Background and Aims: Hepatitis C virus (HCV) leads to chronic liver disease, but more rarely it causes lymphoproliferative disorders (LPDs). The most frequent HCV-related LPD is mixed cryoglobulinemia (MC). MC is clinically benign, but it evolves in about 10% of cases into a non Hodgkin’s lymphoma (NHL). The exact pathogenesis of HCV-related LPDs is still unknown and few and conflicting data exists about the host genetic contribution. Recently, a GWAS study allowed the discovery of an association of two particular SNPs on chromosome 6 and HCV-related MC vasculitis; the first one is a SNP (rs2071286) located in an intronic region of the NOTCH4 gene, the second one is a SNP (rs9461776) located between HLA-DRB1 and HLA-DQA1 gene segments. Aim: To define the contribution of rs2071286 and rs9461776 in the predisposition to develop HCV-related LPDs (MC and NHL). Methods: rs2071286 and rs9461776 SNP were determined using TaqMan SNP Genotyping Assay in 438 patients: 85 HCV patients without LPDs (HCV), 73 HCV patients with circulating cryoglobulins (MC-HCV), 108 with HCV-associated MC syndrome (MCS-HCV), 62 with HCV-related NHL (NHL-HCV) and 110 HCV negative patients with NHL (NHL). Results: Concerning rs2071286, significantly higher minor allele frequency (maf) was observed in all the case groups respect to controls (MC-HCV, p = 0.035; MCS-HCV, p < 0.001; NHL-HCV, p = 0.001 and NHL, p = 0.019). Comparing to HCV group, the odds-ratio associated with rs2071286 maf were: MC-HCV, OR 1.79; MCS-HCV, OR 2.59; NHL-HCV, OR 2.6; NHL, OR 1.81. Regarding rs9461776, the higher maf was observed in NHL-HCV and in NHL groups (p = 0.011 and p = 0.0283 respect to HCV, respectively). Furthermore, we described an increasing trend, although not significant, following the evolution of the LPDs. The presence of minor allele of rs9461776 conferred an OR of 2.42 to NHL-HCV and an OR of 1.7 to NHL group, in respect to controls. Conclusions: We confirm the previously demonstrated association between the two SNPs and HCV-related MC vasculitis (Zignego et al, 2014), and showed a similar associations for HCV-related NHLs and, regarding NOTCH4 SNP, also for patients with CGs but without symptoms. Furthermore, HCV negative NHLs showed higher frequencies of the two minor alleles respect to controls, but lower compared to HCV positive lymphomas. This suggests that HCV acts on a permissive genetic substrate and confirms the virus contribution to the pathogenesis of lymphoma.

P0752 : NOTCH4 and MHC class II polymorphisms contibute to HCV-related benign and malignant lymphoproliferative diseases

Gragnani L;
2015-01-01

Abstract

Background and Aims: Hepatitis C virus (HCV) leads to chronic liver disease, but more rarely it causes lymphoproliferative disorders (LPDs). The most frequent HCV-related LPD is mixed cryoglobulinemia (MC). MC is clinically benign, but it evolves in about 10% of cases into a non Hodgkin’s lymphoma (NHL). The exact pathogenesis of HCV-related LPDs is still unknown and few and conflicting data exists about the host genetic contribution. Recently, a GWAS study allowed the discovery of an association of two particular SNPs on chromosome 6 and HCV-related MC vasculitis; the first one is a SNP (rs2071286) located in an intronic region of the NOTCH4 gene, the second one is a SNP (rs9461776) located between HLA-DRB1 and HLA-DQA1 gene segments. Aim: To define the contribution of rs2071286 and rs9461776 in the predisposition to develop HCV-related LPDs (MC and NHL). Methods: rs2071286 and rs9461776 SNP were determined using TaqMan SNP Genotyping Assay in 438 patients: 85 HCV patients without LPDs (HCV), 73 HCV patients with circulating cryoglobulins (MC-HCV), 108 with HCV-associated MC syndrome (MCS-HCV), 62 with HCV-related NHL (NHL-HCV) and 110 HCV negative patients with NHL (NHL). Results: Concerning rs2071286, significantly higher minor allele frequency (maf) was observed in all the case groups respect to controls (MC-HCV, p = 0.035; MCS-HCV, p < 0.001; NHL-HCV, p = 0.001 and NHL, p = 0.019). Comparing to HCV group, the odds-ratio associated with rs2071286 maf were: MC-HCV, OR 1.79; MCS-HCV, OR 2.59; NHL-HCV, OR 2.6; NHL, OR 1.81. Regarding rs9461776, the higher maf was observed in NHL-HCV and in NHL groups (p = 0.011 and p = 0.0283 respect to HCV, respectively). Furthermore, we described an increasing trend, although not significant, following the evolution of the LPDs. The presence of minor allele of rs9461776 conferred an OR of 2.42 to NHL-HCV and an OR of 1.7 to NHL group, in respect to controls. Conclusions: We confirm the previously demonstrated association between the two SNPs and HCV-related MC vasculitis (Zignego et al, 2014), and showed a similar associations for HCV-related NHLs and, regarding NOTCH4 SNP, also for patients with CGs but without symptoms. Furthermore, HCV negative NHLs showed higher frequencies of the two minor alleles respect to controls, but lower compared to HCV positive lymphomas. This suggests that HCV acts on a permissive genetic substrate and confirms the virus contribution to the pathogenesis of lymphoma.
https://www.journal-of-hepatology.eu/article/S0168-8278(15)30955-7/pdf
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11568/1163456
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