Notch4 and mhc class II polymorphisms are associated with hcv-related benign and malignant lymphoproliferative diseases

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// Laura Gragnani 1, * , Elisa Fognani 1, * , Valli De Re 2 , Massimo Libra 3 , Adriana Garozzo 3 , Patrizio Caini 1 , Guia Cerretelli 1 , Andrea Giovannelli 1 , Serena Lorini 1 , Monica Monti 1 , Silvia Bagnoli 4 , Irene Piaceri 4 and Anna Linda Zignego 1 1 Center for Systemic Manifestations of Hepatitis Viruses (MaSVE), Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy 2 Centro di Riferimento oncologico, National Cancer Institute, Aviano, Italy 3 Department of Biomedical and Biotechnological Sciences, Section of Microbiology, University of Catania, Italy 4 Department of Neuroscience, Psychology, Drug Research and Children’s Health, University of Florence, Florence, Italy * These authors contributed equally to this work Correspondence to: Anna Linda Zignego, email: a.zignego@dmi.unifi.it Keywords: HCV, mixed cryoglobulinemia, NOTCH4, HLA-II, lymphoma Received: January 31, 2017 Accepted: March 29, 2017 Published: May 06, 2017 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.

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