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Interferon γ receptor 2 gene variants are associated with liver fibrosis in patients with chronic hepatitis C infection
  1. Bertrand Nalpas1,
  2. Roubila Lavialle-Meziani2,
  3. Sabine Plancoulaine3,4,
  4. Emmanuelle Jouanguy3,5,
  5. Antoine Nalpas1,
  6. Mona Munteanu6,
  7. Frederic Charlotte6,
  8. Brigitte Ranque3,4,
  9. Etienne Patin3,4,
  10. Simon Heath2,
  11. Hélène Fontaine1,4,
  12. Anaïs Vallet-Pichard1,4,
  13. Dominique Pontoire7,
  14. Marc Bourlière8,
  15. Jean-Laurent Casanova3,4,9,10,
  16. Mark Lathrop2,
  17. Christian Bréchot11,
  18. Thierry Poynard6,
  19. Fumihiko Matsuda2,12,
  20. Stanislas Pol1,4,
  21. Laurent Abel3,4,9
  1. 1Unité d'Hépatologie, Institut National de la Santé et de la Recherche Médicale, U567, Hôpital Cochin, Paris, France
  2. 2Centre National de Génotypage, Evry, France
  3. 3Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale, U550, Necker Medical School, Paris, France
  4. 4Université Paris Descartes, Paris, France
  5. 5Center for the Study of Hepatitis C, The Rockefeller University, New York, USA
  6. 6Assistance Publique-Hôpitaux de Paris (AP-HP)/Université Pierre et Marie Curie (UPMC) Liver Center, Hôpital Pitié-Salpêtrière, Paris, France
  7. 7Banque de Cellules Cochin-APHP, Service de Biochimie et Génétique Moléculaire, Hôpital Cochin, Paris, France
  8. 8Department of Hepato-gastroenterology, Hôpital Saint Joseph, Marseille, France
  9. 9Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, USA
  10. 10Pediatric Hematology and Immunology Unit, Necker Children's Hospital, Paris, France
  11. 11Institut National de la Santé et de la Recherche Médicale, U785, Villejuif, France
  12. 12Unit of Human Disease Genomics, Institut National de la Santé et de la Recherche Médicale, Kyoto University, Kyoto, Japan
  1. Correspondence to Dr Laurent Abel, Laboratoire de Génétique Humaine des Maladies Infectieuses, Université Paris Descartes-INSERM U550, Faculté de Médecine Necker, 156 rue de Vaugirard, 75015 Paris, France; laurent.abel{at}inserm.fr

Abstract

Background Only a minority of patients with chronic hepatitis C virus (HCV) infection develops severe liver fibrosis, a process that may be controlled by human genetic factors.

Objective To investigate the role of 384 single nucleotide polymorphisms (SNPs) located in 36 candidate genes related to the fibrogenesis/fibrolysis process.

Methods Patients with chronic HCV infection were gathered from two French cohorts (prospectively and retrospectively). The overall sample consisted of 393 HCV-infected subjects without known risk factors for fibrosis progression, including 134 patients with severe liver fibrosis and 259 without severe fibrosis.

Results Only two SNPs in strong linkage disequilibrium (LD) in the interferon γ receptor 2 gene (IFNGR2) were significantly associated with liver fibrosis in both the prospective and the retrospective samples. The strongest association (p=8×10−5) was observed with the G/A SNP rs9976971 with an OR of severe fibrosis for AA versus AG or GG subjects at 2.95 (95% CI 1.70 to 5.11). This effect was higher (p=9×10−7) when taking into account the time of follow-up, and the hazard ratio of progression towards severe fibrosis for AA patients was 2.62 (1.76 to 3.91). Refined sequencing and analysis of the IFNGR2 region identified two additional variants in strong LD with rs9976971. No haplotypes derived from this cluster of four variants provided stronger evidence for association than rs9976971 alone.

Conclusions This identification of a cluster of four IFNGR2 variants strongly associated with fibrosis progression in chronic HCV infection underlines the role of IFNγ in the development of liver fibrosis that may pave the way for new treatments.

  • Genetic polymorphisms
  • hepatic fibrosis
  • hepatitis C
  • liver cirrhosis

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Footnotes

  • Funding This work was supported by grants from Institut National de la Santé et de la Recherche Médicale (4CH08G), Japanese Society for Promotion of Science (JSPS)/Inserm cooperation agreement, and Agence Nationale de Recherche sur le SIDA et les hépatites virales (ANRS HC EP13). LA was supported, in part, by a grant from Assistance Publique-Hôpitaux de Paris.

  • Competing interests None.

  • Ethics approval This study was conducted with the approval of the institutional review board (CPP: Comité de Protection des Personnes) of Ile de France - Paris - Saint Antoine, on 5 March 2002.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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