DEPDC5 variants increase fibrosis progression in Europeans with chronic hepatitis C virus infection

Maria Antonella Burza, Benedetta Maria Motta, Rosellina Margherita Mancina, Piero Pingitore, Carlo Pirazzi, Saverio Massimo Lepore, Rocco Spagnuolo, Patrizia Doldo, Cristina Russo, Veronica Lazzaro, Janett Fischer, Thomas Berg, Alessio Aghemo, Cristina Cheroni, Raffaele De Francesco, Silvia Fargion, Massimo Colombo, Christian Datz, Felix Stickel, Luca ValentiStefano Romeo

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Abstract

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.

Original languageEnglish
Pages (from-to)418-427
Number of pages10
JournalHepatology
Volume63
Issue number2
DOIs
Publication statusPublished - Feb 1 2016

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Chronic Hepatitis C
Virus Diseases
Hepacivirus
Fibrosis
Catenins
Hepatocellular Carcinoma
Metalloproteases
Down-Regulation
Hepatic Stellate Cells
Disease Progression
Liver Diseases
Enzymes

ASJC Scopus subject areas

  • Hepatology

Cite this

Burza, M. A., Motta, B. M., Mancina, R. M., Pingitore, P., Pirazzi, C., Lepore, S. M., ... Romeo, S. (2016). DEPDC5 variants increase fibrosis progression in Europeans with chronic hepatitis C virus infection. Hepatology, 63(2), 418-427. https://doi.org/10.1002/hep.28322

DEPDC5 variants increase fibrosis progression in Europeans with chronic hepatitis C virus infection. / Burza, Maria Antonella; Motta, Benedetta Maria; Mancina, Rosellina Margherita; Pingitore, Piero; Pirazzi, Carlo; Lepore, Saverio Massimo; Spagnuolo, Rocco; Doldo, Patrizia; Russo, Cristina; Lazzaro, Veronica; Fischer, Janett; Berg, Thomas; Aghemo, Alessio; Cheroni, Cristina; De Francesco, Raffaele; Fargion, Silvia; Colombo, Massimo; Datz, Christian; Stickel, Felix; Valenti, Luca; Romeo, Stefano.

In: Hepatology, Vol. 63, No. 2, 01.02.2016, p. 418-427.

Research output: Contribution to journalArticle

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 2016, 'DEPDC5 variants increase fibrosis progression in Europeans with chronic hepatitis C virus infection', Hepatology, vol. 63, no. 2, pp. 418-427. https://doi.org/10.1002/hep.28322
Burza MA, Motta BM, Mancina RM, Pingitore P, Pirazzi C, Lepore SM et al. DEPDC5 variants increase fibrosis progression in Europeans with chronic hepatitis C virus infection. Hepatology. 2016 Feb 1;63(2):418-427. https://doi.org/10.1002/hep.28322
Burza, Maria Antonella ; Motta, Benedetta Maria ; Mancina, Rosellina Margherita ; Pingitore, Piero ; Pirazzi, Carlo ; Lepore, Saverio Massimo ; Spagnuolo, Rocco ; Doldo, Patrizia ; Russo, Cristina ; Lazzaro, Veronica ; Fischer, Janett ; Berg, Thomas ; Aghemo, Alessio ; Cheroni, Cristina ; De Francesco, Raffaele ; Fargion, Silvia ; Colombo, Massimo ; Datz, Christian ; Stickel, Felix ; Valenti, Luca ; Romeo, Stefano. / DEPDC5 variants increase fibrosis progression in Europeans with chronic hepatitis C virus infection. In: Hepatology. 2016 ; Vol. 63, No. 2. pp. 418-427.
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AU - Pirazzi, Carlo

AU - Lepore, Saverio Massimo

AU - Spagnuolo, Rocco

AU - Doldo, Patrizia

AU - Russo, Cristina

AU - Lazzaro, Veronica

AU - Fischer, Janett

AU - Berg, Thomas

AU - Aghemo, Alessio

AU - Cheroni, Cristina

AU - De Francesco, Raffaele

AU - Fargion, Silvia

AU - Colombo, Massimo

AU - Datz, Christian

AU - Stickel, Felix

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AU - Romeo, Stefano

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