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Genetic diversity of the KIR/HLA system and susceptibility to hepatitis C virus-related diseases.

Authors: Valli V. De Re, Laura L. Caggiari, Mariangela M. De Zorzi, Ombretta O. Repetto, Anna Linda AL. Zignego, Francesco F. Izzo, Maria Lina ML. Tornesello, Franco Maria FM. Buonaguro, Alessandra A. Mangia, Domenico D. Sansonno, Vito V. Racanelli, Salvatore S. De Vita, Pietro P. Pioltelli, Emanuela E. Vaccher, Massimiliano M. Berretta, Massimiliano M. Beretta, Cesare C. Mazzaro, Massimo M. Libra, Andrea A. Gini, Antonella A. Zucchetto, Renato R. Cannizzaro, Paolo P. De Paoli
Published: 02/20/2015, PloS one


The variability in the association of host innate immune response to Hepatitis C virus (HCV) infection requires ruling out the possible role of host KIR and HLA genotypes in HCV-related disorders: therefore, we therefore explored the relationships between KIR/HLA genotypes and chronic HCV infection (CHC) as they relate to the risk of HCV-related hepatocarcinoma (HCC) or lymphoproliferative disease progression.

Methods And Findings

We analyzed data from 396 HCV-positive patients with CHC (n = 125), HCC (118), and lymphoproliferative diseases (153), and 501 HCV-negative patients. All were HIV and HBV negative. KIR-SSO was used to determine the KIR typing. KIR2DL5 and KIR2DS4 variants were performed using PCR and GeneScan analysis. HLA/class-I genotyping was performed using PCR-sequence-based typing. The interaction between the KIR gene and ligand HLA molecules was investigated. Differences in frequencies were estimated using Fisher's exact test, and Cochran-Armitage trend test. The non-random association of KIR alleles was estimated using the linkage disequilibrium test. We found an association of KIR2DS2/KIR2DL2 genes, with the HCV-related lymphoproliferative disorders. Furthermore, individuals with a HLA-Bw6 KIR3DL1+ combination of genes showed higher risk of developing lymphoma than cryoglobulinemia. KIR2DS3 gene was found to be the principal gene associated with chronic HCV infection, while a reduction of HLA-Bw4 + KIR3DS1+ was associated with an increased risk of developing HCC.


Our data highlight a role of the innate-system in developing HCV-related disorders and specifically KIR2DS3 and KIR2D genes demonstrated an ability to direct HCV disease progression, and mainly towards lymphoproliferative disorders. Moreover the determination of KIR3D/HLA combination of genes direct the HCV progression towards a lymphoma rather than an hepatic disease. In this contest IFN-α therapy, a standard therapy for HCV-infection and lymphoproliferative diseases, known to be able to transiently enhance the cytotoxicity of NK-cells support the role of NK cells to counterstain HCV-related and lymphoproliferative diseases.

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