López-Rodríguez Rosario, Hernández-Bartolomé Ángel, Borque María Jesús, Rodríguez-Muñoz Yolanda, Martín-Vílchez Samuel, García-Buey Luisa, González-Moreno Leticia, Real-Martínez Yolanda, Muñoz de Rueda Paloma, Salmerón Javier, Vidal-Castiñeira José Ramón, López-Larrea Carlos, Rodrigo Luis, Moreno-Otero Ricardo, Sanz-Cameno Paloma
Liver Unit, Gastroenterology Service, Instituto Investigación Sanitaria Princesa, IIS-IP, Madrid, Spain.
Molecular Biology Unit, Instituto Investigación Sanitaria Princesa, IIS-IP, Madrid, Spain.
PLoS One. 2017 Jul 12;12(7):e0180927. doi: 10.1371/journal.pone.0180927. eCollection 2017.
Chronic hepatitis C (CHC) is a major cause of liver disease worldwide which often leads to progressive liver inflammation, fibrosis, cirrhosis and hepatocellular carcinoma (HCC). CHC displays heterogeneous progression depending on a broad set of factors, some of them intrinsic to each individual such as the patient's genetic profile. This study aims to evaluate the contribution of certain genetic variants of crucial interferon alpha and lambda signaling pathways to the hepatic necroinflammatory activity (NIA) grade of CHC patients.
NIA was evaluated in 119 CHC patients by METAVIR scale and classified as low (NIA = 0-2, n = 80) or high grade (NIA = 3, n = 39). In a candidate gene approach, 64 SNPs located in 30 different genes related to interferon pathways (IL-28B, IFNAR1-2, JAK-STAT and OAS1-3, among others) were genotyped using the Illumina GoldenGate® Genotyping Assay. Statistical association was determined by logistic regression and expressed as OR and 95% CI. Those SNPs significantly associated were further adjusted by other covariates.
Seven SNPs located in IL-28B (rs12979860), JAK1 (rs11576173 and rs1497056), TYK2 (rs280519), OAS1 (rs2057778), SOCS1 (rs33932899) and RNASEL (rs3738579) genes were significantly related to severe NIA grade (p<0.05). Regarding to clinical variables, elevated NIA was notably associated with aspartate aminotransferase (AST) serum levels >40 IU/L (p<0.05) but not with other clinical factors. Multivariate logistic regression analysis of these factors reflected that AST (>40 IU/L), TYK2 rs280519 (G allele) and RNASEL rs3738579 (G allele) were factors independently associated with elevated NIA (p<0.05). AST concentration showed a moderate AUC value (AUC = 0.63), similar to TYK2 (rs280519) and RNASEL (rs3738579) SNPs (AUC = 0.61, both) in the ROC_AUC analysis. Interestingly, the model including all significant variables reached a considerable predictive value (AUC = 0.74).
The identified genetic variants in interferon signaling pathways may constitute useful prognostic markers of CHC progression. Further validation in larger cohorts of patients is needed.
慢性丙型肝炎（CHC）是全球肝病的主要病因，常导致进行性肝脏炎症、纤维化、肝硬化和肝细胞癌（HCC）。CHC的进展具有异质性，取决于一系列广泛的因素，其中一些因素是个体内在的，如患者的基因谱。本研究旨在评估关键的干扰素α和λ信号通路的某些基因变异对CHC患者肝脏坏死性炎症活动（NIA）分级的影响。
采用METAVIR量表对119例CHC患者的NIA进行评估，并分为低级别（NIA = 0 - 2，n = 80）或高级别（NIA = 3，n = 39）。采用候选基因方法，使用Illumina GoldenGate®基因分型检测对位于与干扰素通路相关的30个不同基因（包括IL - 28B、IFNAR1 - 2、JAK - STAT和OAS1 - 3等）中的64个单核苷酸多态性（SNP）进行基因分型。通过逻辑回归确定统计关联，并以比值比（OR）和95%置信区间（CI）表示。对那些显著相关的SNP进一步进行其他协变量调整。
位于IL - 28B（rs12979860）、JAK1（rs11576173和rs1497056）、TYK2（rs280519）、OAS1（rs2057778）、SOCS1（rs33932899）和RNASEL（rs3738579）基因中的7个SNP与严重NIA分级显著相关（p < 0.05）。关于临床变量，NIA升高与天冬氨酸转氨酶（AST）血清水平>40 IU/L显著相关（p < 0.05），但与其他临床因素无关。对这些因素进行多变量逻辑回归分析表明，AST（>40 IU/L）、TYK2 rs280519（G等位基因）和RNASEL rs3738579（G等位基因）是与NIA升高独立相关的因素（p < 0.05）。在ROC_AUC分析中，AST浓度显示出中等的曲线下面积值（AUC = 0.63），与TYK2（rs280519）和RNASEL（rs3738579）SNP相似（两者AUC = 0.61）。有趣的是，包含所有显著变量的模型具有相当高的预测价值（AUC = 0.74）。
在干扰素信号通路中鉴定出的基因变异可能构成CHC进展的有用预后标志物。需要在更大的患者队列中进行进一步验证。
