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Clinical Trial
. 2013 Dec 12;8(12):e83381.
doi: 10.1371/journal.pone.0083381. eCollection 2013.

KIR, HLA, and IL28B variant predict response to antiviral therapy in genotype 1 chronic hepatitis C patients in Japan

Yuichi Nozawa  1 , Takeji Umemura  1 , Satoru Joshita  1 , Yoshihiko Katsuyama  2 , Soichiro Shibata  1 , Takefumi Kimura  1 , Susumu Morita  1 , Michiharu Komatsu  1 , Akihiro Matsumoto  1 , Eiji Tanaka  1 , Masao Ota  3
Affiliations
Clinical Trial

KIR, HLA, and IL28B variant predict response to antiviral therapy in genotype 1 chronic hepatitis C patients in Japan

Yuichi Nozawa et al. PLoS One. .

Abstract

Natural killer cell responses play a crucial role in virus clearance by the innate immune system. Although the killer immunoglobulin-like receptor (KIR) in combination with its cognate human leukocyte antigen (HLA) ligand, especially KIR2DL3-HLA-C1, is associated with both treatment-induced and spontaneous clearance of hepatitis C virus (HCV) infection in Caucasians, these innate immunity genes have not been fully clarified in Japanese patients. We therefore investigated 16 KIR genotypes along with HLA-B and -C ligands and a genetic variant of interleukin (IL) 28B (rs8099917) in 115 chronic hepatitis C genotype 1 patients who underwent pegylated-interferon-α2b (PEG-IFN) and ribavirin therapy. HLA-Bw4 was significantly associated with a sustained virological response (SVR) to treatment (P = 0.017; odds ratio [OR] = 2.50, ), as was the centromeric A/A haplotype of KIR (P = 0.015; OR 3.37). In contrast, SVR rates were significantly decreased in patients with KIR2DL2 or KIR2DS2 (P = 0.015; OR = 0.30, and P = 0.025; OR = 0.32, respectively). Multivariate logistic regression analysis subsequently identified the IL28B TT genotype (P = 0.00009; OR = 6.87, 95% confidence interval [CI] = 2.62 - 18.01), KIR2DL2/HLA-C1 (P = 0.014; OR = 0.24, 95% CI = 0.08 - 0.75), KIR3DL1/HLA-Bw4 (P = 0.008, OR = 3.32, 95% CI = 1.37 - 8.05), and white blood cell count at baseline (P = 0.009; OR = 3.32, 95% CI = 1.35 - 8.16) as independent predictive factors of an SVR. We observed a significant association between the combination of IL28B TT genotype and KIR3DL1-HLA-Bw4 in responders (P = 0.0019), whereas IL28B TT along with KIR2DL2-HLA-C1 was related to a non-response (P = 0.0067). In conclusion, combinations of KIR3DL1/HLA-Bw4, KIR2DL2/HLA-C1, and a genetic variant of the IL28B gene are predictive of the response to PEG-IFN and ribavirin therapy in Japanese patients infected with genotype 1b HCV.

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Conflict of interest statement

Competing Interests: MSD partly funded this study. There are no patents, products in development or marketed products to declare. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Figure 1
Figure 1. Frequency of HLA-Bw and -C alleles in 56 patients with a sustained virological response (SVR) and 59 patients with a non-SVR to pegylated interferon and ribavirin therapy of chronic hepatitis C.
Figure 2
Figure 2. Frequency of each KIR gene in 56 patients with a sustained virological response (SVR) and 59 patients with a non-SVR to pegylated interferon and ribavirin therapy of chronic hepatitis C.
Figure 3
Figure 3. KIR gene profile frequencies in 56 patients with a sustained virological response (SVR) and 59 patients with a non-SVR to pegylated interferon and ribavirin therapy of chronic hepatitis C.
Numerical data represent the number of individuals (%). The presence of KIR genes is indicated by gray shading. Cen, centromeric; Tel, telomeric.
See this image and copyright information in PMC

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Grants and funding

This work was supported by a grant from the Ministry of Health, Labor, and Welfare of Japan. Takeji Umemura and Eiji Tanaka report receiving grant support from MSD. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.