Abstract
The prevalence of genetic polymorphisms identified as predictors of therapeutic-induced hepatitis C virus (HCV) clearance differs among ethnic groups. However, there is a paucity of information about their prevalence in South American populations, whose genetic background is highly admixed. Hence, single-nucleotide polymorphisms rs12979860, rs1127354 and rs7270101 were characterized in 1350 healthy individuals, and ethnicity was assessed in 259 randomly selected samples. The frequency of rs12979860CC, associated to HCV treatment response, and rs1127354nonCC, related to protection against hemolytic anemia, were significantly higher among individuals with maternal and paternal Non-native American haplogroups (64.5% and 24.2%), intermediate among admixed samples (44.1% and 20.4%) and the lowest for individuals with Native American ancestry (30.4% and 6.5%). This is the first systematic study focused on analyzing HCV predictors of antiviral response and ethnicity in South American populations. The characterization of these variants is critical to evaluate the risk–benefit of antiviral treatment according to the patient ancestry in admixed populations.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 6 print issues and online access
$259.00 per year
only $43.17 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Alter MJ . Epidemiology of hepatitis C virus infection. World J Gastroenterol 2007; 13: 2436–2441.
Hoofnagle JH . Course and outcome of hepatitis C. Hepatology 2002; 36: S21–S29.
Heathcote EJ . Prevention of hepatitis C virus-related hepatocellular carcinoma. Gastroenterology 2004; 127: S294–S302.
Lake-Bakaar G . Current and future therapy for chronic hepatitis C virus liver disease. Curr Drug Targets Infect Disord 2003; 3: 247–253.
Halfon P, Locarnini S . Hepatitis C virus resistance to protease inhibitors. J Hepatol 2011; 55: 192–206.
Suppiah V, Moldovan M, Ahlenstiel G, Berg T, Weltman M, Abate ML et al. IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy. Nat Genet 2009; 41: 1100–1104.
Ge D, Fellay J, Thompson AJ, Simon JS, Shianna KV, Urban TJ et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature 2009; 461: 399–401.
Thomas DL, Thio CL, Martin MP, Qi Y, Ge D, O'Huigin C et al. Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature 2009; 461: 798–801.
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: 1105–1109.
Mangia A, Thompson AJ, Santoro R, Piazzolla V, Tillmann HL, Patel K 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: 821–827.
Sarrazin C, Susser S, Doehring A, Lange CM, Müller T, Schlecker C et al. Importance of IL28B gene polymorphisms in hepatitis C virus genotype 2 and 3 infected patients. J Hepatol 2011; 54: 415–421.
Scherzer TM, Stättermayer AF, Strasser M, Laferl H, Maieron A, Stauber R et al. Impact of IL28B on treatment outcome in hepatitis C virus G1/4 patients receiving response-guided therapy with peginterferon alpha-2a (40KD)/ribavirin. Hepatology 2011; 54: 1518–1526.
Montes-Cano MA, García-Lozano JR, Abad-Molina C, Romero-Gómez M, Barroso N, Aguilar-Reina J et al. Interleukin-28B genetic variants and hepatitis virus infection by different viral genotypes. Hepatology 2010; 52: 33–37.
Rallon NI, Naggie S, Benito JM, Medrano J, Restrepo C, Goldstein D 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: F23–F29.
Rauch A, Kutalik Z, Descombes P, Cai T, Di Iulio J, Mueller T et al. Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure: a genome-wide association study. Gastroenterology 2010; 138: 1338–1345.
Holmes JA, Desmond PV, Thompson AJ . Does IL28B genotyping still have a role in the era of direct-acting antiviral therapy for chronic hepatitis C infection? J Viral Hepat 2012; 19: 677–684.
Barreiro P, Vispo E, Poveda E, Fernandez-Montero JV, Soriano V . Hepatitis C therapy—highlights from EASL 2012. Clin Infect Dis 2012; 56: 560–566.
Manns M, McHutchison J, Gordon S, Rustgi VK, Shiffman M, Reindollar R 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: 958–965.
Fried M, Shiffman M, Reddy K, Smith C, Marinos G, Gonçales FL Jr et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002; 347: 975–982.
Fellay J, Thompson AJ, Ge D, Gumbs CE, Urban TJ, Shianna KV et al. ITPA gene variants protect against anemia in patients treated for chronic hepatitis C. Nature 2010; 464: 405–408.
Bierau J, Lindhout M, Bakker JA . Pharmacogenetic significance of inosine triphosphatase. Pharmacogenomics 2007; 8: 1221–1228.
Stocco G . Genetic polymorphism of inosine triphosphate pyrophosphatase is a determinant of mercaptopurine metabolism and toxicity during treatment for acute lymphoblastic leukemia. Clin Pharmacol Ther 2009; 85: 164–172.
Thompson A, Fellay J, Patel K, Tillmann HL, Naggie S, Ge D et al. Variants in the ITPA gene protect against ribavirin-induced hemolytic anemia and decrease the need for ribavirin dose reduction. Gastroenterology 2010; 139: 1181–1189.
Thompson A, Santoro R, Piazzolla V, Clark PJ, Naggie S, Tillmann HL et al. Inosine triphosphatase genetic variants are protective against anemia during antiviral therapy for HCV-2/3 but do not decrease dose reductions of RBV or increase SVR. Hepatology 2011; 53: 389–395.
Rallon NI, Morello J, Labarga P, Benito JM, Rodriguez-Novoa S, Vispo E et al. Impact of ITPA gene variants on the risk of anemia in HIV/HCV-coinfected patients treated for chronic hepatitis C. Clin Infect Dis 2011; 53: 1291–1295.
Suzuki F, Suzuki Y, Akuta N, Sezaki H, Hirakawa M, Kawamura Y et al. Influence of ITPA polymorphisms on decreases of hemoglobin during treatment with pegylated interferon, ribavirin, and telaprevir. Hepatology 2011; 53: 415–421.
Ogawa E, Furusyo N, Nakamuta M, Kajiwara E, Nomura H, Dohmen K et al. Clinical milestones for the prediction of severe anemia by chronic hepatitis C patients receiving telaprevir-based triple therapy. J Hepatol 2013; 59: 667–674.
Domingo P, Guardiola JM, Salazar J, Torres F, Mateo MG, Pacho C et al. Association of ITPA gene polymorphisms and the risk of ribavirin-induced anemia in HIV/hepatitis C virus (HCV)-coinfected patients receiving HCV combination therapy. Antimicrob Agents Chemother 2012; 56: 2987–2993.
Kim JS, Ahn SM, Jung YK, Kwon OS, Kim YS, Choi DJ et al. The impact of inosine triphosphatase variants on hemoglobin level and sustained virologic response of chronic hepatitis C in Korean. J Korean Med Sci 2013; 28: 1213–1219.
D'Avolio A, De Nicolò A, Cusato J, Ciancio A, Boglione L, Strona S et al. Association of ITPA polymorphisms rs6051702/rs1127354 instead of rs7270101/rs1127354 as predictor of ribavirin-associated anemia in chronic hepatitis C treated patients. Antiviral Res 2013; 100: 114–119.
von Ahsen N, Armstrong VW, Behrens C, von Tirpitz C, Stallmach A, Herfarth H et al. Association of inosine triphosphatase 94C>A and thiopurine S-methyltransferase deficiency with adverse events and study drop-outs under azathioprine therapy in a prospective Crohn disease study. Clin Chem 2005; 51: 2282–2288.
Marinaki AM, Ansari A, Duley JA, Arenas M, Sumi S, Lewis CM et al. Adverse drug reactions to azathioprine therapy are associated with polymorphism in the gene encoding inosine triphosphate pyrophosphatase (ITPase). Pharmacogenetics 2004; 14: 181–187.
Corach D, Lao O, Bobillo C, van Der Gaag K, Zuniga S, Vermeulen M et al. Inferring continental ancestry of Argentineans from autosomal, Y-chromosomal and mitochondrial DNA. Ann Hum Genet 2010; 74: 65–76.
Censo Nacional, INDEC 2010. www.censo2010.indec.gov.ar.
Ito K, Higami K, Masaki N, Sugiyama M, Mukaide M, Saito H et al. The rs8099917 polymorphism, when determined by a suitable genotyping method, is a better predictor for response to pegylated alpha interferon/ribavirin therapy in Japanese patients than other single nucleotide polymorphisms associated with interleukin-28B. J Clin Microbiol 2011; 49: 1853–1860.
Kudo M, Saito Y, Sasaki T, Akasaki H, Yamaguchi Y, Uehara M et al. Genetic variations in the HGPRT, ITPA, IMPDH1, IMPDH2, and GMPS genes in Japanese individuals. Drug Metab Pharmacokinet 2009; 24: 557–564.
Zuccarelli G, Alechine E, Caputo M, Bobillo C, Corach D, Sala A . Rapid screening for Native American mitochondrial and Y-chromosome haplogroups detection in routine DNA analysis. Forensic Sci Int Genet 2011; 5: 105–108.
Osier MV, Cheung KH, Kidd JR, Pakstis AJ, Miller PL, Kidd KK . ALFRED: an allele frequency database for anthropology. Am J Phys Anthropol 2002; 119: 77–83.
Marsh S, King CR, Ahluwalia R, McLeod HL . Distribution of ITPA P32T alleles in multiple world populations. J Hum Genet 2004; 49: 579–581.
Galván CA, Elbarcha OC, Fernández EJ, Beltramo DM, Soria NW . Distribution of polymorphisms in cytochrome P450 2B6, histocompatibility complex P5, chemokine coreceptor 5, and interleukin 28B genes in inhabitants from the central area of Argentina. Genet Test Mol Biomarkers 2012; 16: 130–133.
Klein RG . The Human Career: Human Biological and Cultural Origins. University of Chicago Press: Chicago, IL, USA, 1999.
Klein J, Takahata N . Where Do We Come From? The Molecular Evidence for Human Descent. Springer: New York, NY, USA, 2002.
Bamshad M, Wooding SP . Signatures of natural selection in the human genome. Nat Rev Genet 2003; 4: 99–111.
Manry J, Laval G, Patin E, Fornarino S, Itan Y, Fumagalli M et al. Evolutionary genetic dissection of human interferons. J Exp Med 2011; 208: 2747–2759.
Consenso Argentino de Hepatitis C 2013, Asociación Argentina para el Estudio de las Enfermedades de Hígado (AAEEH) 2013. www.aaeeh.org.ar.
Kershenobich D, Razavi HA, Sánchez-Avila JF, Bessone F, Coelho HS, Dagher L et al. Trends and projections of hepatitis C virus epidemiology in Latin America. Liver Int 2011; 31: 18–29.
Acknowledgements
We thank the volunteers for their cooperation and also thank Tech. Noelia Bravo, Fiorella Caro, BSc and Ms Valeria Cabrera for technical assistance. Our work is supported by grants from ICBME, FUCIBA and Italian Hospital of Buenos Aires Research Bureau.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Rights and permissions
About this article
Cite this article
Trinks, J., Hulaniuk, M., Caputo, M. et al. Distribution of genetic polymorphisms associated with hepatitis C virus (HCV) antiviral response in a multiethnic and admixed population. Pharmacogenomics J 14, 549–554 (2014). https://doi.org/10.1038/tpj.2014.20
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/tpj.2014.20
This article is cited by
-
IL28B gene polymorphism rs12979860, but not rs8099917, contributes to the occurrence of chronic HCV infection in Uruguayan patients
Virology Journal (2018)
-
SVR Rates of HCV-infected population under PEG-IFN-α/R treatment in Northwest China
Virology Journal (2017)
-
Influence of ethnicity on the distribution of genetic polymorphisms associated with risk of chronic liver disease in South American populations
BMC Genetics (2015)