KIR and HLA Loci Are Associated with Hepatocellular Carcinoma Development in Patients with Hepatitis B Virus Infection: A Case-Control Study

Ning Pan,Hang Sun,Wei Xie,Hui Jin,Jianqiong Zhang,Fengqin Miao,Jie Qiu,Wei Jiang,Jinhuan Xu,Qian Shi,Johan K Sandberg

doi:10.1371/journal.pone.0025682

Abstract

BackgroundNatural killer (NK) cells activation has been reported to contribute to inflammation and liver injury during hepatitis B virus (HBV) infection both in transgenic mice and in patients. However, the role of NK cells in the process of HBV-associated hepatocellular carcinoma (HCC) development has not been addressed. Killer cell immunoglobulin-like receptors (KIRs) are involved in regulating NK cell activation through recognition of specific human leukocyte antigen (HLA) class I allotypes.Methodology/Principal FindingsTo investigate whether KIR and HLA genes could influence the risk of HBV-associated HCC development, 144 HBV-infected patients with HCC and 189 well-matched HBV infectors with chronic hepatitis or cirrhosis as non-HCC controls were enrolled in this study. The presence of 12 loci of KIR was detected individually. HLA-A, -B, -C loci were genotyped with high-resolution. HLA-C group 1 homozygote (OR = 2.02; p = 0.005), HLA-Bw4-80I (OR = 2.67; p = 2.0E-04) and combination of full-length form and 22 bp-deleted form of KIR2DS4 (KIR2DS4/1D) (OR = 1.89; p = 0.017) were found associated with HCC incidence. When the combined effects of these three genetic factors were evaluated, more risk factors were observed correlating with higher odds ratios for HCC incidence (P trend = 7.4E-05). Because all the risk factors we found have been reported to result in high NK cell functional potential by previous studies, our observations suggest that NK cell activation may contribute to HBV-associated HCC development.Conclusions/SignificanceIn conclusion, this study has identified significant associations that suggest an important role for NK cells in HCC incidence in HBV-infected patients. Our study is useful for HCC surveillance and has implications for novel personalized therapy strategy development aiming at HCC prevention in HBV-infected patients.

Highlights

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the third most common cause of cancer mortality
The data suggest that human leukocyte antigen (HLA)-C1C1 may be the major risk factor among Bw4-80I, HLA-C1C1 and KIR2DS4/1D. The presence of both Bw4-80I and KIR2DS4/1D may have stronger susceptive effect than having only one of these risk genes when HLA-C1C1 is present. This is the first report to establish a close correlation between Killer cell immunoglobulin-like receptors (KIRs), HLA loci and hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) development
For HLA-C1C1, direct binding assay and disease association studies all suggest that KIR2DL3/HLA-C group 1 (HLA-C1) interaction results in higher Natural killer (NK) cell function level than other HLA-C/KIR interactions [16]

Summary

Introduction

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the third most common cause of cancer mortality. Hepatitis B virus (HBV) is the most frequent underlying cause of HCC. In hyperendemic areas such as China and Africa, chronic HBV infection contributes to at least 80% of cases of HCC [1]. Accumulating reports support that NK cell activation contribute to inflammation and liver injury during HBV infection both in HBV transgenic mice and in HBV infected patients [4,5,6,7], the role of NK cells in the process of HBVassociated HCC development has not been addressed. Natural killer (NK) cells activation has been reported to contribute to inflammation and liver injury during hepatitis B virus (HBV) infection both in transgenic mice and in patients. Killer cell immunoglobulin-like receptors (KIRs) are involved in regulating NK cell activation through recognition of specific human leukocyte antigen (HLA) class I allotypes

Methods

Results

Conclusion