PDCD1 and IFNL4 genetic variants and risk of developing hepatitis C virus-related diseases.
Liver Int
; 41(1): 133-149, 2021 01.
Article
em En
| MEDLINE
| ID: mdl-32937024
ABSTRACT
BACKGROUND:
Genetic variants of IFNL4 and PDCD1 genes have been shown to influence the spontaneous clearance of hepatitis C virus (HCV) infection. We investigated the IFNL4 rs12979860 and the PDCD1 polymorphisms in 734 HCV-positive patients, including 461 cases with liver disease of varying severity and 273 patients with lymphoproliferative disorders to determine the association of these genes with patient's outcome.METHODS:
Expression levels of PDCD1 mRNA encoded by haplotypes were investigated by quantitative PCR in hepatocellular carcinoma (HCC) tissue and peripheral blood mononuclear cells. Flow cytometry was used to detect PD-1 and its ligand PD-L1.RESULTS:
The frequency of IFNL4 rs12979860 C/T or T/T genotypes was significantly higher in patients with HCV-related diseases than blood donors (P < .0001). Patients expressing the IFNλ4 variant with one amino acid change that reduces IFNλ4 secretion was found increased in frequency in HCV-related diseases compared to HCC PDCD1 mRNA levels in HCC tissue were significantly higher in cases carrying the PD-1.3 A or the PD-1.7 G allele (P = .0025 and P = .0167). Linkage disequilibrium (LD) between PD-1.3 and IFNL4 was found in patients with mixed cryoglobulinaemia (MC) only (LD = 0 in HCC; LD = 72 in MC). PBMCs of MC patients expressed low levels of PD-L1 in CD19+IgM+B cells and of PD-1 in CD4+T cells suggesting the involvement of regulatory B cell-T cell interaction to the pathogenesis of MC.CONCLUSION:
Collectively, our data indicate an important contribution of IFNλ4 expression to the development of HCV-related HCC and an epistatic contribution of IFNL4 and PDCD1 in MC. LAYSUMMARY:
Studies of IFNL4 and PDCD1 genes are helpful to better understand the role of host genetic factors and immune antigens influencing the outcome of HCV-related diseases. Our data support an association between the expression of IFNλ4, which prevents the expression of IFNλ3, with all the different HCV-related diseases studied, and besides, evidence that a higher IFNλ4 expression is associated with hepatocellular at a younger age. The expression pattern of low PD-L1 on B cells and high PD-1 on CD4+T-cells in patients with HCV-positive cryoglobulinaemia suggests a critical role of the PD-1/PD-L1 signaling in modulating B cell-T cell interaction in this lymphoproliferative disease.Palavras-chave
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Hepatite C
/
Carcinoma Hepatocelular
/
Hepatite C Crônica
/
Neoplasias Hepáticas
Tipo de estudo:
Etiology_studies
/
Risk_factors_studies
Limite:
Humans
Idioma:
En
Revista:
Liver Int
Assunto da revista:
GASTROENTEROLOGIA
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Itália