Abstract
Mixed cryoglobulinemia (MC), is a HCV-related, clinically benign, lymphoproliferative disorder (LPD) that may evolve into a non Hodgkin's lymphoma (NHL). Significant associations were found between two single nucleotide polymorphisms near NOTCH4 (rs2071286) and the HLA class II (rs9461776) genes and HCV-related MC syndrome (MCS). We analyzed NOTCH4 rs2071286 and HLA-II rs9461776 in 3 HCV-related LPD groups (asymptomatic MC, MCS, NHL) with HCV infection without lymphoproliferative disorders.We found a positive relationship between NOTCH4 rs207186 T minor allele frequency (MAF) and patients with HCV-related LPDs at risk of NHL (Chi-square test for trend = 14.84 p = 0.0001), in accordance with an over-dominant model in the NHL group (CT vs CC + TT, OR=1.88, 95% CI 1.24–2.83, p = 0.0026).Regarding HLA II rs9461776, G MAF increased in patients with HCV-related LPDs at risk of NHL (Chi-square test for trend = 8.40 p = 0.0038), in accordance with a recessive genotypic model in the NHL group (G/G vs A/A + A/G, OR = 11.07, 95% CI 2.37–51.64, p = 0.0022).Both NOTCH4 rs2071286 and HLA-II rs9461776 were present on chromosome 6 and showed D’ and r values of linkage disequilibrium (LD) of about 0.5 values, thereby suggesting there is no extensive LD in the HCV+ population.This data shows that the previously demonstrated association between NOTCH4 rs2071286 and HLA-II rs9461776 polymorphisms and HCV-related MCS could be extended to overall patients with HCV-related LPDs. The significant relationship between rs2071286 and rs9461776 MAF and the increased risk for NHL, suggests their use as non-invasive markers to categorize patients at risk of lymphoma.
Highlights
Hepatitis C Virus (HCV) has a high propensity to persist in the host, leading to chronic liver disease but it is known that in a smaller percentage of patients it can cause lymphoproliferative disorders (LPDs) [1]: the most frequent one is called mixed cryoglobulinemia (MC) [2, 3]
We found a positive relationship between NOTCH4 rs207186 T minor allele frequency (MAF) and patients with HCV-related LPDs at risk of non Hodgkin’s lymphoma (NHL) (Chi-square test for trend = 14.84 p = 0.0001), in accordance with an over-dominant model in the NHL group (CT vs CC + TT, OR=1.88, 95% CI 1.24–2.83, p = 0.0026)
Based on the Genome Wide Association Study (GWAS) results, we evaluated the allelic frequencies of the NOTCH4 rs2071286 and the human leukocyte antigen (HLA)-II rs9461776 single nucleotide polymorphism (SNP), in a wide cohort of patients with different HCV-related LPDs with circulating cryoglobulins, with and without vasculitis, or with HCV−
Summary
Hepatitis C Virus (HCV) has a high propensity to persist in the host, leading to chronic liver disease but it is known that in a smaller percentage of patients it can cause lymphoproliferative disorders (LPDs) [1]: the most frequent one is called mixed cryoglobulinemia (MC) [2, 3]. Several genetic studies had focused their attention on the human leukocyte antigen (HLA) variants highlighting an association between specific classes of genes and the susceptibility to the development of HCV-related MC and NHL [18,19,20,21,22]. A multicenter Genome Wide Association Study (GWAS) showed an association of two particular polymorphisms located on chromosome 6 with HCV-related MC Vasculitis compared to HCV controls without LPDs [23]; the first one is a single nucleotide polymorphism (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 of the class II major histocompatibility complex (MHC). Based on the GWAS results, we evaluated the allelic frequencies of the NOTCH4 rs2071286 and the HLA-II rs9461776 SNPs, in a wide cohort of patients with different HCV-related LPDs with circulating cryoglobulins, with and without vasculitis, or with HCV−. Related NHL, comparing them to a group of HCV+ patients without LPDs
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