Identification of an Endoglin Variant Associated With HCV-Related Liver Fibrosis Progression by Next-Generation Sequencing

Frédégonde About; Stéphanie Bibert; Emmanuelle Jouanguy; Bertrand Nalpas; Lazaro Lorenzo; Vimel Rattina; Mohammed Zarhrate; Sylvain Hanein; Mona Munteanu; Beat Müllhaupt; David Semela; Nasser Semmo; Jean-Laurent Casanova; Ioannis Theodorou; Philippe Sultanik; Thierry Poynard; Stanislas Pol; Pierre-Yves Bochud; Aurélie Cobat; Laurent Abel; Swiss Hepatitis C Cohort Study Group; French ANRS HC EP 26 Genoscan Study Group

doi:10.3389/fgene.2019.01024

Identification of an Endoglin Variant Associated With HCV-Related Liver Fibrosis Progression by Next-Generation Sequencing

Front Genet. 2019 Nov 4:10:1024. doi: 10.3389/fgene.2019.01024. eCollection 2019.

Authors

Frédégonde About^{1

2}, Stéphanie Bibert³, Emmanuelle Jouanguy^{1

2}, Bertrand Nalpas⁴, Lazaro Lorenzo^{1

2}, Vimel Rattina^{1

2}, Mohammed Zarhrate⁵, Sylvain Hanein^{2

6}, Mona Munteanu⁷, Beat Müllhaupt⁸, David Semela⁹, Nasser Semmo¹⁰, Jean-Laurent Casanova^{1

2

11

12

13}, Ioannis Theodorou¹⁴, Philippe Sultanik¹⁵, Thierry Poynard^{16

17}, Stanislas Pol¹⁵, Pierre-Yves Bochud³, Aurélie Cobat^{1

2}, Laurent Abel^{1

2

11}; Swiss Hepatitis C Cohort Study Group; French ANRS HC EP 26 Genoscan Study Group

Affiliations

¹ Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Inserm U1163, Paris, France.
² Paris Descartes University, Imagine Institute, Paris, France.
³ Infectious Diseases Service, University Hospital and University of Lausanne, Lausanne, Switzerland.
⁴ Inserm Scientific Information and Communication Department, Inserm, Paris, France.
⁵ Genomics Core Facility, Imagine Institute, Research Federative Structure Necker, Inserm U1163 and Inserm US24/CNRS UMS3633, Paris Descartes Sorbonne Paris Cite University, Paris, France.
⁶ Translational Genetics Platform, Inserm U1163, Imagine Institute, Paris Descartes University, Paris, France.
⁷ BioPredictive Research, Paris, France.
⁸ Gastroenterology and Hepatology Service, University Hospital of Zürich, Zürich, Switzerland.
⁹ Division of Gastroenterology and Hepatology, Kantonsspital Sankt Gallen, Sankt Gallen, Switzerland.
¹⁰ Department of Visceral Surgery and Medicine, Department of Hepatology, Inselspital Bern, Bern, Switzerland.
¹¹ St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, United States.
¹² Howard Hughes Medical Institute, New York, NY, United States.
¹³ Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, AP-HP, Paris, France.
¹⁴ Center for Immunology and Infectious Diseases, Inserm UMR S 1135, Pierre et Marie Curie University, Paris, France.
¹⁵ Université Paris Centre; U1223, Institut Pasteur; Liver Department, Hôpital Cochin, APHP; Paris, France.
¹⁶ Hepatology Department, Assistance Publique-Hôpitaux de Paris, Pitié-Salpétrière Hospital, Paris, France.
¹⁷ Saint-Antoine Research Center & Institute of Cardiometabolism and Nutrition (ICAN), Inserm, Sorbonne University, Paris, France.

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: HCV-related liver fibrosis; TGF-beta; endoglin; exome sequencing; rare-variant association study.

Copyright © 2019 About, Bibert, Jouanguy, Nalpas, Lorenzo, Rattina, Zarhrate, Hanein, Munteanu, Müllhaupt, Semela, Semmo, Casanova, Theodorou, Sultanik, Poynard, Pol, Bochud, Cobat, and Abel, The Swiss Hepatitis C Cohort Study Group and The French ANRS HC EP 26 Genoscan Study Group.