DEPDC5 variants increase fibrosis progression in Europeans with chronic hepatitis C virus infection.
DEPDC5 variants increase fibrosis progression in Europeans with chronic hepatitis C virus infection.
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DOI：
10.1002/hep.28322
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发表时间：
2016-02
期刊：
影响因子：
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通讯作者：
Romeo S
中科院分区：
文献类型：
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作者：
Burza MA;Motta BM;Mancina RM;Pingitore P;Pirazzi C;Lepore SM;Spagnuolo R;Doldo P;Russo C;Lazzaro V;Fischer J;Berg T;Aghemo A;Cheroni C;De Francesco R;Fargion S;Colombo M;Datz C;Stickel F;Valenti L;Romeo S
慢性丙型肝炎病毒（HCV）感染可能进展为肝硬化和肝细胞癌（HCC）。最近，两种基因变异，DEPDC5 rs1012068 和 MICA rs2596542，与亚洲慢性 HCV 感染受试者的 HCC 发病相关。本研究的目的是分析 DEPDC5 和 MICA 遗传变异是否与欧洲慢性 HCV 感染受试者的肝病进展相关。在意大利北部的发现队列 (n = 477) 中，DEPDC5 rs1012068 和 MICA rs2596542 均与 HCC 无关 (n = 150)。然而，DEPDC5 rs1012068 与肝硬化独立相关（n = 300；P = 0.049）。 rs1012068 与中度至重度纤维化的关联在一个独立的德国横断面队列中得到证实（n = 415；P = 0.006）。此外，DEPDC5 rs1012068 预测前瞻性队列中纤维化进展更快（n = 247；P = 0.027）。接下来，我们检查了非同义 DEPDC5 变体在整个横截面队列中的分布 (n = 912)。至少一种变异的存在会使中度/重度纤维化的风险增加 54% (P = 0.040)。为了了解 DEPDC5 变异与纤维化进展遗传关联的分子机制，我们对永生化肝星状细胞 (LX-2) 进行了体外研究。在这些细胞中，DEPDC5 的下调导致 β-连环蛋白的表达增加及其靶基质金属肽酶 2 (MMP2) 的产生，MMP2 是一种参与纤维化进展的分泌酶。结论：DEPDC5 变异会增加欧洲慢性 HCV 感染受试者的纤维化进展。我们的研究结果表明，DEPDC5 下调可能通过 β-catenin 途径增加 MMP2 合成，从而导致 HCV 相关纤维化。 （肝病学 2016 年；63：418–427）
Chronic hepatitis C virus (HCV) infection may progress to cirrhosis and hepatocellular carcinoma (HCC). Recently, two genetic variants, DEPDC5 rs1012068 and MICA rs2596542, were associated with the onset of HCC in Asian subjects with chronic HCV infection. The aim of the present study was to analyze whether DEPDC5 and MICA genetic variants were associated with liver disease progression in European subjects with chronic HCV infection. In a Northern Italian discovery cohort (n = 477), neither DEPDC5 rs1012068 nor MICA rs2596542 were associated with HCC (n = 150). However, DEPDC5 rs1012068 was independently associated with cirrhosis (n = 300; P = 0.049). The association of rs1012068 with moderate to severe fibrosis was confirmed in an independent cross‐sectional German cohort (n = 415; P = 0.006). Furthermore, DEPDC5 rs1012068 predicted faster fibrosis progression in a prospective cohort (n = 247; P = 0.027). Next, we examined the distribution of nonsynonymous DEPDC5 variants in the overall cross‐sectional cohort (n = 912). The presence of at least one variant increased the risk of moderate/severe fibrosis by 54% (P = 0.040). To understand the molecular mechanism underlying the genetic association of DEPDC5 variants with fibrosis progression, we performed in vitro studies on immortalized hepatic stellate cells (LX‐2). In these cells, down‐regulation of DEPDC5 resulted in increased expression of β‐catenin and production of its target matrix metallopeptidase 2 (MMP2), a secreted enzyme involved in fibrosis progression. Conclusion: DEPDC5 variants increase fibrosis progression in European subjects with chronic HCV infection. Our findings suggest that DEPDC5 down‐regulation may contribute to HCV‐related fibrosis by increasing MMP2 synthesis through the β‐catenin pathway. (Hepatology 2016;63:418–427)