Journal of Hepatology
Volume 49, Issue 2 , Pages 184-191, August 2008

Association of single nucleotide polymorphisms in interferon signaling pathway genes and interferon-stimulated genes with the response to interferon therapy for chronic hepatitis C☆

  • Xiaowen Su

      Affiliations

    • Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
    • ,
  • Leland J. Yee

      Affiliations

    • Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, A511 Crabtree Hall, 130 DeSoto Street, Pittsburgh, PA 15232, USA
    • Division of Infectious Diseases, Department of Medicine, School of Medicine, University of Pittsburgh, A511 Crabtree Hall, 130 DeSoto Street, Pittsburgh, PA, USA
    • Corresponding Author InformationCorresponding author. Tel.: +1 412 624 5326; fax: +1 412 624 7397.
    • ,
  • KyungAh Im

      Affiliations

    • Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, A511 Crabtree Hall, 130 DeSoto Street, Pittsburgh, PA 15232, USA
    • Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA
    • ,
  • Shannon L. Rhodes

      Affiliations

    • Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
    • ,
  • YongMing Tang

      Affiliations

    • Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
    • ,
  • Xiaomei Tong

      Affiliations

    • Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
    • ,
  • Charles Howell

      Affiliations

    • Department of Medicine, Division of Gastroenterology and Hepatology, University of Maryland, School of Medicine, Baltimore, MD, USA
    • ,
  • Darmendra Ramcharran

      Affiliations

    • Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, A511 Crabtree Hall, 130 DeSoto Street, Pittsburgh, PA 15232, USA
    • ,
  • Hugo R. Rosen

      Affiliations

    • Integrated Program in Immunology and Hepatitis C Research Center, Division of Gastroenterology & Hepatology, University of Colorado, Denver, CO, USA
    • ,
  • Milton W. Taylor

      Affiliations

    • Department of Biology, Indiana University, Bloomington, IN, USA
    • ,
  • T. Jake Liang

      Affiliations

    • Division of Digestive Diseases, NIDDK, National Institutes of Health, Bethesda, MD, USA
    • ,
  • Huiying Yang

      Affiliations

    • Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
    • Present address: Department of Patient Safety and Global Epidemiology, AstraZeneca Pharmaceuticals LP, Wilmington, DE, USA.
    • ,
  • for the Virahep-C Study Group

Received 17 December 2007; received in revised form 18 March 2008; accepted 17 April 2008. published online 21 May 2008.

Associate Editor: M.P. Manns

Background/Aims

Interferon signaling pathway genes (IPGs) and interferon-stimulated genes (ISGs) are associated with the host response to hepatitis C virus (HCV) infection. We studied single nucleotide polymorphisms (SNPs) in IPGs and ISGs for their associations with response to pegylated interferon α-2a (Peg-IFN-α) plus ribavirin therapy in HCV genotype-1 infected patients.

Methods

A two-stage study design was used. First, out of 118 SNPs selected, 91 SNPs from 5 IPGs and 12 ISGs were genotyped in a cohort of 374 treatment-naı¨ve HCV patients and assessed for association with sustained virologic response (SVR). Next, 14 potentially functional SNPs from the OASL gene were studied in this cohort.

Results

Three OASL SNPs (rs3213545 and rs1169279 from stage I, and rs2859398 from stage II), were significantly associated with SVR [rs3213545: p=0.03, RR=1.27 (1.03–1.58); rs1169279: p=0.02, RR=1.32 (1.05–1.65) p=0.02; rs2859398: p=0.02, RR=1.29 (1.04–1.61)] after adjusting for other covariates. Further analysis showed that these three SNPs independently associated with SVR. Additionally, a similar trend towards the associations of these three SNPs with SVR was observed in a smaller, independent HCV cohort consisting of subjects from a number of clinical practice settings.

Conclusions

Our study suggests that OASL variants are involved in the host response to IFN-based therapy in HCV patients.

Abbreviations: HCV, hepatitis C virus, AA, African Americans, CA, Caucasian Americans, SVR, sustained viralogic response

Keywords: Pharmacogenetics, Hepatitis C, Interferon therapy, Interferon signaling pathway genes, Interferon-stimulated genes, Genetics, Race, Therapy, Interferon

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☆ This study was a cooperative agreement funded by the NIDDK and co-funded by the National Center on Minority Health and Health Disparities (NCMHD), with a Cooperative Research and Development Agreement (CRADA) with Roche Laboratories, Inc. Grant Nos. U01 DK60329, U01 DK60340, U01 DK60324, U01 DK60344, U01 DK60327, U01 DK60335, U01 DK60352, U01 DK60342, U01 DK60345, U01 DK60309, U01 DK60346, U01 DK60349, and U01 DK60341. Other support: National Center for Research Resources (NCRR), Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, General Clinical Research Centers Program Grants: M01 RR00645 (New York Presbyterian), M02 RR000079 (University of California, San Francisco), M01 RR16500 (University of Maryland), M01 RR000042 (University of Michigan), and M01 RR00046 (University of North Carolina). Additional support was provided to L.J.Y. by 1KL2 RR024154-01. NIH funded study.

PII: S0168-8278(08)00292-4

doi:10.1016/j.jhep.2008.04.011

Journal of Hepatology
Volume 49, Issue 2 , Pages 184-191, August 2008

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