) 124-134
    Google Scholar
  • 23 Hadziyannis S J, Sette Jr H, Morgan T R PEGASYS International Study Group et al. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose.  Ann Intern Med. 2004;  140 (5) 346-355
    Google Scholar
  • 24 Moghaddam A, Melum E, Reinton N et al.. IL28B genetic variation and treatment response in patients with hepatitis C virus genotype 3 infection.  Hepatology. 2011;  53 (3) 746-754
    Google Scholar
  • 25 Mangia A, Thompson A J, Santoro R et al.. An IL28B polymorphism determines treatment response of hepatitis C virus genotype 2 or 3 patients who do not achieve a rapid virologic response.  Gastroenterology. 2010;  139 (3) 821-827, 827, e1
    Google Scholar
  • 26 Kim A Y, Chung R T. Coinfection with HIV-1 and HCV—a one-two punch.  Gastroenterology. 2009;  137 (3) 795-814
    Google Scholar
  • 27 Torriani F J, Rodriguez-Torres M, Rockstroh J K APRICOT Study Group et al. Peginterferon Alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients.  N Engl J Med. 2004;  351 (5) 438-450
    Google Scholar
  • 28 Chung R T, Andersen J, Volberding P AIDS Clinical Trials Group A5071 Study Team et al. Peginterferon Alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons.  N Engl J Med. 2004;  351 (5) 451-459
    Google Scholar
  • 29 Carrat F, Bani-Sadr F, Pol S ANRS HCO2 RIBAVIC Study Team et al. Pegylated interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic hepatitis C in HIV-infected patients: a randomized controlled trial.  JAMA. 2004;  292 (23) 2839-2848
    Google Scholar
  • 30 Rallón N I, Naggie S, Benito J M et al.. Association of a single nucleotide polymorphism near the interleukin-28B gene with response to hepatitis C therapy in HIV/hepatitis C virus-coinfected patients.  AIDS. 2010;  24 (8) F23-F29
    Google Scholar
  • 31 Rallón N I, Soriano V, Naggie S et al.. IL28B gene polymorphisms and viral kinetics in HIV/hepatitis C virus-coinfected patients treated with pegylated interferon and ribavirin.  AIDS. 2011;  25 (8) 1025-1033
    Google Scholar
  • 32 Motomura T, Taketomi A, Fukuhara T et al.. The impact of IL28B genetic variants on recurrent hepatitis C in liver transplantation: significant lessons from a dual graft case.  Am J Transplant. 2011;  11 (6) 1325-1329
    Google Scholar
  • 33 Coto-Llerena M, Pérez-Del-Pulgar S, Crespo G et al.. Donor and recipient IL28B polymorphisms in HCV-infected patients undergoing antiviral therapy before and after liver transplantation.  Am J Transplant. 2011;  11 (5) 1051-1057
    Google Scholar
  • 34 Fukuhara T, Taketomi A, Motomura T et al.. Variants in IL28B in liver recipients and donors correlate with response to peg-interferon and ribavirin therapy for recurrent hepatitis C.  Gastroenterology. 2010;  139 (5) 1577-1585, 1585, e1–e3
    Google Scholar
  • 35 Eurich D, Boas-Knoop S, Ruehl M et al.. Relationship between the interleukin-28b gene polymorphism and the histological severity of hepatitis C virus-induced graft inflammation and the response to antiviral therapy after liver transplantation.  Liver Transpl. 2011;  17 (3) 289-298
    Google Scholar
  • 36 Charlton M R, Thompson A, Veldt B J et al.. Interleukin-28B polymorphisms are associated with histological recurrence and treatment response following liver transplantation in patients with hepatitis C virus infection.  Hepatology. 2011;  53 (1) 317-324
    Google Scholar
  • 37 Lange C M, Moradpour D, Doehring A et al.. Impact of donor and recipient IL28B rs12979860 genotypes on hepatitis C virus liver graft reinfection.  J Hepatol. 2011;  55 (2) 322-327
    Google Scholar
  • 38 Fabris C, Falleti E, Cussigh A et al.. IL-28B rs12979860 C/T allele distribution in patients with liver cirrhosis: role in the course of chronic viral hepatitis and the development of HCC.  J Hepatol. 2011;  54 (4) 716-722
    Google Scholar
  • 39 Barreiro P, Pineda J A, Rallón N et al.. Influence of interleukin-28B single-nucleotide polymorphisms on progression to liver cirrhosis in human immunodeficiency virus-hepatitis C virus-coinfected patients receiving antiretroviral therapy.  J Infect Dis. 2011;  203 (11) 1629-1636
    Google Scholar
  • 40 Marabita F, Aghemo A, De Nicola S et al.. Genetic variation in the interleukin-28B gene is not associated with fibrosis progression in patients with chronic hepatitis C and known date of infection.  Hepatology. 2011;  54 (4) 1127-1134
    Google Scholar
  • 41 Tillmann H L, Patel K, Muir A J et al.. Beneficial IL28B genotype associated with lower frequency of hepatic steatosis in patients with chronic hepatitis C.  J Hepatol. 2011;  Epub ahead of print
    Google Scholar
  • 42 Cai T, Dufour J F, Muellhaupt B Swiss Hepatitis C Cohort Study Group et al. Viral genotype-specific role of PNPLA3, PPARG, MTTP, and IL28B in hepatitis C virus-associated steatosis.  J Hepatol. 2011;  55 (3) 529-535
    Google Scholar
  • 43 Jacobson I M, McHutchison J G, Dusheiko G ADVANCE Study Team et al. Telaprevir for previously untreated chronic hepatitis C virus infection.  N Engl J Med. 2011;  364 (25) 2405-2416
    Google Scholar
  • 44 Poordad F, McCone Jr J, Bacon B R SPRINT-2 Investigators et al. Boceprevir for untreated chronic HCV genotype 1 infection.  N Engl J Med. 2011;  364 (13) 1195-1206
    Google Scholar
  • 45 Zeuzem S, Andreone P, Pol S REALIZE Study Team et al. Telaprevir for retreatment of HCV infection.  N Engl J Med. 2011;  364 (25) 2417-2428
    Google Scholar
  • 46 Bacon B R, Gordon S C, Lawitz E HCV RESPOND-2 Investigators et al. Boceprevir for previously treated chronic HCV genotype 1 infection.  N Engl J Med. 2011;  364 (13) 1207-1217
    Google Scholar
  • 47 Akuta N, Suzuki F, Hirakawa M et al.. Amino acid substitution in hepatitis C virus core region and genetic variation near the interleukin 28B gene predict viral response to telaprevir with peginterferon and ribavirin.  Hepatology. 2010;  52 (2) 421-429
    Google Scholar
  • 48 Chayama K, Hayes C N, Abe H et al.. IL28B but not ITPA polymorphism is predictive of response to pegylated interferon, ribavirin, and telaprevir triple therapy in patients with genotype 1 hepatitis C.  J Infect Dis. 2011;  204 (1) 84-93
    Google Scholar
  • 49 Doyle S E, Schreckhise H, Khuu-Duong K et al.. Interleukin-29 uses a type 1 interferon-like program to promote antiviral responses in human hepatocytes.  Hepatology. 2006;  44 (4) 896-906
    Google Scholar
  • 50 Ank N, West H, Bartholdy C et al.. Lambda interferon (IFN-lambda), a type III IFN, is induced by viruses and IFNs and displays potent antiviral activity against select virus infections in vivo.  J Virol. 2006;  80 (9) 4501-4509
    Google Scholar
  • 51 Kotenko S V, Gallagher G, Baurin V V et al.. IFN-lambdas mediate antiviral protection through a distinct class II cytokine receptor complex.  Nat Immunol. 2003;  4 (1) 69-77
    Google Scholar
  • 52 Sheppard P, Kindsvogel W, Xu W et al.. IL-28, IL-29 and their class II cytokine receptor IL-28R.  Nat Immunol. 2003;  4 (1) 63-68
    Google Scholar
  • 53 Gad H H, Dellgren C, Hamming O J et al.. Interferon-lambda is functionally an interferon but structurally related to the interleukin-10 family.  J Biol Chem. 2009;  284 (31) 20869-20875
    Google Scholar
  • 54 Diegelmann J, Beigel F, Zitzmann K et al.. Comparative analysis of the lambda-interferons IL-28A and IL-29 regarding their transcriptome and their antiviral properties against hepatitis C virus.  PLoS ONE. 2010;  5 (12) e15200
    Google Scholar
  • 55 Zhou Z, Hamming O J, Ank N et al.. Type III interferon (IFN) induces a type I IFN-like response in a restricted subset of cells through signaling pathways involving both the Jak-STAT pathway and the mitogen-activated protein kinases.  J Virol. 2007;  81 (14) 7749-7758
    Google Scholar
  • 56 Li M, Liu X, Zhou Y, Su S B. Interferon-lambdas: the modulators of antivirus, antitumor, and immune responses.  J Leukoc Biol. 2009;  86 (1) 23-32
    Google Scholar
  • 57 Marcello T, Grakoui A, Barba-Spaeth G et al.. Interferons alpha and lambda inhibit hepatitis C virus replication with distinct signal transduction and gene regulation kinetics.  Gastroenterology. 2006;  131 (6) 1887-1898
    Google Scholar
  • 58 Zhang L, Jilg N, Shao R X et al.. IL28B inhibits hepatitis C virus replication through the JAK-STAT pathway.  J Hepatol. 2011;  55 (2) 289-298
    Google Scholar
  • 59 Urban T J, Thompson A J, Bradrick S S et al.. IL28B genotype is associated with differential expression of intrahepatic interferon-stimulated genes in patients with chronic hepatitis C.  Hepatology. 2010;  52 (6) 1888-1896
    Google Scholar
  • 60 Honda M, Sakai A, Yamashita T Hokuriku Liver Study Group et al. Hepatic ISG expression is associated with genetic variation in interleukin 28B and the outcome of IFN therapy for chronic hepatitis C.  Gastroenterology. 2010;  139 (2) 499-509
    Google Scholar
  • 61 Sarasin-Filipowicz M, Oakeley E J, Duong F H et al.. Interferon signaling and treatment outcome in chronic hepatitis C.  Proc Natl Acad Sci U S A. 2008;  105 (19) 7034-7039
    Google Scholar
  • 62 Sixtos-Alonso M S, Sánchez-Muñoz F, Sánchez-Ávila J F et al.. IFN-stimulated gene expression is a useful potential molecular marker of response to antiviral treatment with Peg-IFNα 2b and ribavirin in patients with hepatitis C virus genotype 1.  Arch Med Res. 2011;  42 (1) 28-33
    Google Scholar
  • 63 Abe H, Hayes C N, Ochi H et al.. Inverse association of IL28B genotype and liver mRNA expression of genes promoting or suppressing antiviral state.  J Med Virol. 2011;  83 (9) 1597-1607
    Google Scholar
  • 64 Cyr D D, Lucas J E, Thompson J W et al.. Characterization of serum proteins associated with IL28B genotype among patients with chronic hepatitis C.  PLoS ONE. 2011;  6 (7) e21854
    Google Scholar
  • 65 Aizawa Y, Yohizawa K, Aida Y et al.. Genotype rs8099917 near the IL28B gene and amino acid substitution at position 70 in the core region of the hepatitis C virus are determinants of serum apolipoprotein B-100 concentration in chronic hepatitis C.  Mol Cell Biochem. 2011;  epub
    Google Scholar
  • 66 Li J H, Lao X Q, Tillmann H L et al.. Interferon-lambda genotype and low serum low-density lipoprotein cholesterol levels in patients with chronic hepatitis C infection.  Hepatology. 2010;  51 (6) 1904-1911
    Google Scholar
  • 67 Martin M P, Qi Y, Goedert J J et al.. IL28B polymorphism does not determine outcomes of hepatitis B virus or HIV infection.  J Infect Dis. 2010;  202 (11) 1749-1753
    Google Scholar
  • 68 Manns M P, McHutchison J G, Gordon S C et al.. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial.  Lancet. 2001;  358 (9286) 958-965
    Google Scholar
  • 69 Fellay J, Thompson A J, Ge D et al.. ITPA gene variants protect against anaemia in patients treated for chronic hepatitis C.  Nature. 2010;  464 (7287) 405-408
    Google Scholar
  • 70 Ochi H, Maekawa T, Abe H et al.. ITPA polymorphism affects ribavirin-induced anemia and outcomes of therapy—a genome-wide study of Japanese HCV virus patients.  Gastroenterology. 2010;  139 (4) 1190-1197
    Google Scholar
  • 71 Thompson A J, Fellay J, Patel K et al.. Variants in the ITPA gene protect against ribavirin-induced hemolytic anemia and decrease the need for ribavirin dose reduction.  Gastroenterology. 2010;  139 (4) 1181-1189
    Google Scholar
  • 72 Thompson A J, Santoro R, Piazzolla V et al.. Inosine triphosphatase genetic variants are protective against anemia during antiviral therapy for HCV2/3 but do not decrease dose reductions of RBV or increase SVR.  Hepatology. 2011;  53 (2) 389-395
    Google Scholar
  • 73 Sumi S, Marinaki A M, Arenas M et al.. Genetic basis of inosine triphosphate pyrophosphohydrolase deficiency.  Hum Genet. 2002;  111 (4-5) 360-367
    Google Scholar
  • 74 De Franceschi L, Fattovich G, Turrini F et al.. Hemolytic anemia induced by ribavirin therapy in patients with chronic hepatitis C virus infection: role of membrane oxidative damage.  Hepatology. 2000;  31 (4) 997-1004
    Google Scholar
  • 75 Hitomi Y, Cirulli E T, Fellay J et al.. Inosine triphosphate protects against ribavirin-induced adenosine triphosphate loss by adenylosuccinate synthase function.  Gastroenterology. 2011;  140 (4) 1314-1321
    Google Scholar
  • 76 Thomas D L, Astemborski J, Rai R M et al.. The natural history of hepatitis C virus infection: host, viral, and environmental factors.  JAMA. 2000;  284 (4) 450-456
    Google Scholar
  • 77 Romeo S, Kozlitina J, Xing C et al.. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease.  Nat Genet. 2008;  40 (12) 1461-1465
    Google Scholar
  • 78 Speliotes E K, Yerges-Armstrong L M, Wu J NASH CRN et al. Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits.  PLoS Genet. 2011;  7 (3) e1001324
    Google Scholar
  • 79 Sookoian S, Pirola C J. Meta-analysis of the influence of I148M variant of patatin-like phospholipase domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic fatty liver disease.  Hepatology. 2011;  53 (6) 1883-1894
    Google Scholar
  • 80 Tian C, Stokowski R P, Kershenobich D, Ballinger D G, Hinds D A. Variant in PNPLA3 is associated with alcoholic liver disease.  Nat Genet. 2010;  42 (1) 21-23
    Google Scholar
  • 81 Stickel F, Buch S, Lau K et al.. Genetic variation in the PNPLA3 gene is associated with alcoholic liver injury in caucasians.  Hepatology. 2011;  53 (1) 86-95
    Google Scholar
  • 82 Valenti L, Rumi M, Galmozzi E et al.. Patatin-like phospholipase domain-containing 3 I148M polymorphism, steatosis, and liver damage in chronic hepatitis C.  Hepatology. 2011;  53 (3) 791-799
    Google Scholar
  • 83 Trépo E, Pradat P, Potthoff A et al.. Impact of patatin-like phospholipase-3 (rs738409 C> G) polymorphism on fibrosis progression and steatosis in chronic hepatitis C.  Hepatology. 2011;  54 (1) 60-69
    Google Scholar
  • 84 He S, McPhaul C, Li J Z et al.. A sequence variation (I148M) in PNPLA3 associated with nonalcoholic fatty liver disease disrupts triglyceride hydrolysis.  J Biol Chem. 2010;  285 (9) 6706-6715
    Google Scholar

Esperance A.K. SchaeferM.D. M.P.H. 

GI Unit, Massachusetts General Hospital, Harvard Medical School

55 Fruit Street, Boston, MA 02114

Email: eschaefer@partners.org

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