title: Genetic diversity of the KIR/HLA system and susceptibility to hepatitis C virus-related diseases.
abstract: 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.
  
  
  RESULTS
  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.
authors.affiliation: Facility Bio-proteomica/Dir. Sc, CRO National Cancer Institute, Aviano, Pordenone, Italy.
authors.forename: Valli
authors.initials: V
authors.lastname: De Re
authors.affiliation: Facility Bio-proteomica/Dir. Sc, CRO National Cancer Institute, Aviano, Pordenone, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Caggiari
authors.affiliation: Facility Bio-proteomica/Dir. Sc, CRO National Cancer Institute, Aviano, Pordenone, Italy.
authors.forename: Mariangela
authors.initials: M
authors.lastname: De Zorzi
authors.affiliation: Facility Bio-proteomica/Dir. Sc, CRO National Cancer Institute, Aviano, Pordenone, Italy.
authors.forename: Ombretta
authors.initials: O
authors.lastname: Repetto
authors.affiliation: Experimental and Clinical Medicine, University of Florence, Florence, Italy.
authors.forename: Anna Linda
authors.initials: AL
authors.lastname: Zignego
authors.affiliation: Hepatobiliary Unit, National Cancer Institute "Fondazione Pascale", Naples, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Izzo
authors.affiliation: Molecular Biology and Viral Oncology, National Cancer Institute "Fondazione Pascale", Naples, Italy.
authors.forename: Maria Lina
authors.initials: ML
authors.lastname: Tornesello
authors.affiliation: Molecular Biology and Viral Oncology, National Cancer Institute "Fondazione Pascale", Naples, Italy.
authors.forename: Franco Maria
authors.initials: FM
authors.lastname: Buonaguro
authors.affiliation: Liver, IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Mangia
authors.affiliation: Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Sansonno
authors.affiliation: Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy.
authors.forename: Vito
authors.initials: V
authors.lastname: Racanelli
authors.affiliation: Medical and Biological Sciences, University Hospital Santa Maria della Misericordia, Udine, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: De Vita
authors.affiliation: Hematology and Transplant Unit, San Gerardo Hospital, University of Milano-Bicocca, Monza, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Pioltelli
authors.affiliation: Medical Oncology, Centro di riferimento oncologico, Aviano, Pordenone, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Vaccher
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Berretta
authors.affiliation: Medical Oncology, Centro di riferimento oncologico, Aviano, Pordenone, Italy.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Beretta
authors.affiliation: Medical Oncology, Centro di riferimento oncologico, Aviano, Pordenone, Italy.
authors.forename: Cesare
authors.initials: C
authors.lastname: Mazzaro
authors.affiliation: Biomedical Sciences, University of Catania, Catania, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Libra
authors.affiliation: Epidemiology and Biostatistics, CRO National Cancer Institute, Aviano, Pordenone, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Gini
authors.affiliation: Epidemiology and Biostatistics, CRO National Cancer Institute, Aviano, Pordenone, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Zucchetto
authors.affiliation: Gastroenterology, CRO National Cancer Institute, Aviano, Pordenone, Italy.
authors.forename: Renato
authors.initials: R
authors.lastname: Cannizzaro
authors.affiliation: Facility Bio-proteomica/Dir. Sc, CRO National Cancer Institute, Aviano, Pordenone, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: De Paoli
mesh_terms: D000328:Adult; D000368:Aged; D002503:Centromere / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006680:HLA Antigens / Q000235:genetics*; D016174:Hepacivirus / Q000502:physiology*; D006526:Hepatitis C / Q000150:complications / Q000235:genetics / Q000473:pathology*; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D054340:Receptors, KIR / Q000235:genetics*; D054346:Receptors, KIR2DL5 / Q000235:genetics; D016615:Telomere / Q000235:genetics
chemical_list: D006680:HLA Antigens; C473953:KIR2DS4 protein, human; D054340:Receptors, KIR; D054346:Receptors, KIR2DL5