PDCD1 and IFNL4 genetic variants and risk of developing hepatitis C virus-related diseases

Valli De Re, Maria Lina Tornesello, Mariangela De Zorzi, Laura Caggiari, Francesca Pezzuto, Patrizia Leone, Vito Racanelli, Gianfranco Lauletta, Stefania Zanussi, Ombretta Repetto, Laura Gragnani, Francesca Maria Rossi, Riccardo Dolcetti, Anna Linda Zignego, Franco M Buonaguro, Agostino Steffan

Research output: Contribution to journalArticlepeer-review

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 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<0.0001). 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=0.0025 and P=0.0167). Linkage disequilibrium (LD) between PD-1.3 and IFNL4 was found in patients with mixed cryoglobulinemia (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-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.

Original languageEnglish
JournalLiver Int.
DOIs
Publication statusE-pub ahead of print - Sep 16 2020

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