PLoS ONE (Jan 2015)

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

  • Valli De Re,
  • Laura Caggiari,
  • Mariangela De Zorzi,
  • Ombretta Repetto,
  • Anna Linda Zignego,
  • Francesco Izzo,
  • Maria Lina Tornesello,
  • Franco Maria Buonaguro,
  • Alessandra Mangia,
  • Domenico Sansonno,
  • Vito Racanelli,
  • Salvatore De Vita,
  • Pietro Pioltelli,
  • Emanuela Vaccher,
  • Massimiliano Berretta,
  • Cesare Mazzaro,
  • Massimo Libra,
  • Andrea Gini,
  • Antonella Zucchetto,
  • Renato Cannizzaro,
  • Paolo De Paoli

DOI
https://doi.org/10.1371/journal.pone.0117420
Journal volume & issue
Vol. 10, no. 2
p. e0117420

Abstract

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BACKGROUND: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. CONCLUSIONS: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.