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

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
• 2 Hayashi N, Takehara T. Antiviral therapy for chronic hepatitis C: past, present, and future.  J Gastroenterol. 2006;  41 (1) 17-27
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 26 Kim A Y, Chung R T. Coinfection with HIV-1 and HCV—a one-two punch.  Gastroenterology. 2009;  137 (3) 795-814
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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