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Genome-wide association of IL28B with response to pegylated interferon-α and ribavirin therapy for chronic hepatitis C


The recommended treatment for patients with chronic hepatitis C, pegylated interferon-α (PEG-IFN-α) plus ribavirin (RBV), does not provide sustained virologic response (SVR) in all patients. We report a genome-wide association study (GWAS) to null virological response (NVR) in the treatment of patients with hepatitis C virus (HCV) genotype 1 within a Japanese population. We found two SNPs near the gene IL28B on chromosome 19 to be strongly associated with NVR (rs12980275, P = 1.93 × 10−13, and rs8099917, 3.11 × 10−15). We replicated these associations in an independent cohort (combined P values, 2.84 × 10−27 (OR = 17.7; 95% CI = 10.0–31.3) and 2.68 × 10−32 (OR = 27.1; 95% CI = 14.6–50.3), respectively). Compared to NVR, these SNPs were also associated with SVR (rs12980275, P = 3.99 × 10−24, and rs8099917, P = 1.11 × 10−27). In further fine mapping of the region, seven SNPs (rs8105790, rs11881222, rs8103142, rs28416813, rs4803219, rs8099917 and rs7248668) located in the IL28B region showed the most significant associations (P = 5.52 × 10−28–2.68 × 10−32; OR = 22.3–27.1). Real-time quantitative PCR assays in peripheral blood mononuclear cells showed lower IL28B expression levels in individuals carrying the minor alleles (P = 0.015).

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Figure 1: Genome-wide association results with PEG-IFN-α/RBV treatment in 142 Japanese patients with HCV (78 NVR and 64 VR samples).
Figure 2: Genomic structure, P value and OR plots in association analysis and LD map around IL28B and IL28A (chr.19, nucleotide positions 44421319–44461718; build 35).
Figure 3: Quantification of IL28 mRNA expression.


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This study was supported by a grant-in-aid from the Ministry of Health, Labour, and Welfare of Japan (H19-kannen-013). This study is based on 15 multicenter hospitals throughout Japan, in the Hokkaido area (Hokkaido University Hospital), Kanto area (Saitama University Hospital; Konodai Hospital; Musashino Red Cross Hospital; Tokyo Medical and Dental University Hospital), Koshin area (Shinshu University Hospital; Kanazawa University Hospital), Tokai area (Nagoya City University Hospital), Kinki area (Kyoto Prefectural University of Medicine Hospital; National Hospital Organization Osaka National Hospital; Hyogo College of Medicine Hospital) and Chugoku/Shikoku area (Tottori University Hospital; Ehime University Hospital; Yamaguchi University Hospital; Kawasaki Medical College Hospital). We thank Y. Uehara-Shibata, Y. Ogasawara, Y. Ishibashi and M. Yamaoka-Sageshima (Tokyo University) for technical assistance; A. Matsumoto (Shinshu), K. Naiki (Saitama), K. Nishimura (Kyoto), H. Enomoto (Hyogo), K. Oyama (Tottori) and the Ochanomizu Liver Conference Study Group for collecting samples; M. Watanabe (Tokyo Medical and Dental University), S. Kaneko (Kanazawa University) and M. Onji (Ehime University) for their advice throughout the study; and H. Ito (Aichi Cancer Center) for conducting statistical analyses.

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Authors and Affiliations



Study design and discussion: Y.T., N.N., N.M., K.T., M.M.; sample collection: Y.T., M.K., K.M., N.S., M.N., M.K., K.H., S.H., Y.I., E.M., E.T., S.M., Y.M., M.H., A.S., Y.H., S.N., I.S., M.I., K.I., K.Y., F.S., N.I.; genotyping: N.N.; statistical analysis: N.N., A.K., K.I.; quantitative RT-PCR: M.S.; manuscript writing: Y.T., N.N., K.T., M.M.

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Correspondence to Masashi Mizokami.

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Tanaka, Y., Nishida, N., Sugiyama, M. et al. Genome-wide association of IL28B with response to pegylated interferon-α and ribavirin therapy for chronic hepatitis C. Nat Genet 41, 1105–1109 (2009).

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