Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2015 Sep 9;10(9):e0137351.
doi: 10.1371/journal.pone.0137351. eCollection 2015.

Genetic Polymorphisms of IL28B and PNPLA3 Are Predictive for HCV Related Rapid Fibrosis Progression and Identify Patients Who Require Urgent Antiviral Treatment with New Regimens

Nobuharu Tamaki  1 , Masayuki Kurosaki  1 , Mayu Higuchi  1 , Hitomi Takada  1 , Natsuko Nakakuki  1 , Yutaka Yasui  1 , Shoko Suzuki  1 , Kaoru Tsuchiya  1 , Hiroyuki Nakanishi  1 , Jun Itakura  1 , Yuka Takahashi  1 , Shintaro Ogawa  2 , Yasuhito Tanaka  2 , Yasuhiro Asahina  3 , Namiki Izumi  1
Affiliations

Genetic Polymorphisms of IL28B and PNPLA3 Are Predictive for HCV Related Rapid Fibrosis Progression and Identify Patients Who Require Urgent Antiviral Treatment with New Regimens

Nobuharu Tamaki et al. PLoS One. .

Abstract

The assessment of individual risk of fibrosis progression in patients with chronic hepatitis C is an unmet clinical need. Recent genome-wide association studies have highlighted several genetic alterations as predictive risk factors of rapid fibrosis progression in chronic hepatitis C. However, most of these results require verification, and whether the combined use of these genetic predictors can assess the risk of fibrosis progression remains unclear. Therefore, genetic risk factors associated with fibrosis progression were analyzed in 176 chronic hepatitis C patients who did not achieve sustained virological response by interferon-based therapy and linked to the fibrosis progression rate (FPR). FPR was determined in all patients by paired liver biopsy performed before and after therapy (mean interval: 6.2 years). Mean FPR in patients with IL28B (rs8099917) TG/GG and PNPLA3 (rs738409) CG/GG were significantly higher than in those with IL28B TT (FPR: 0.144 vs. 0.034, P < 0.001) and PNPLA3 CC (FPR: 0.10 vs. 0.018, P = 0.005), respectively. IL28B TG/GG [hazard ratio (HR): 3.9, P = 0.001] and PNPLA3 CG/GG (HR: 3.1, P = 0.04) remained independent predictors of rapid fibrosis progression upon multivariate analysis together with average alanine aminotransferase after interferon therapy ≥40 IU/l (HR: 4.2, P = 0.002). Based on these data, we developed a new clinical score predicting the risk of fibrosis progression (FPR-score). The FPR-score identified subgroups of patients with a low (FPR: 0.005), intermediate (FPR: 0.103, P < 0.001), and high (FPR: 0.197, P < 0.001) risk of fibrosis progression. In conclusion, IL28B and PNPLA3 genotypes are associated with rapid fibrosis progression, and the FPR-score identifies patients who has a high risk of fibrosis progression and require urgent antiviral treatment.

PubMed Disclaimer

Conflict of interest statement

Competing Interests: The authors have read the journal's policy and the authors of this manuscript have the following competing interests: Namiki Izumi received lecture fees from Chugai Pharmaceutical Co. Ltd., and MSD Co. Yasuhiro Asahina belongs to a donation-funded department funded by Chugai Pharmaceutical Co. Ltd., Toray Industries, Inc., Bristol-Myers Squibb, Dainippon Sumitomo Pharma Co.,Ltd., and Merck Sharp and Dohme. Yasuhito Tanaka received grants from Chugai Pharmaceutical Co. Ltd., Bristol-Myers Squibb, and Janssen Pharmaceutical K.K. and lecture fees from Chugai Pharmaceutical Co. Ltd., and MSD Co. The remaining authors disclose no conflicts. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1
Fig 1. Changes of fibrosis stage over time.
Progression of fibrosis was defined as a 1 point or more increase in the METAVIR score. Regression of fibrosis was defined as 1 point or more decrease in the METAVIR score.
Fig 2
Fig 2. Association of SNPs genotype with fibrosis progression rate.
Error bars indicate the standard error.
Fig 3
Fig 3. Association between fibrosis progression rate and combining risk analysis (FPR score).
IL28B TG/GG, PNPLA3 CG/GG, and average ALT after interferon therapy ≥ 40 IU/l were scored as 1 point. Similarly, IL28B TT, PNPLA3 CC, and average ALT after interferon therapy < 40 IU/l were scored as 0 point. Patients scored 0–1, 2 and 3 were defined as a low, intermediate, and high risk group, respectively. Error bars indicate the standard error.
See this image and copyright information in PMC

References

    1. Kiyosawa K, Sodeyama T, Tanaka E, Gibo Y, Yoshizawa K, Nakano Y, et al. (1990) Interrelationship of blood transfusion, non-A, non-B hepatitis and hepatocellular carcinoma: analysis by detection of antibody to hepatitis C virus. Hepatology 12: 671–675. - PubMed
    1. Poynard T, McHutchison J, Davis GL, Esteban-Mur R, Goodman Z, Bedossa P, et al. (2000) Impact of interferon alfa-2b and ribavirin on progression of liver fibrosis in patients with chronic hepatitis C. Hepatology 32: 1131–1137. - PubMed
    1. Poynard T, Bedossa P, Opolon P (1997) Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet 349: 825–832. - PubMed
    1. Tanaka Y, Nishida N, Sugiyama M, Kurosaki M, Matsuura K, Sakamoto N, et al. (2009) Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C. Nat Genet 41: 1105–1109. 10.1038/ng.449 - DOI - PubMed
    1. Ge D, Fellay J, Thompson AJ, Simon JS, Shianna KV, Urban TJ, et al. (2009) Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature 461: 399–401. 10.1038/nature08309 - DOI - PubMed

Publication types

MeSH terms