Oncotarget

Research Papers:

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

Laura Gragnani, Elisa Fognani, Valli De Re, Massimo Libra, Adriana Garozzo, Patrizio Caini, Guia Cerretelli, Andrea Giovannelli, Serena Lorini, Monica Monti, Silvia Bagnoli, Irene Piaceri and Anna Linda Zignego _

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Oncotarget. 2017; 8:71528-71535. https://doi.org/10.18632/oncotarget.17655

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Abstract

Laura Gragnani1,*, Elisa Fognani1,*, Valli De Re2, Massimo Libra3, Adriana Garozzo3, Patrizio Caini1, Guia Cerretelli1, Andrea Giovannelli1, Serena Lorini1, Monica Monti1, Silvia Bagnoli4, Irene Piaceri4 and Anna Linda Zignego1

1Center for Systemic Manifestations of Hepatitis Viruses (MaSVE), Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy

2Centro di Riferimento oncologico, National Cancer Institute, Aviano, Italy

3Department of Biomedical and Biotechnological Sciences, Section of Microbiology, University of Catania, Italy

4Department 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: [email protected]

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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