Frontiers in Genetics (Nov 2019)
Identification of an Endoglin Variant Associated With HCV-Related Liver Fibrosis Progression by Next-Generation Sequencing
- Frédégonde About,
- Frédégonde About,
- Stéphanie Bibert,
- Emmanuelle Jouanguy,
- Emmanuelle Jouanguy,
- Bertrand Nalpas,
- Lazaro Lorenzo,
- Lazaro Lorenzo,
- Vimel Rattina,
- Vimel Rattina,
- Mohammed Zarhrate,
- Sylvain Hanein,
- Sylvain Hanein,
- Mona Munteanu,
- Beat Müllhaupt,
- David Semela,
- Nasser Semmo,
- Jean-Laurent Casanova,
- Jean-Laurent Casanova,
- Jean-Laurent Casanova,
- Jean-Laurent Casanova,
- Jean-Laurent Casanova,
- Ioannis Theodorou,
- Philippe Sultanik,
- Thierry Poynard,
- Thierry Poynard,
- Stanislas Pol,
- Pierre-Yves Bochud,
- Aurélie Cobat,
- Aurélie Cobat,
- Laurent Abel,
- Laurent Abel,
- Laurent Abel,
- The Swiss Hepatitis C Cohort Study Group,
- The French ANRS HC EP 26 Genoscan Study Group,
- Francesco Negro,
- Antoine Hadengue,
- Laurent Kaiser,
- Laura Rubbia-Brandt,
- Darius Moradpour,
- Cristina Cellerai,
- Martin Rickenbach,
- Andreas Cerny,
- Gladys Martinetti,
- Jean-François Dufour,
- Meri Gorgievski,
- Virginie Masserey Spicher,
- Markus Heim,
- Hans Hirsch,
- Beat Helbling,
- Stephan Regenass,
- Raffaele Malinverni,
- Guenter Dollenmaier,
- Gieri Cathomas
Affiliations
- Frédégonde About
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Inserm U1163, Paris, France
- Frédégonde About
- Paris Descartes University, Imagine Institute, Paris, France
- Stéphanie Bibert
- Infectious Diseases Service, University Hospital and University of Lausanne, Lausanne, Switzerland
- Emmanuelle Jouanguy
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Inserm U1163, Paris, France
- Emmanuelle Jouanguy
- Paris Descartes University, Imagine Institute, Paris, France
- Bertrand Nalpas
- Inserm Scientific Information and Communication Department, Inserm, Paris, France
- Lazaro Lorenzo
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Inserm U1163, Paris, France
- Lazaro Lorenzo
- Paris Descartes University, Imagine Institute, Paris, France
- Vimel Rattina
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Inserm U1163, Paris, France
- Vimel Rattina
- Paris Descartes University, Imagine Institute, Paris, France
- Mohammed Zarhrate
- Genomics Core Facility, Imagine Institute, Research Federative Structure Necker, Inserm U1163 and Inserm US24/CNRS UMS3633, Paris Descartes Sorbonne Paris Cite University, Paris, France
- Sylvain Hanein
- Paris Descartes University, Imagine Institute, Paris, France
- Sylvain Hanein
- Translational Genetics Platform, Inserm U1163, Imagine Institute, Paris Descartes University, Paris, France
- Mona Munteanu
- BioPredictive Research, Paris, France
- Beat Müllhaupt
- Gastroenterology and Hepatology Service, University Hospital of Zürich, Zürich, Switzerland
- David Semela
- Division of Gastroenterology and Hepatology, Kantonsspital Sankt Gallen, Sankt Gallen, Switzerland
- Nasser Semmo
- 0Department of Visceral Surgery and Medicine, Department of Hepatology, Inselspital Bern, Bern, Switzerland
- Jean-Laurent Casanova
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Inserm U1163, Paris, France
- Jean-Laurent Casanova
- Paris Descartes University, Imagine Institute, Paris, France
- Jean-Laurent Casanova
- 1St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, United States
- Jean-Laurent Casanova
- 2Howard Hughes Medical Institute, New York, NY, United States
- Jean-Laurent Casanova
- 3Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, AP-HP, Paris, France
- Ioannis Theodorou
- 4Center for Immunology and Infectious Diseases, Inserm UMR S 1135, Pierre et Marie Curie University, Paris, France
- Philippe Sultanik
- 5Université Paris Centre; U1223, Institut Pasteur; Liver Department, Hôpital Cochin, APHP; Paris, France
- Thierry Poynard
- 6Hepatology Department, Assistance Publique-Hôpitaux de Paris, Pitié-Salpétrière Hospital, Paris, France
- Thierry Poynard
- 7Saint-Antoine Research Center & Institute of Cardiometabolism and Nutrition (ICAN), Inserm, Sorbonne University, Paris, France
- Stanislas Pol
- 5Université Paris Centre; U1223, Institut Pasteur; Liver Department, Hôpital Cochin, APHP; Paris, France
- Pierre-Yves Bochud
- Infectious Diseases Service, University Hospital and University of Lausanne, Lausanne, Switzerland
- Aurélie Cobat
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Inserm U1163, Paris, France
- Aurélie Cobat
- Paris Descartes University, Imagine Institute, Paris, France
- Laurent Abel
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Inserm U1163, Paris, France
- Laurent Abel
- Paris Descartes University, Imagine Institute, Paris, France
- Laurent Abel
- 1St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, United States
- The Swiss Hepatitis C Cohort Study Group
- The French ANRS HC EP 26 Genoscan Study Group
- Francesco Negro
- Antoine Hadengue
- Laurent Kaiser
- Laura Rubbia-Brandt
- Darius Moradpour
- Cristina Cellerai
- Martin Rickenbach
- Andreas Cerny
- Gladys Martinetti
- Jean-François Dufour
- Meri Gorgievski
- Virginie Masserey Spicher
- Markus Heim
- Hans Hirsch
- Beat Helbling
- Stephan Regenass
- Raffaele Malinverni
- Guenter Dollenmaier
- Gieri Cathomas
- DOI
- https://doi.org/10.3389/fgene.2019.01024
- Journal volume & issue
-
Vol. 10
Abstract
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
