Genetic polymorphism and response to treatment in chronic hepatitis C: The future of personalized medicine
Authors: Tarik Asselah
Journal: Journal of Hepatology (2010)

Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Dongliang Ge, Jacques Fellay, Alexander J. Thompson, Jason S. Simon, Kevin V. Shianna, Thomas J. Urban, Erin L. Heinzen, Ping Qiu, Arthur H. Bertelsen, Andrew J. Muir, Mark Sulkowski, John G. McHutchison, David B. Goldstei. Abstract reprinted by permission from Macmillan Publishers Ltd: Nature 200;461(7262):399–401. copyright 2009Abstract: Chronic infection with hepatitis C virus (HCV) affects 170 million people worldwide and is the leading cause of cirrhosis in North America. Although the recommended treatment for chronic infection involves a 48-week course of peginterferon-2b (PegIFN-2b) or -2a (PegIFN-2a) combined with ribavirin (RBV), it is well known that many patients will not be cured by treatment, and that patients of European ancestry have a significantly higher probability of being cured than patients of African ancestry. In addition to limited efficacy, treatment is often poorly tolerated because of side effects that prevent some patients from completing therapy. For these reasons, identification of the determinants of response to treatment is a high priority. Here we report that a genetic polymorphism near the IL28B gene, encoding interferon-3 (IFN-3), is associated with an approximately twofold change in response to treatment, both among patients of European ancestry (P = 1.06 10–25) and African-Americans (P = 2.06 10–30). Because the genotype leading to better response is in substantially greater frequency in European than African populations, this genetic polymorphism also explains approximately half of the difference in response rates between African-Americans and patients of European ancestry. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Dongliang Ge, Jacques Fellay, Alexander J. Thompson, Jason S. Simon, Kevin V. Shianna, Thomas J. Urban, Erin L. Heinzen, Ping Qiu, Arthur H. Bertelsen, Andrew J. Muir, Mark Sulkowski, John G. McHutchison, David B. Goldstei. Abstract reprinted by permission from Macmillan Publishers Ltd: Nature 200;461(7262):399–401. copyright 2009 Abstract: Chronic infection with hepatitis C virus (HCV) affects 170 million people worldwide and is the leading cause of cirrhosis in North America. Although the recommended treatment for chronic infection involves a 48-week course of peginterferon-2b (PegIFN-2b) or -2a (PegIFN-2a) combined with ribavirin (RBV), it is well known that many patients will not be cured by treatment, and that patients of European ancestry have a significantly higher probability of being cured than patients of African ancestry. In addition to limited efficacy, treatment is often poorly tolerated because of side effects that prevent some patients from completing therapy. For these reasons, identification of the determinants of response to treatment is a high priority. Here we report that a genetic polymorphism near the IL28B gene, encoding interferon-3 (IFN-3), is associated with an approximately twofold change in response to treatment, both among patients of European ancestry (P = 1.06 10–25) and African-Americans (P = 2.06 10–30). Because the genotype leading to better response is in substantially greater frequency in European than African populations, this genetic polymorphism also explains approximately half of the difference in response rates between African-Americans and patients of European ancestry. HCV is a major cause of chronic liver disease worldwide. In addition to viral and environmental behavioural factors, host genetic diversity is thought to contribute to the spectrum of the disease [[1]Asselah T. Bieche I. Sabbagh A. Bedossa P. Moreau R. Valla D. et al.Gene expression and hepatitis C virus infection.Gut. 2009; 58: 846-858Crossref PubMed Scopus (91) Google Scholar]. In genotype 1 naïve patients, the combination of pegylated interferons (PEG-IFN) with ribavirin gives a sustained virological response (SVR) rate of about 50%. Because a significant number of patients will fail to respond or will have significant side effects, it is of major interest for both patient care and economic approach to predict non response. The sequencing of the human genome, together with the development of high-throughput technologies that measure the function of the genome, have afforded unique opportunities to predict treatment response. Ge and colleagues used a genome-wide association study (GWAS) to identify genetic variants that predict treatment outcome in chronic hepatitis C [[2]Ge D. Fellay J. Thompson A.J. Simon J.S. Shianna K.V. Urban T.J. et al.Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance.Nature. 2009; 461: 399-401Crossref PubMed Scopus (3114) Google Scholar]. Shortly, GWAS use dense maps of genetic markers that cover the human genome to look for allele frequency differences between cases and controls. A significant frequency difference suggests that the corresponding region of the genome contains functional DNA variants that influence the trait of interest. The strength of the genome-wide screening is its ability to reveal not only genes that would be expected to play a significant role, but also genes that would not, potentially adding new insight into physiopathology. In 2009, three independent GWASs reported single nucleotide polymorphisms (SNPs) near the IL-28B (IFN-λ3) region and associated with treatment response ([2Ge D. Fellay J. Thompson A.J. Simon J.S. Shianna K.V. Urban T.J. et al.Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance.Nature. 2009; 461: 399-401Crossref PubMed Scopus (3114) Google Scholar, 3Suppiah V. Moldovan M. Ahlenstiel G. Berg T. Weltman M. Abate M.L. et al.IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy.Nat Genet. 2009; 41: 1100-1104Crossref PubMed Scopus (1717) Google Scholar, 4Tanaka Y. Nishida N. Sugiyama M. Kurosaki M. Matsuura K. Sakamoto N. et al.Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C.Nat Genet. 2009; 41: 1105-1109Crossref PubMed Scopus (2000) Google Scholar]; Table 1). All patients were infected by genotype 1 and received PEG-IFN plus ribavirin. Interestingly, different ethnicities (European, African-American, Australian and Japanese) were included in these studies.Table 1Genome wide association studies and response to treatment in chronic hepatitis C.ReferencesCountryNumber of patients (n)Ethnic originTechnologySNP identifiedGe et al. [2]Ge D. Fellay J. Thompson A.J. Simon J.S. Shianna K.V. Urban T.J. et al.Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance.Nature. 2009; 461: 399-401Crossref PubMed Scopus (3114) Google ScholarNorth America1137African–Americans 191Illumina Human 610 – Quad BeadChip 566,759 SNPsrs12979860 (∼3 kb upstream IL-28B) linkage disequilibrium with rs8099917European–Americans 871Hispanics 75Suppiah et al. [3]Suppiah V. Moldovan M. Ahlenstiel G. Berg T. Weltman M. Abate M.L. et al.IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy.Nat Genet. 2009; 41: 1100-1104Crossref PubMed Scopus (1717) Google ScholarAustralia848Australian 293 (training set)Illumina Infinium HumanHap300 or CNV370 – Quad genotyping BeadChip ∼311,159 SNPsrs8099917 (∼8 kb upstream IL-28B) 16 others SNP identifiedEuropeEuropean 555 (validation set)Tanaka et al. [4]Tanaka Y. Nishida N. Sugiyama M. Kurosaki M. Matsuura K. Sakamoto N. et al.Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C.Nat Genet. 2009; 41: 1105-1109Crossref PubMed Scopus (2000) Google ScholarJapan314Japanese 314Affymetrix SNP 6.0 SNP typing array ∼621,220 SNPsrs8099917 (∼8 kb upstream IL-28B)rs12980275rs1188122rs8105790 Open table in a new tab Ge et al. analysed 1137 patients, and they identified several SNPs in or near the IL-28B gene on chromosome 19 that were significantly more common in responders than in non responders [[2]Ge D. Fellay J. Thompson A.J. Simon J.S. Shianna K.V. Urban T.J. et al.Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance.Nature. 2009; 461: 399-401Crossref PubMed Scopus (3114) Google Scholar]. The genetic polymorphism was associated with an approximately twofold change in SVR. Thomas and colleagues reported that the same IL-28B variant described by Ge et al. was also associated with HCV spontaneous clearance [[5]Thomas D.L. Thio C.L. Martin M.P. Qi Y. Ge D. O'Huigin C. et al.Genetic variation in IL28B and to spontaneous clearance of hepatitis C virus.Nature. 2009; 461: 798-801Crossref PubMed Scopus (1854) Google Scholar]. They genotyped the rs12979860 variant in HCV cohorts comprised of individuals who spontaneously cleared the virus (n = 388) or had persistent infection (n = 620). They showed that the C/C genotype strongly enhances resolution of HCV infection among individuals of both European and African ancestry. Interestingly, Suppiah et al. and Tanaka et al. identified rs8099917 (located ∼8 kb upstream of IL-28B) as the variant the most strongly associated with SVR [3Suppiah V. Moldovan M. Ahlenstiel G. Berg T. Weltman M. Abate M.L. et al.IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy.Nat Genet. 2009; 41: 1100-1104Crossref PubMed Scopus (1717) Google Scholar, 4Tanaka Y. Nishida N. Sugiyama M. Kurosaki M. Matsuura K. Sakamoto N. et al.Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C.Nat Genet. 2009; 41: 1105-1109Crossref PubMed Scopus (2000) Google Scholar]. Interferon (IFN)-λs, including IFN-λ 1, 2 and 3 (also known as IL-29, IL-28A and IL-28B) are a newly described group of antiviral cytokines distantly related to the type I IFNs and IL-10 family members. The IFN-λ R complex consists of a unique ligand-binding chain, IFN-λ R1, and an accessory chain, IL-10R2, which is shared with receptors for IL-10-related cytokines. IFN-λs binding to its receptor activates pathways of JAK-STATs and MAPKs and induces antiviral, antiproliferative, anti-tumor and immune responses (Fig. 1). IFN-λ proteins seem to have lower antiviral activity than IFN-α in vitro [[6]Sheppard P. Kindsvogel W. Xu W. Henderson K. Schlutsmeyer S. Whitmore T.E. et al.IL-28, IL-29 and their class II cytokine receptor IL-28R.Nat Immunol. 2003; 4: 63-68Crossref PubMed Scopus (1325) Google Scholar]. IFN-λ1 has been shown to exhibit dose- and time-dependent HCV inhibition, to increase IFN-stimulated genes expression, and to enhance the antiviral efficacy of IFN-α [[7]Marcello T. Grakoui A. Barba-Spaeth G. Machlin E.S. Kotenko S.V. MacDonald M.R. et al.Interferons alpha and lambda inhibit hepatitis C virus replication with distinct signal transduction and gene regulation kinetics.Gastroenterology. 2006; 131: 1887-1898Abstract Full Text Full Text PDF PubMed Scopus (519) Google Scholar]. Interestingly, it has been demonstrated that non responders (NR) and sustained virological responders (SVR) patients have different gene expression profiles prior to treatment [[8]Asselah T. Bieche I. Narguet S. Sabbagh A. Laurendeau I. Ripault M.P. et al.Liver gene expression signature to predict response to pegylated interferon plus ribavirin combination therapy in patients with chronic hepatitis C.Gut. 2008; 57: 516-524Crossref PubMed Scopus (193) Google Scholar]. The basal liver levels of expression of IFN-stimulated genes were higher in NRs than in SVRs. In NRs, the failure to respond to exogenous PEG-IFN may indicate a blunted response to IFN. The very impressive results from GWASs highlight the importance of a better understanding of IFN signalling pathway for the discovery of novel potential targets. Although all of the identified variants in these studies lie in or near the IL-28B gene, none of them appear to have an obvious effect on the function of this gene. There are many challenges in the future. Of course, these new genetic predictive factors will have to compete with other predictors of response. The probability of SVR essentially depends on the genotype and viral load, but also on viral kinetic (rapid virological response at 4 weeks). What will be the importance of this genetic predictor among all others? Furthermore, will this genetic marker predictor be superseded by future therapies? The development of new viral enzyme inhibitors (protease and polymerase) is ongoing and promising results have been reported with two protease inhibitors (telaprevir and boceprevir) that are currently in phase III [[9]Asselah T. Benhamou Y. Marcellin P. Protease and polymerase inhibitors for the treatment of hepatitis C.Liver Int. 2009; 29: 57-67Crossref PubMed Scopus (74) Google Scholar]. Protease inhibitors are direct antivirals and we can hypothesize that genetic markers of IFN resistance will have no effects. However, we believe that these markers will have their importance, since it is likely that IFN-based therapy will remain the backbone of the treatment in the near future as they are needed to prevent HCV resistance and subsequently to increase SVR. Furthermore it should be noted that HCV RNA encodes specific proteins that may inhibit the induction of type I IFNs. An example is the HCV NS3-4A protease which blocks dsRNA-induced IFN production by interfering with IRF-3 phosphorylation [[10]Foy E. Li K. Wang C. Sumpter Jr., R. Ikeda M. Lemon S.M. et al.Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease.Science. 2003; 300: 1145-1148Crossref PubMed Scopus (707) Google Scholar]. Thus, the NS3-4A protease is a dual therapeutic target whose inhibition may block viral replication and restore IRF-3 control of HCV infection. Finally, very consistent data were reported by three independent studies finding SNPs near the IL-28B (IFN-3λ) region and associated with treatment response, thus opening a window for personalized medicine [2Ge D. Fellay J. Thompson A.J. Simon J.S. Shianna K.V. Urban T.J. et al.Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance.Nature. 2009; 461: 399-401Crossref PubMed Scopus (3114) Google Scholar, 3Suppiah V. Moldovan M. Ahlenstiel G. Berg T. Weltman M. Abate M.L. et al.IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy.Nat Genet. 2009; 41: 1100-1104Crossref PubMed Scopus (1717) Google Scholar, 4Tanaka Y. Nishida N. Sugiyama M. Kurosaki M. Matsuura K. Sakamoto N. et al.Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C.Nat Genet. 2009; 41: 1105-1109Crossref PubMed Scopus (2000) Google Scholar]. All patients were from different ethnicity origin, all infected by genotype 1, and received PEG-IFN plus ribavirin. The question that remains is the biological significance of this genetic variant.