Gragnani Laura, Fognani Elisa, De Re Valli, Libra Massimo, Garozzo Adriana, Caini Patrizio, Cerretelli Guia, Giovannelli Andrea, Lorini Serena, Monti Monica, Bagnoli Silvia, Piaceri Irene, Zignego Anna Linda
Center for Systemic Manifestations of Hepatitis Viruses (MaSVE), Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
Centro di Riferimento oncologico, National Cancer Institute, Aviano, Italy.
Oncotarget. 2017 May 6;8(42):71528-71535. doi: 10.18632/oncotarget.17655. eCollection 2017 Sep 22.
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 = 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, = 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 = 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, = 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.
混合性冷球蛋白血症（MC）是一种与丙型肝炎病毒（HCV）相关的临床良性淋巴增殖性疾病（LPD），可能会发展为非霍奇金淋巴瘤（NHL）。在NOTCH4基因附近的两个单核苷酸多态性（rs2071286）和人类白细胞抗原（HLA）II类基因（rs9461776）与HCV相关的MC综合征（MCS）之间发现了显著关联。我们分析了3组与HCV相关的LPD患者（无症状MC、MCS、NHL）以及无淋巴增殖性疾病的HCV感染者的NOTCH4 rs2071286和HLA-II rs9461776。我们发现NOTCH4 rs207186 T次要等位基因频率（MAF）与有患NHL风险的HCV相关LPD患者之间存在正相关（趋势卡方检验=14.84，P = 0.0001），这与NHL组的超显性模型一致（CT与CC + TT相比，OR = 1.88，95%可信区间1.24 - 2.83，P = 0.0026）。关于HLA II rs9461776，有患NHL风险的HCV相关LPD患者中G MAF增加（趋势卡方检验=8.40，P = 0.0038），这与NHL组的隐性基因型模型一致（G/G与A/A + A/G相比，OR = 11.07，95%可信区间2.37 - 51.64，P = 0.0022）。NOTCH4 rs2071286和HLA-II rs9461776均位于6号染色体上，连锁不平衡（LD）的D'和r值约为0.5，这表明HCV阳性人群中不存在广泛的LD。该数据表明，先前证明的NOTCH4 rs2071286和HLA-II rs9461776多态性与HCV相关MCS之间的关联可扩展至所有HCV相关LPD患者。rs2071286和rs9461776 MAF与患NHL风险增加之间的显著关系，表明它们可作为对有淋巴瘤风险患者进行分类的非侵入性标志物。
