<i>KIR</i>, <i>HLA</i>, and <i>IL28B</i> Variant Predict Response to Antiviral Therapy in Genotype 1 Chronic Hepatitis C Patients in Japan

<div><p>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 <i>KIR2DL3-HLA-C1</i>, 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 <i>HLA-B</i> and <i>-C</i> 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. <i>HLA-Bw4</i> was significantly associated with a sustained virological response (SVR) to treatment (<i>P</i> = 0.017; odds ratio [OR] = 2.50, ), as was the centromeric A/A haplotype of <i>KIR</i> (<i>P</i> = 0.015; OR 3.37). In contrast, SVR rates were significantly decreased in patients with <i>KIR2DL2</i> or <i>KIR2DS2</i> (<i>P</i> = 0.015; OR = 0.30, and <i>P</i> = 0.025; OR = 0.32, respectively). Multivariate logistic regression analysis subsequently identified the <i>IL28B</i> TT genotype (<i>P</i> = 0.00009; OR = 6.87, 95% confidence interval [CI] = 2.62 - 18.01), <i>KIR2DL2/HLA-C1</i> (<i>P</i> = 0.014; OR = 0.24, 95% CI = 0.08 - 0.75), <i>KIR3DL1/HLA-Bw4</i> (<i>P</i> = 0.008, OR = 3.32, 95% CI = 1.37 - 8.05), and white blood cell count at baseline (<i>P</i> = 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 <i>IL28B</i> TT genotype and <i>KIR3DL1</i>-<i>HLA-Bw4</i> in responders (<i>P</i> = 0.0019), whereas <i>IL28B</i> TT along with <i>KIR2DL2-HLA-C1</i> was related to a non-response (<i>P</i> = 0.0067). In conclusion, combinations of <i>KIR3DL1/HLA-Bw4</i>, <i>KIR2DL2/HLA-C1</i>, and a genetic variant of the <i>IL28B</i> gene are predictive of the response to PEG-IFN and ribavirin therapy in Japanese patients infected with genotype 1b HCV.</p>