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Front. Genet. | doi: 10.3389/fgene.2019.01024

Identification of an endoglin variant associated with HCV-related liver fibrosis progression by next-generation sequencing

Frédégonde About1,  Stephanie Bibert2, Emmanuelle Jouanguy1, Bertrand Nalpas3, Lazaro Lorenzo1, Vimel Rattina1, Mohammed Zarhate1, 4,  Sylvain Hanein1, 4, Mona Munteanu5, Beat Muellhaupt6, David Semela7,  Nasser Semmo8, Jean-Laurent Casanova9, Ioannis Theodorou10, Philippe Sultanik11, Thierry Poynard12, Stanislas Pol11,  Pierre-Yves Bochud2,  Aurélie Cobat1* and  Laurent Abel1
  • 1INSERM U1163 Institut Imagine, France
  • 2Lausanne University Hospital (CHUV), Switzerland
  • 3Département d'Information Scientifique et de Communication (INSERM), France
  • 4INSERM U1163 Institut Imagine, France
  • 5Other, France
  • 6Department of Gastroenterology and Hepatology, University Hospital Zürich, Switzerland
  • 7Department of Gastroenterology and Hepatology, Cantonal Hospital St. Gallen, Switzerland
  • 8Department for Visceral Surgery and Medicine, Bern University Hospital, Switzerland
  • 9St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University, United States
  • 10INSERM U1135 Centre d'Immunologie et de Maladies Infectieuses, France
  • 11Département des Maladies du Foie, Hôpital Cochin, France
  • 12Service d’hépato Gastroentérologie, Hôpitaux Universitaires Pitié Salpêtrière, France

Despite the astonishing progress in treating chronic hepatitis C virus (HCV) infection with direct-acting antiviral agents, liver fibrosis remains a major health concern in HCV infected patients, in particular due to the treatment cost and insufficient HCV screening in many countries. Only a fraction of patients with chronic HCV infection develop liver fibrosis. While there is evidence that host genetic factors are involved in the development of liver fibrosis, the common variants identified so far, in particular by genome-wide association studies, were found to have limited effects. Here, we conducted an exome association study in 88 highly selected HCV-infected patients with and without fibrosis. A strategy focusing on TGF-β pathway genes revealed an enrichment in rare variants of the endoglin gene (ENG) in fibrosis patients. Replication studies in additional cohorts (617 patients) identified one specific ENG variant, Thr5Met, with an overall odds ratio for fibrosis development in carriers of 3.04 (1.39-6.69). Our results suggest that endoglin, a key player in TGF-β signaling, is involved in HCV-related liver fibrogenesis.

Keywords: Endoglin (CD105), HCV-related liver fibrosis, Exome Sequencing (ES), TGF-beta, rare-variant association study

Received: 13 Jun 2019; Accepted: 24 Sep 2019.

Copyright: © 2019 About, Bibert, Jouanguy, Nalpas, Lorenzo, Rattina, Zarhate, Hanein, Munteanu, Muellhaupt, Semela, Semmo, Casanova, Theodorou, Sultanik, Poynard, Pol, Bochud, Cobat and Abel. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Aurélie Cobat, INSERM U1163 Institut Imagine, Paris, France, aurelie.cobat@inserm.fr