Association analysis of KIR/HLA genotype with liver cirrhosis, hepatocellular carcinoma, and NUC freedom in chronic hepatitis B patients

AbstractNatural killer cells are modulated through the binding of killer cell immunoglobulin-like receptors (KIRs) with human leukocyte antigen (HLA) class I ligands. This study investigated the association of KIR/HLA pairs with progression to liver cirrhosis, hepatocellular carcinoma (HCC) development, and nucleot(s)ide (NUC) treatment freedom in hepatitis B virus (HBV) infection. KIR, HLA-Bw, and HLA-C were genotyped in 280 Japanese HBV patients for clinical comparisons. No significant associations of KIR/HLA pairs were detected in terms of liver cirrhosis development. The KIR2DS3 positive rate was significantly higher in patients with HCC (n = 39) than in those without (n = 241) [30.8% vs. 14.9%, odds ratio (OR) 2.53, P = 0.015]. The KIR3DL1/HLA-Bw4 pair rate was significantly lower in the NUC freedom group (n = 20) than in the NUC continue group (n = 114) (25.0% vs. 52.6%, OR 0.30, P = 0.042). In conclusion, this study indicated remarkable associations of KIR/HLA with HCC development (KIR2DS3) and freedom from NUC therapy (KIR3DL1/HLA-Bw4) in HBV patients, although the number of cases was insufficient for statistical purposes. Additional multi-center analyses of larger groups are needed to clarify whether KIR/HLA pairs play a role in HBV patient status.

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Association Analysis of KIR/HLA Genotype with Liver Cirrhosis, Hepatocellular Carcinoma, and NUC Freedom in Chronic Hepatitis B Patients

10.21203/rs.3.rs-741018/v1 ◽

2021 ◽

Author(s):

Satoru Joshita ◽

Masao Ota ◽

Hiroyuki Kobayashi ◽

Shun-ichi Wakabayashi ◽

Yuki Yamashita ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Cirrhosis ◽

Hepatitis B ◽

Killer Cell ◽

Human Leukocyte ◽

Hla Class I ◽

Leukocyte Antigen ◽

Patient Status ◽

Positive Rate ◽

Hla Genotype

Abstract Natural killer cells are modulated through the binding of killer cell immunoglobulin-like receptors (KIRs) with human leukocyte antigen (HLA) class I ligands. This study investigated the association of KIR/HLA pairs with progression to liver cirrhosis, hepatocellular carcinoma (HCC) development, and nucleot(s)ide (NUC) treatment freedom in hepatitis B virus (HBV) infection. KIR, HLA-Bw, and HLA-C were genotyped in 280 Japanese HBV patients for clinical comparisons. The proportion of the KIR2DS4/HLA-C2 pair was significantly higher in patients with liver cirrhosis (n = 40) than in those without (n = 240) (12.5% vs. 4.2%, odds ratio [OR] 3.29, P = 0.029). The KIR2DS3 positive rate was significantly higher in patients with HCC (n = 39) than in those without (n = 241) (30.8% vs. 14.9%, OR 2.53, P = 0.015). The KIR3DL1/HLA-Bw4 pair rate was significantly lower in the NUC freedom group (n = 20) than in the NUC continue group (n = 114) (25.0% vs. 52.6%, OR 0.30, P = 0.042). In conclusions, this study revealed significant KIR/HLA associations with progression to liver cirrhosis (KIR2DS4/HLA-C2), HCC development (KIR2DS3), and freedom from NUC therapy (KIR3DL1/HLA-Bw4) in HBV patients. KIR/HLA pairs may therefore play a role in HBV patient status.

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Impacts of human leukocyte antigen DQ genetic polymorphisms and their interactions with hepatitis B virus mutations on the risks of viral persistence, liver cirrhosis, and hepatocellular carcinoma

Infection Genetics and Evolution ◽

10.1016/j.meegid.2014.09.032 ◽

2014 ◽

Vol 28 ◽

pp. 201-209 ◽

Cited By ~ 14

Author(s):

Xiaowei Ji ◽

Qi Zhang ◽

Bin Li ◽

Yan Du ◽

Jianhua Yin ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Cirrhosis ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Human Leukocyte Antigen ◽

Genetic Polymorphisms ◽

Viral Persistence ◽

Human Leukocyte ◽

Leukocyte Antigen ◽

B Virus

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Combination of Human Leukocyte Antigen and Killer Cell Immunoglobulin-Like Receptor Genetic Background Influences the Onset Age of Hepatocellular Carcinoma in Male Patients with Hepatitis B Virus Infection

Clinical and Developmental Immunology ◽

10.1155/2013/874514 ◽

2013 ◽

Vol 2013 ◽

pp. 1-7 ◽

Cited By ~ 5

Author(s):

Ning Pan ◽

Jie Qiu ◽

Hang Sun ◽

Fengqin Miao ◽

Qian Shi ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Genetic Background ◽

Killer Cell ◽

Human Leukocyte ◽

Onset Age ◽

Leukocyte Antigen ◽

B Virus ◽

Male Patients

To investigate whether killer cell immunoglobulin-like receptor(KIR)and human leukocyte antigen(HLA)genetic background could influence the onset age of hepatocellular carcinoma (HCC) in patients with hepatitis B virus (HBV) infection, one hundred and seventy-one males with HBV-related HCC were enrolled. The presence of 12 loci ofKIRwas detected individually.HLA-A, -B, and -Cloci were genotyped with high resolution by a routine sequence-based typing method. The effect of eachKIRlocus,HLAligand, andHLA-KIRcombination was examined individually by Kaplan-Meier (KM) analysis. Multivariate Cox hazard regression model was also applied. We identifiedC1C1-KIR2DS2/2DL2as an independent risk factor for earlier onset age of HCC (median onset age was 44 forC1C1-KIR2DS2/2DL2positive patients compared to 50 for negative patients,P=0.04for KM analysis; HR = 1.70,P=0.004for multivariate Cox model). We conclude thatKIRandHLAgenetic background can influence the onset age of HCC in male patients with HBV infection. This study may be useful to improve the current HCC surveillance program in HBV-infected patients. Our findings also suggest an important role of natural killer cells (or otherKIR-expressing cells) in the progress of HBV-related HCC development.

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The molecular basis of how buried human leukocyte antigen polymorphism modulates natural killer cell function

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1920570117 ◽

2020 ◽

Vol 117 (21) ◽

pp. 11636-11647 ◽

Cited By ~ 1

Author(s):

Philippa M. Saunders ◽

Bruce J. MacLachlan ◽

Phillip Pymm ◽

Patricia T. Illing ◽

Yuanchen Deng ◽

...

Keyword(s):

Human Leukocyte Antigen ◽

Natural Killer ◽

Nk Cell ◽

Killer Cell ◽

Peptide Binding ◽

Human Leukocyte ◽

Hla Class I ◽

Cell Recognition ◽

Leukocyte Antigen ◽

Binding Cleft

Micropolymorphisms within human leukocyte antigen (HLA) class I molecules can change the architecture of the peptide-binding cleft, leading to differences in peptide presentation and T cell recognition. The impact of such HLA variation on natural killer (NK) cell recognition remains unclear. Given the differential association of HLA-B*57:01 and HLA-B*57:03 with the control of HIV, recognition of these HLA-B57 allomorphs by the killer cell immunoglobulin-like receptor (KIR) 3DL1 was compared. Despite differing by only two polymorphic residues, both buried within the peptide-binding cleft, HLA-B*57:01 more potently inhibited NK cell activation. Direct-binding studies showed KIR3DL1 to preferentially recognize HLA-B*57:01, particularly when presenting peptides with positively charged position (P)Ω-2 residues. In HLA-B*57:01, charged PΩ-2 residues were oriented toward the peptide-binding cleft and away from KIR3DL1. In HLA-B*57:03, the charged PΩ-2 residues protruded out from the cleft and directly impacted KIR3DL1 engagement. Accordingly, KIR3DL1 recognition of HLA class I ligands is modulated by both the peptide sequence and conformation, as determined by the HLA polymorphic framework, providing a rationale for understanding differences in clinical associations.

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