Genetic Variants in KIR/HLA-C Genes Are Associated With the Susceptibility to HCV Infection in a High-Risk Chinese Population

Shen, Chao; Zhang, Ge; Dong, Chen; Wang, Chunhui; Shao, Jianghua; Cai, Wei; Huang, Peng; Fan, Haozhi; Li, Jun; Zhang, Yun; Yue, Ming

doi:10.3389/fimmu.2021.632353

Cited by 7 publications

(7 citation statements)

References 61 publications

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“…However, further validation of this observation in an independent cohort with various HCV-genotypes is recommended. The KIR diversity between different populations reported by other groups [13,14] is not a likely explanation as there was no statistically significant difference between the frequency of KIR allelotype in the non-cancer HCV patients in the Italian cohort and the Egyptian cohort (25.6% vs. 27%, p = 0.8843).…”

Section: Discussionmentioning

confidence: 79%

KIR Genotypes Impact Progression to Hepatocellular Carcinoma in Patients with Chronic Hepatitis C Infection

Abdelmaguid,

Maher,

Kohla

et al. 2023

Livers

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In Egypt, hepatocellular carcinoma (HCC) is the most prevalent cancer in men and the second most prevalent cancer in women. In addition, Egypt has one of the highest prevalences of hepatitis C infection in the world. The aim of the present work was to study the potential role of the 16 KIR genes in the outcome of individuals with chronic hepatitis C virus (HCV) infection in Egypt. The study was carried out under an IRB-approved protocol. Sequence-Specific-Primer-PCR (SSP-PCR) was used for KIR genotyping of germline DNA extracted from peripheral blood leukocytes or from the non-tumor liver of 83 HCC patients, 100 patients with chronic HCV infection without HCC, and 120 matched healthy controls. Out of the 83 HCC patients, only 7 (8.4%) were treated by interferon and/or interferon Ribavirin combination, while for the remaining patients 50 (60.2%) received no prior HCV therapy and 26 (31.3%) were treated with direct-acting antiviral (DAA). Our results showed that KIR haplotype AA that contains more inhibitory KIR genes and fewer activating genes was observed with a significantly lower frequency in HCC patients (6/83, 7.2%) compared to chronic HCV (27/100, 27.0%) (p = 0.0005, OR = 0.21 [0.08–0.53]) and healthy controls (29/119, 24.4%) (p = 0.001, OR = 0.24 [0.09–0.61]). In addition, the frequency of genotype 6 (G6) which contains all the KIR genes was significantly high in the HCC patients (16/83, 19.3%) compared to chronic HCV (8/100, 8.0%) (p = 0.02, OR = 2.7 [1.11–6.79]) and healthy controls (8/119, 6.7%) (p = 0.006, OR = 3.31 [1.35–8.16]). Activating KIR genes 2DS1 and 3DS1 were significantly higher in HCC patients (48/83, 57.83% and 45/83, 54.22%) compared to the chronic HCV patients (36/100, 36% and 34/100, 34%), p = 0.028, 0.027, respectively. Our results are contrary to a prior work on HCC from patients with HCV who were mostly treated by interferon-based therapies. In conclusion, KIR haplotype AA has an important role in host defense against HCC progression especially in patients treated by DAA, suggesting an important role of the KIR genotype status on the outcome of chronic HCV infection.

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Section: Discussionmentioning

confidence: 79%

KIR Genotypes Impact Progression to Hepatocellular Carcinoma in Patients with Chronic Hepatitis C Infection

Abdelmaguid,

Maher,

Kohla

et al. 2023

Livers

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“…Takeji et al found that KIR3DL1 + HLA‐Bw4 are associated with HCC development in HCV cirrhosis, and Zhengang et al found that KIR2DL5A−/2DL5B + associated with HCV spontaneous clearance 22,23 . Recently, single nucleotide polymorphisms (SNPs) of KIR2DS4/KIR2DS1/KIR2DL1 and HLA‐C have been linked to an elevated vulnerability to HCV infection in our previous study 24 …”

Section: Introductionmentioning

confidence: 70%

“…[19][20][21] 22,23 Recently, single nucleotide polymorphisms (SNPs) of KIR2DS4/KIR2DS1/KIR2DL1 and HLA-C have been linked to an elevated vulnerability to HCV infection in our previous study. 24 KIR2DL4 is referred to as one of the "framework" genes, which was detected 100% in random populations. 25 Structured questionnaires designed by professionals were completed to collect subjects' information with demographic information, harmful behavior exposure, and clinical histories of HCV infection.…”

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confidence: 99%

KIR2DL4/HLA‐G polymorphisms were associated with HCV infection susceptibility among Chinese high‐risk population

Feng

Huang

Zhang

et al. 2023

Journal of Medical Virology

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Killer-cell immunoglobulin-like receptors 2DL4 (KIR2DL4) and the human leukocyte antigen class I-G (HLA-G) display vital parts in immune responses against hepatitis C virus (HCV) infection. We select four potentially functional single nucleotide polymorphisms (SNPs) of KIR/HLA to explore the associations between KIR2DL4/ HLA-G genetic variants and HCV infection results. In the present case-control study, a total of 2225 HCV-infected high-risk subjects, including 1778 paid blood donors (PBD) and 447 drug users were consecutively recruited before treatment from 2011 to 2018. KIR2DL4-rs660773, KIR2DL4-rs660437, HLA-G-rs9380142, and HLA-G-rs1707 SNPs were sorted as genotypes in the subdivided groups, involving 1095 uninfected controls subjects, 432 spontaneous HCV clearance subjects and 698 HCV persistent infection subjects. After genotyping experiments using the TaqMan-MGB assay, modified logistic regression was used to calculate the correlation among the SNPs and HCV infection. The SNPs were functionally annotated using bioinformatics analysis. Following adjusting by age, sex, alanine aminotransferase, aspartate aminotransferase, IFNL3-rs12979860, IFNL3-rs8099917, and the infection route, the logistic regression analysis discovered that KIR2DL4-rs660773 and HLA-G-rs9380142 were correlated with vulnerability to HCV infection (all p < 0.05). In a locus-dosage way, compared with subjects carrying the rs9380142-AA or rs660773-AA genotypes, subjects with rs9380142-AG or rs660773-AG/GG (all p < 0.05) were more vulnerable to HCV infection; the overall impact of their risk genotypes (rs9380142-AGrs660773-AG/GG) was correlated with an elevated incidence of HCV infection (p trend < 0.001). In the Haplotype analysis, patients with haplotype AG were more likely to contract HCV compared to those with the highest common AA haplotype (p = 0.002) were higher in susceptibility to infect HCV. The SNPinfo web server estimated that rs660773 is a transcription factor binding site, whereas rs9380142 is a potential microRNA-binding site. In two Chinese high-risk population (PBD and drug uesrs), KIR2DL4 rs660773-G and HLA-G rs9380142-G alleles polymorphisms are related to HCV susceptibility. KIR2DL4/HLA-G pathway genes

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“…Interestingly, NK-cell proteins with the highest donor-variations in the BL group can be functionally associated in a protein-protein-interaction network and enrich lysosomal and endosomal as well as HLA classes I and II components. HLA genotypes have been associated with viral load and more recently with susceptibilities in HCV risk groups and now may support the further classification of chronic HCV patients [96][97][98]. In this context, it is reasonable to speculate on the role of sex hormones and sex-specific cytokine levels to explain donor-variations in the NK-cell proteomes of female patients.…”

Section: Discussionmentioning

confidence: 99%

Proteomics reveals a global phenotypic shift of NK cells in HCV patients treated with direct‐acting antivirals

Kraft

Engelskircher

et al. 2023

Eur J Immunol

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Chronic hepatitis C virus (HCV) infections compromise natural killer (NK)‐cell immunity. Direct‐acting antivirals (DAA) effectively eliminate HCV, but the long‐term effects on NK cells in cured patients are debated. We conducted a proteomic study on CD56+ NK cells of chronic HCV‐infected patients before and 1 year after DAA therapy. Donor‐variation was observed in NK‐cell proteomes of HCV‐infected patients, with 46 dysregulated proteins restored after DAA therapy. However, 30% of the CD56+ NK‐cell proteome remained altered 1 year post‐therapy, indicating a phenotypic shift with low donor‐variation. NK cells from virus‐negative cured patients exhibited global regulation of RNA‐processing and pathways related to “stimuli response”, “chemokine signaling”, and “cytotoxicity regulation”. Proteomics identified downregulation of vesicle transport components (CD107a, COPI/II complexes) and altered receptor expression profiles, indicating an inhibited NK‐cell phenotype. Yet, activated NK cells from HCV patients before and after therapy effectively upregulated IFN‐γ and recruited CD107a. Conversely, reduced surface expression levels of Tim‐3 and 2B4 were observed before and after therapy. In conclusion, this study reveals long‐term effects on the CD56+ NK‐cell compartment in convalescent HCV patients 1 year after therapy, with limited abundance of vesicle transport complexes and surface receptors, associated with a responsive NK‐cell phenotype.

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Genetic Variants in KIR/HLA-C Genes Are Associated With the Susceptibility to HCV Infection in a High-Risk Chinese Population

Cited by 7 publications

References 61 publications

KIR Genotypes Impact Progression to Hepatocellular Carcinoma in Patients with Chronic Hepatitis C Infection

KIR Genotypes Impact Progression to Hepatocellular Carcinoma in Patients with Chronic Hepatitis C Infection

KIR2DL4/HLA‐G polymorphisms were associated with HCV infection susceptibility among Chinese high‐risk population

Proteomics reveals a global phenotypic shift of NK cells in HCV patients treated with direct‐acting antivirals

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