Genetic Determinants in Hepatitis C Virus-Associated Mixed Cryoglobulinemia: Role of Polymorphic Variants of BAFF Promoter and Fcγ Receptors

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 Fc gamma receptor (Fc gamma R) genes and BAFF promoter. Methods. Fc gamma R 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 Fc gamma R 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). Conclusion. 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 Fc gamma R variants seem to be crucial to the effectiveness of rituximab therapy.