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

Centre for Systemic Manifestations of Hepatitis Viruses and University of Florence, Florence, Italy
Arthritis & Rheumatology (Impact Factor: 7.76). 05/2011; 63(5):1446 - 1451. DOI: 10.1002/art.30274


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.ResultsA 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).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 FcγR variants seem to be crucial to the effectiveness of rituximab therapy.

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Available from: Anna Linda Zignego
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    • "In a recent multi-centre genome-wide association study performed in 356 HCV-MC patients and 447 HCV-positive controls, significant associations were identified on chromosome 6, a SNP (Single Nucleotide Polymorphism) located within an intronic region of NOTCH4 (p = 6.2 × 10 −9 ) and another found between HLA- DRB1 and HLA-DQA1 (p = 1.2 × 10 −7 ) [16]. It has been shown that a higher percentage of a particular allele of the promoter of the B-cell activating factor (BAFF) – known to be related to higher translational activity of the gene [17] – and different expression patterns on circulating lymphocytes of microRNAs are involved in lymphoproliferative and/or autoimmune disorders [18]. In contrast , specific virological factors have not yet been identified. "
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    ABSTRACT: Hepatitis C virus (HCV) infected patients are known to be at risk of developing liver complications i.e. cirrhosis and liver cancer. However, the risks of morbidity and mortality are underestimated because they do not take into account non-liver consequences of chronic hepatitis C virus infection. Numerous extrahepatic manifestations have been reported in up to 74% of patients, from perceived to disabling conditions. The majority of data concern hepatitis C virus-related autoimmune and/or lymphoproliferative disorders, from mixed cryoglobulinaemia vasculitis to frank lymphomas. More recently, other hepatitis C virus-associated disorders have been reported including cardiovascular, renal, metabolic, and central nervous system diseases. This review aims to outline most of the extrahepatic manifestations that are currently being investigated, including some of autoimmune and/or lymphoproliferative nature, and others in which the role of immune mechanisms appears less clear.Beyond the liver, hepatitis C virus chronic infection should be analyzed as a multifaceted systemic disease leading to heavy direct and indirect costs. The accurate consideration of extrahepatic consequences of such a systemic infection significantly increases the weight of its pathological burden. The need for effective viral eradication measures is underlined.
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    • "This might suggest a genetic origin of such a persistent increase in BAFF level. The –871 C→T single nucleotide gene polymorphism (SNP) has not been associated with pSS but with the serum BAFF concentration in patients with pSS [30], [31], with mixed cryoglobulinemia [32], with familial chronic lymphoproliferations [33], [34], and in patients with idiopathic thrombopenic purpura [35]. However, the study of a haplotype block including four SNPs (−2841 T→C, −2704 T→C, −2701 T→A, −871 C→T), suggested that the −871 T allele was unlikely to be a sole, major determinant of serum BAFF levels [31]. "
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    ABSTRACT: To analyze the clinical and immunological characteristics at enrollment in a large prospective cohort of patients with primary Sjögren's syndrome (pSS) and to investigate the association between serum BAFF, beta2-microglobulin and free light chains of immunoglobulins and systemic disease activity at enrollment. Three hundred and ninety five patients with pSS according to American-European Consensus Criteria were included from fifteen centers of Rheumatology and Internal Medicine in the "Assessment of Systemic Signs and Evolution of Sjögren's Syndrome" (ASSESS) 5-year prospective cohort. At enrollment, serum markers were assessed as well as activity of the disease measured with the EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI). Patient median age was 58 (25(th)-75(th): 51-67) and median disease duration was 5 (2-9) years. Median ESSDAI at enrollment was 2 (0-7) with 30.9% of patients having features of systemic involvement. Patients with elevated BAFF, beta2-microglobulin and kappa, lambda FLCS had higher ESSDAI scores at enrollment (4 [2]-[11] vs 2 [0-7], P = 0.03; 4 [1]-[11] vs 2 [0-7], P< 0.0001); 4 [2]-[10] vs 2 [0-6.6], P< 0.0001 and 4 [2-8.2] vs 2 [0-7.0], P = 0.02, respectively). In multivariate analysis, increased beta2-microglobulin, kappa and lambda FLCs were associated with a higher ESSDAI score. Median BAFF and beta2-microglobulin were higher in the 16 patients with history of lymphoma (1173.3(873.1-3665.5) vs 898.9 (715.9-1187.2) pg/ml, P = 0.01 and 2.6 (2.2-2.9) vs 2.1 (1.8-2.6) mg/l, P = 0.04, respectively). In pSS, higher levels of beta2-microglobulin and free light chains of immunoglobulins are associated with increased systemic disease activity.
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    • "We have investigated the reasons for such elevated levels and shown that MC patients were characterized by a higher prevalence of a particular allele of the gene promoter previously shown to be associated with enhanced transcriptional activity. Furthermore, T homozygosis was associated with significantly higher levels of the cytokine in the patients’ serum [84]. "
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