IL-28 Gene Variations Predict Who Will Respond to Interferon-based Treatment fro Chronic Hepatitis C

Single-position variations in the gene region encoding interleukin 28 (IL-28, also known as interferon lambda) may help predict which individuals are likely to respond to treatment for hepatitis C virus (HCV) infection using pegylated interferon plus ribavirin, according to 2 studies published in the October 2009 issue of Nature Genetics. Predicting likely responders in advance can spare patients who probably will not respond the side effects and expense of treatment.

By Liz Highleyman

Australian Study As described in the first report, an international research team performed a genome-wide association study, analyzing genetic material from more than 800 chronic hepatitis C patients receiving interferon-based therapy.

The authors first looked for genetic associations with treatment response in a group of 293 Australian individuals with genotype 1 chronic hepatitis C (131 responders to pegylated interferon/ribavirin and 162 non-responders). Results were then validated in an independent cohort of 555 patients.

The researchers identified a link between sustained virological response (SVR) and a single nucleotide polymorphism (SNP), or variation at a single position -- known as rs8099917 -- in the gene region on chromosome 19 that encodes IL-28 (located between the segments for the IL-28 A and B subunits). The same SNP also had the strongest association with sustained response in the validation cohort (combined odds ratio [OR] 1.98 in the 2 cohorts).

The study authors noted that IL-28B contributes to viral resistance and is known to be up-regulated by interferons and by infection with RNA viruses such as HCV. "These data suggest that host genetics may be useful for the prediction of drug response" and support the investigation of the role of IL-28B in the treatment of HCV and other diseases treated with interferon alfa, they concluded.

Westmead Millennium Institute, University of Sydney, Sydney, Australia; Walter and Eliza Hall Institute of Medical Research, University of Melbourne, Victoria, Australia; University of Bonn, Sigmund-Freud-Strasse, Bonn, Germany; Medizinische Klinik m.S. Hepatologie und Gastroenterologie, Universitätsmedizin Berlin, Berlin, Germany; Nepean Hospital, Penrith, Sydney, Australia; Liver Physiopathology Lab, University of Turin, Torino, Italy; Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK; National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, Australia; St. Vincent's Hospital, Sydney, Australia; Princess Alexandra Hospital, Woolloongabba, Queensland, Australia; University of Queensland School of Medicine, Woolloongabba, Queensland, Australia; Prince of Wales Hospital and University of New South Wales, Sydney, Australia.

Japanese Study

In the second report, investigators described another genome-wide association study, this one looking at 154 Japanese genotype 1 hepatitis C patients (72 responders to pegylated interferon/ribavirin and 82 non-responders).

This research team found 2 single-nucleotide polymorphism (SNPs) near the IL-28B gene on chromosome 19 -- rs12980275 and, again, rs8099917 -- that were strongly and significantly associated with virological response. These findings were also confirmed in an independent validation cohort of 174 patients. The IL-28B SNP was detected in 85% of patients who did not respond to treatment.

Further fine mapping of the region revealed that 7 SNPs (rs8105790, rs11881222, rs8103142, rs28416813, rs4803219, rs8099917, and rs7248668) in the IL-28B region showed the most significant associations with treatment response. Furthermore, PCR assays of peripheral blood mononuclear cells showed that individuals carrying these minor alleles, or variations, had significantly lower levels of IL-28B expression.

Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan; Graduate School of Medicine, University of Tokyo, Tokyo, Japan; Musashino Red Cross Hospital, Tokyo, Japan; Tokyo Medical and Dental University, Tokyo, Japan; Kawasaki Medical College, Kurashiki, Japan; Hokkaido University Graduate School of Medicine, Sapporo, Japan; Kyoto Prefectural University of Medicine, Kyoto, Japan; National Hospital Organization Osaka National Hospital, Osaka, Japan; Shinshu University School of Medicine, Matsumoto, Japan; Saitama Medical University, Saitama, Japan; Tottori University, Yonago, Japan; Kanazawa University Graduate School of Medicine, Kanazawa, Japan; Ehime University Graduate School of Medicine, Ehime, Japan; Hyogo College of Medicine, Nishinomiya, Japan; Central Research Laboratory, Hitachi Ltd., Kokubunji, Japan; Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan; Research Center for Hepatitis and Immunology, International Medical Center of Japan Konodai Hospital, Ichikawa, Japan.

Future Directions

These 2 studies -- as well as other recent research implicating the IL-28 gene in hepatitis C treatment response -- offer the possibility that a pre-treatment screening test might be developed that could be combined with the host and virus characteristics now used -- such as HCV genotype, viral load, insulin resistance, obesity, and extent of liver fibrosis -- to more reliably predict who will respond to therapy.

Further in the future, these findings may inform research on interferon lambda for hepatitis C, as well as development of potential therapies that mimic the genetic advantages of good responders.

10/06/09

References

V Suppiah, M Moldovan, G Ahlenstiel, and others. IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy. Nature Genetics 41(10): 1100-1104. October 2009. (Abstract).

Y Tanaka, N Nishida, M Sugiyama, and others. Genome-wide association of IL28B with response to pegylated interferon- and ribavirin therapy for chronic hepatitis C. Nature Genetics 41(10): 1105-1109. October 2009. (Abstract).