{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T01:41:56Z","timestamp":1747186916349,"version":"3.40.5"},"reference-count":79,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2020,12,29]],"date-time":"2020-12-29T00:00:00Z","timestamp":1609200000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Liver International"],"published-print":{"date-parts":[[2021,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Genetic variants of <jats:italic>IFNL4<\/jats:italic> and <jats:italic>PDCD1<\/jats:italic> genes have been shown to influence the spontaneous clearance of hepatitis C virus (HCV) infection. We investigated the <jats:italic>IFNL4<\/jats:italic> rs12979860 and the <jats:italic>PDCD1<\/jats:italic> polymorphisms in 734 HCV\u2010positive 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Expression levels of <jats:italic>PDCD1<\/jats:italic> 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\u20101 and its ligand PD\u2010L1.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The frequency of <jats:italic>IFNL4<\/jats:italic> rs12979860 C\/T or T\/T genotypes was significantly higher in patients with HCV\u2010related diseases than blood donors (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a0.0001). Patients expressing the IFN\u03bb4 variant with one amino acid change that reduces IFN\u03bb4 secretion was found increased in frequency in HCV\u2010related diseases compared to HCC <jats:italic>PDCD1<\/jats:italic> mRNA levels in HCC tissue were significantly higher in cases carrying the PD\u20101.3 A or the PD\u20101.7 G allele (<jats:italic>P<\/jats:italic>\u00a0=\u00a0.0025 and <jats:italic>P<\/jats:italic>\u00a0=\u00a0.0167). Linkage disequilibrium (LD) between PD\u20101.3 and IFNL4 was found in patients with mixed cryoglobulinaemia (MC) only (LD\u00a0=\u00a00 in HCC; LD\u00a0=\u00a072 in MC). PBMCs of MC patients expressed low levels of PD\u2010L1 in CD19+IgM+B cells and of PD\u20101 in CD4+T cells suggesting the involvement of regulatory B cell\u2010T cell interaction to the pathogenesis of MC.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Collectively, our data indicate an important contribution of IFN\u03bb4 expression to the development of HCV\u2010related HCC and an epistatic contribution of <jats:italic>IFNL4<\/jats:italic> and <jats:italic>PDCD1<\/jats:italic> in MC.<\/jats:p><\/jats:sec><jats:sec><jats:title>Lay summary<\/jats:title><jats:p>Studies of <jats:italic>IFNL4<\/jats:italic> and <jats:italic>PDCD1<\/jats:italic> genes are helpful to better understand the role of host genetic factors and immune antigens influencing the outcome of HCV\u2010related diseases. Our data support an association between the expression of IFN\u03bb4, which prevents the expression of IFN\u03bb3, with all the different HCV\u2010related diseases studied, and besides, evidence that a higher IFN\u03bb4 expression is associated with hepatocellular at a younger age. The expression pattern of low PD\u2010L1 on B cells and high PD\u20101 on CD4+T\u2010cells in patients with HCV\u2010positive cryoglobulinaemia suggests a critical role of the PD\u20101\/PD\u2010L1 signaling in modulating B cell\u2010T cell interaction in this lymphoproliferative disease.<\/jats:p><\/jats:sec>","DOI":"10.1111\/liv.14667","type":"journal-article","created":{"date-parts":[[2020,9,16]],"date-time":"2020-09-16T23:31:01Z","timestamp":1600299061000},"page":"133-149","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["<i>PDCD1<\/i> and <i>IFNL4<\/i> genetic variants and risk of developing hepatitis C virus\u2010related diseases"],"prefix":"10.1111","volume":"41","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6100-9373","authenticated-orcid":false,"given":"Valli","family":"De Re","sequence":"first","affiliation":[{"name":"Immunopathology and Cancer Biomarkers\/Bioproteomic facility Department of Translational Research Centro di Riferimento Oncologico (CRO) IRCCS Cancer Institute Aviano Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3523-3264","authenticated-orcid":false,"given":"Maria Lina","family":"Tornesello","sequence":"additional","affiliation":[{"name":"Molecular biology viral oncology Istituto Nazionale Tumori IRCCS \"Fondazione G. 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