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Interleukin-6 haplotypes and the response to therapy of chronic hepatitis C virus infection

Genes & Immunity volume 10, pages 365–372 (2009)Cite this article

Abstract

Chronic hepatitis C virus (HCV) infection affects nearly 170 million individuals worldwide. Treatment of HCV with pegylated interferon-α-2a is successful in eradicating virus from only 30 to 80% of those treated. Interleukin-6 (IL-6) is an important cytokine involved in the immune response to infectious agents and in vitro studies suggest that host genetic variation, particularly haplotypes, may affect IL-6 expression. We examined the contribution of haplotypes in the IL-6 gene on sustained viral response (SVR) to the therapy for chronic HCV infection. We observed the IL-6 T-T-G-G-G-G-C-A-G-A haplotype to be associated with a lower risk of achieving SVR among Caucasian Americans (CAs) ((relative risk) RR=0.80; 95% CI: 0.66−0.98; P=0.0261). Using a sliding window approach, the rs1800797-(G)-rs1800796-(G)-rs1800795-(G) haplotype was associated with a reduced chance of SVR (RR=0.79; 95% CI: 0.66–0.94; P=0.0081), as was the rs1800796-(G)-rs1800795-(G)-rs2069830-(C) haplotype (RR=0.78; 95% CI: 0.66–0.94; P=0.0065) among CAs. Overall, the rs1800797-(G)-rs1800796-(G)-rs1800795-(G) haplotype was independently associated with a reduced chance of SVR (RR=0.78; 95% CI: 0.62–1.0; P=0.0489) after adjustment for potential confounding factors. Our findings further illustrate the complexity of IL-6 genetic regulation and the potential importance of haplotypes on IL-6 expression. Our findings provide additional support for the potential importance of genetic variation in the IL-6 gene and the response to HCV therapy.

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Acknowledgements

This clinical study was a co-operative agreement funded by the NIDDK and co-funded by the National Center on Minority Health and Health Disparities (NCMHD), with a Co-operative Research and Development Agreement (CRADA) with Roche Laboratories Inc., Grant numbers: 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, NIDDK, 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). In addition support for Dr Leland J Yee was provided by a National Institutes of Health Clinical Research Career Development Award Grant (1KL2 RR024154-02).

Author information

Author notes

  1. H Yang

    Present address: 5Present address: Department of Discovery, Medicine and Epidemiology, AstraZeneca Pharmaceuticals LP, Wilmington, DE, USA.,

  2. L J Yee, K Im, B Borg, H Yang and T J Liang: Members of Virahep-C contributing to the study are listed in the appendix.

Authors and Affiliations

  1. Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA, USA

    L J Yee & K Im

  2. Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA

    K Im

  3. Liver Diseases Branch, NIDDK, NIH, Bethesda, MD, USA

    B Borg & T J Liang

  4. Cedars-Sinai Medical Center, Medical Genetics Institute, Los Angeles, CA, USA

    H Yang

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  1. L J Yee
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for the Virahep-C Study

Corresponding authors

Correspondence to L J Yee or T J Liang.

Additional information

Supplementary Information accompanies the paper on Genes and Immunity website (http://www.nature.com/gene)

Appendix

Appendix

Members of Virahep-C contributing to the study include: from the Beth Israel Deaconess Medical Center, Boston, MA: Nezam Afdhal, MD (Principal Investigator), Tiffany Geahigan, PA-C, MS (Research Coordinator); from the New York-Presbyterian Medical Center, New York, NY: Robert S Brown, Jr, MD, MPH (Principal Investigator), Lorna Dove, MD, MPH (Co-Investigator), Shana Stovel, MPH (Study Coordinator); from the University of California, San Francisco, San Francisco, CA: Norah Terrault, MD, MPH (Principal Investigator), Stephanie Straley, PA-C, Eliana Agudelo, PA-C, Melissa Hinds, BA (Clinical Research Coordinator); from Rush University, Chicago, IL: Thelma E Wiley, MD (Principal Investigator), Monique Williams, RN (Study Coordinator); from the University of Maryland, Baltimore, MD: Charles D Howell, MD (Principal Investigator), Karen Callison, RN (Study Coordinator); from the University of Miami, Miami, FL: Lennox J Jeffers, MD (Principal Investigator), Shvawn McPherson Baker, PharmD (Co-Investigator), Maria DeMedina, MSPH (Project Manager), Carol Hermitt, MD (Project Coordinator); from the University of Michigan, Ann Arbor, MI: Hari S Conjeevaram, MD, MS (Principal Investigator), Robert J Fontana, MD (Co-Investigator), Donna Harsh, MS (Study Coordinator); from the University of North Carolina, Chapel Hill, NC: Michael W Fried, MD (Principal Investigator,), Scott R Smith, PhD (Co-Investigator), Dickens Theodore, MD, MPH (Co-Investigator), Steven Zacks, MD, MPH, FRCPC (Co-Investigator), Roshan Shrestha, MD (Co-Investigator), Karen Dougherty, NP (Co-Investigator), Paris Davis (Study Coordinator), Shirley Brown (Study Coordinator); from St. Louis University, St. Louis, MO: John E Tavis, PhD (Principal Investigator), Adrian Di Bisceglie, MD (Co-Investigator), Ermei Yao, PhD (Co-Investigator), Maureen Donlin, PhD (Co-Investigator), Nathan Cannon, BS (Graduate Student), Ping Wang, BS (Lab Technician); from Cedars-Sinai Medical Center, Los Angeles, CA: Huiying Yang, MD, PhD (Principal Investigator), George Tang, PhD (Project Scientist), Dai Wang, PhD (Project Scientist); from the University of Colorado Health Sciences Center, Denver, CO: Hugo R Rosen, MD (Principal Investigator), James R Burton, MD (Co-Investigator), Jared Klarquist (Lab Technician); from Veteran's Administration, Portland, OR: Scott Weston (Lab Technician); from Indiana University, Bloomington, IN: Milton W Taylor, PhD (Principal Investigator), Corneliu Sanda, MD (Post-doctoral Associate), Joel Schaley, PhD (Post-doctoral Associate), Mary Ferris (Lab Assistant); from the Data Coordinating Center, Graduate School of Public Health at the University of Pittsburgh, Pittsburgh, PA: Steven H Belle, PhD (Principal Investigator), Richard A Bilonick, PhD (Statistician), Geoffrey Block, MD (Co-Investigator), Jennifer Cline, BS (Data Manager), Marika Haritos, MS (Statistician), KyungAh Im, MS (Statistician), Stephanie Kelley, MS (Data Manager), Sherry Kelsey, PhD (Co-Investigator), Laurie Koozer (Project Coordinator), Sharon Lawlor, MBA (Data Coordinator), Stephen B Thomas, PhD (Co-Investigator), Abdus Wahed, PhD (Statistician), Yuling Wei, MS (Project Coordinator), Leland J Yee, PhD (Consultant); from the National Institute of Diabetes and Digestive and Kidney Diseases: Patricia Robuck, PhD, MPH (Project Scientist), James Everhart, MD, MPH (Scientific Advisor), Jay H Hoofnagle, MD (Scientific Advisor), Edward Doo, MD (Scientific Advisor), T Jake Liang, MD (Scientific Advisor), Leonard B Seeff, MD (Scientific Advisor); from the National Cancer Institute: David E Kleiner, MD, PhD (Central Pathologist).

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Yee, L., Im, K., Borg, B. et al. Interleukin-6 haplotypes and the response to therapy of chronic hepatitis C virus infection. Genes Immun 10, 365–372 (2009). https://doi.org/10.1038/gene.2009.26

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