title: Genetic determinants in hepatitis C virus-associated mixed cryoglobulinemia: role of polymorphic variants of BAFF promoter and Fcγ receptors.
abstract: OBJECTIVE
  Mixed cryoglobulinemia (MC) is a hepatitis C virus (HCV)-related immune complex disorder. Only some HCV-infected patients develop MC, which suggests that the genetic background of the host plays a key role. This study was undertaken to evaluate the contribution of host genetic factors in the pathogenesis of HCV-associated MC (HCV-MC) by analyzing allelic variants of low-affinity Fcγ receptor (FcγR) genes and BAFF promoter.
  
  
  METHODS
  FcγR polymorphisms (FCGR2A 131 R/H, FCGR2B 232 I/T, FCGR3A 176 V/F, and FCGR3B NA1/NA2) and BAFF promoter polymorphism -871 C/T were analyzed in 102 patients with HCV-MC and 108 patients with HCV without MC, using polymerase chain reaction-based techniques.
  
  
  RESULTS
  A higher prevalence of -871 T/T homozygosity (31% versus 16%; P = 0.001) and a greater frequency of T alleles of the BAFF promoter (80% versus 57%; P = 0.004) were found in the HCV-MC group than in the HCV group. A significant increase in serum BAFF concentration was significantly associated with the higher frequency of the T allele in HCV-MC (mean ± SD 4.12 ± 1.29 versus 2.09 ± 0.81 ng/ml; P < 0.0005). The distribution of the FcγR genotypes was not significantly different. In the 21 HCV-MC patients treated with rituximab, the response was strictly related to F allele homozygosity (significantly reduced in 5 of 5 patients with the FCGR3A F/F genotype versus 4 of 16 with V/V or V/F; P < 0.0005).
  
  
  CONCLUSIONS
  These results indicate the importance of host genetic background in the development of HCV-MC, suggesting that mechanisms enhancing Ig production and B cell survival may play a relevant role. Genetic FcγR variants seem to be crucial to the effectiveness of rituximab therapy.
authors.affiliation: Centre for Systemic Manifestations of Hepatitis Viruses and University of Florence, Florence, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Gragnani
authors.forename: Alessia
authors.initials: A
authors.lastname: Piluso
authors.forename: Carlo
authors.initials: C
authors.lastname: Giannini
authors.forename: Patrizio
authors.initials: P
authors.lastname: Caini
authors.forename: Elisa
authors.initials: E
authors.lastname: Fognani
authors.forename: Monica
authors.initials: M
authors.lastname: Monti
authors.forename: Antonio
authors.initials: A
authors.lastname: Petrarca
authors.forename: Jessica
authors.initials: J
authors.lastname: Ranieri
authors.forename: Giulia
authors.initials: G
authors.lastname: Razzolini
authors.forename: Valentina
authors.initials: V
authors.lastname: Froio
authors.forename: Giacomo
authors.initials: G
authors.lastname: Laffi
authors.forename: Anna Linda
authors.initials: AL
authors.lastname: Zignego
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000936:Antigen-Antibody Complex / Q000276:immunology; D053264:B-Cell Activating Factor / Q000235:genetics* / Q000276:immunology; D003449:Cryoglobulinemia / Q000235:genetics* / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005838:Genotype; D016174:Hepacivirus / Q000276:immunology*; D006526:Hepatitis C / Q000235:genetics* / Q000276:immunology; D006801:Humans; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000276:immunology; D011401:Promoter Regions, Genetic / Q000276:immunology; D017452:Receptors, IgG / Q000235:genetics* / Q000276:immunology
chemical_list: D000936:Antigen-Antibody Complex; D053264:B-Cell Activating Factor; D017452:Receptors, IgG; C505719:TNFSF13B protein, human