Research Papers:

KIR2DL2 combined with HLA-C1 confers risk of hepatitis C virus-related hepatocellular carcinoma in younger patients

Hiromi Saito, Takeji Umemura _, Satoru Joshita, Tomoo Yamazaki, Naoyuki Fujimori, Takefumi Kimura, Michiharu Komatsu, Akihiro Matsumoto, Eiji Tanaka and Masao Ota

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Oncotarget. 2018; 9:19650-19661. https://doi.org/10.18632/oncotarget.24752

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Hiromi Saito1,*, Takeji Umemura1,2,*, Satoru Joshita1,2, Tomoo Yamazaki1, Naoyuki Fujimori1, Takefumi Kimura1, Michiharu Komatsu1, Akihiro Matsumoto1, Eiji Tanaka1 and Masao Ota1

1Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan

2Research Center for Next Generation Medicine, Shinshu University, Matsumoto, Japan

*These authors have contributed equally to this work

Correspondence to:

Takeji Umemura, email: [email protected]

Keywords: killer cell immunoglobulin-like receptor; human leukocyte antigen; hepatitis C virus; hepatocellular carcinoma; MICA

Received: December 26, 2017    Accepted: March 06, 2018    Published: April 13, 2018


Killer cell immunoglobulin-like receptors (KIRs) are involved in the activation and inhibition of natural killer cells. Although combinations of KIRs and HLA have been associated with spontaneous and treatment-induced clearance of hepatitis C virus (HCV) infection, their roles are not fully understood in the context of hepatocellular carcinoma (HCC) development. We enrolled 787 consecutive patients with chronic HCV infection, which included 174 cases of HCC, and 325 healthy subjects to clarify the involvement of HLA-Bw and C, KIRs, and major histocompatibility complex class I chain-related gene A (MICA) gene polymorphisms (rs2596542 and rs1051792) in chronic HCV infection and HCV-related HCC. We observed a significant association with chronic hepatitis C susceptibility for HLA-Bw4 (P = 0.00012; odds ratio [OR] = 1.66) and significant protective associations for HLA-C2 and KIR2DL1-HLA-C2 (both P = 0.00099; OR = 0.57). When HCC patients were stratified into younger (<65 years) and older (≥65 years) groups, the frequencies of KIR2DL2-HLA-C1 and KIR2DS2-HLA-C1 (P = 0.008; OR = 2.89 and P = 0.015; OR = 2.79, respectively) as well as rs2596542 and rs1051792 (P = 0.020; OR = 2.17 and P = 0.038; OR = 2.01, respectively) were significantly higher in younger patients. KIR2DL2-HLA-C1 (OR = 2.75; 95% confidence interval: 1.21-6.21, P = 0.015) and rs1051792 (OR = 2.48; 95% confidence interval: 1.23-4.98, P = 0.011) were independently associated with HCC development in younger patients. These results suggest that KIR2DL2-HLA-C1 and rs1051792 may represent molecular biomarkers to identify early onset HCV-related HCC.

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