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Gastroenterology. 2012 Nov;143(5):1244-1252.e12. doi: 10.1053/j.gastro.2012.07.097. Epub 2012 Jul 27.

Genome-wide association study identifies variants associated with progression of liver fibrosis from HCV infection.

Author information

1
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Necker Medical School, INSERM Unité 980, Paris, France; University Paris Descartes, Paris, France.
2
Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland; Swiss Institute of Bioinformatics, Lausanne, Switzerland.
3
Laboratory of Immunity and Infection, INSERM UMR-S 945, UPMC Université Paris 6, Groupe Hospitalier Pitié-Salpêtrière AP-HP, Paris, France.
4
Infectious Diseases Service, Department of Medicine, University Hospital and University of Lausanne, Lausanne, Switzerland.
5
University Paris Descartes, Paris, France; Département d'Hépatologie, INSERM Unité 1016, Groupe Hospitalier Cochin-Hôtel Dieu-Broca, Paris, France.
6
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Necker Medical School, INSERM Unité 980, Paris, France; University Paris Descartes, Paris, France; St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, New York.
7
Biopredictive, Paris, France.
8
Laboratoire d'Immunologie et de Génétique des Maladies Parasitaires, INSERM-UMR 906/Université de la Méditerranée, Marseilles, France.
9
Laboratoire Alphabio, Hôpital Ambroise Paré, Marseilles, France.
10
CEA, Institut de Génomique, Centre National de Génotypage, Evry, France.
11
Division of Gastroenterology and Hepatology, University Hospital, Zurich, Switzerland.
12
Division of Gastroenterology, Canton Hospital, St Gallen, Switzerland.
13
Hepatology, Department of Clinical Research, University Clinic for Visceral Surgery and Medicine, Bern, Switzerland.
14
Division of Gastroenterology and Hepatology, University Hospital, Basel, Switzerland.
15
Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland.
16
Clinica Moncucco, Lugano, Switzerland.
17
Pourtalès Hospital, Neuchâtel, Switzerland.
18
Institute for Medical Microbiology, University Hospital, Basel, Switzerland.
19
Institute of Medical Microbiology, Bellinzona, Switzerland.
20
Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney and University of Sydney Medical Foundation, Sydney, Australia; INSERM Unité 785, Liver Hepatology Centre, Paul Brousse Hospital, University Paris-XI, Villejuif, France.
21
Institute for Immunology and Allergy Research, Westmead Millennium Institute, University of Sydney, Sydney, Australia.
22
Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney and University of Sydney Medical Foundation, Sydney, Australia.
23
INSERM Unité 785, Liver Hepatology Centre, Paul Brousse Hospital, University Paris-XI, Villejuif, France.
24
Center for the Study of Hepatitis C, Rockefeller University, New York, New York.
25
Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, New York.
26
Service d'Hépato-gastroentérologie, Hôpital Saint-Joseph, Marseilles, France.
27
Université Pierre et Marie Curie, Service d'Hépato-gastroentérologie, Hôpital Pitié-Salpêtrière (AP-HP), Paris, France.
28
Divisions of Gastroenterology and Hepatology and of Clinical Pathology, University Hospital, Geneva, Switzerland.
29
Infectious Diseases Service, Department of Medicine, University Hospital and University of Lausanne, Lausanne, Switzerland. Electronic address: pierre-yves.bochud@chuv.ch.
30
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Necker Medical School, INSERM Unité 980, Paris, France; University Paris Descartes, Paris, France; St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, New York. Electronic address: laurent.abel@inserm.fr.

Abstract

BACKGROUND & AIMS:

Polymorphisms in IL28B were shown to affect clearance of hepatitis C virus (HCV) infection in genome-wide association (GWA) studies. Only a fraction of patients with chronic HCV infection develop liver fibrosis, a process that might also be affected by genetic factors. We performed a 2-stage GWA study of liver fibrosis progression related to HCV infection.

METHODS:

We studied well-characterized HCV-infected patients of European descent who underwent liver biopsies before treatment. We defined various liver fibrosis phenotypes on the basis of METAVIR scores, with and without taking the duration of HCV infection into account. Our GWA analyses were conducted on a filtered primary cohort of 1161 patients using 780,650 single nucleotide polymorphisms (SNPs). We genotyped 96 SNPs with P values <5 × 10(-5) from an independent replication cohort of 962 patients. We then assessed the most interesting replicated SNPs using DNA samples collected from 219 patients who participated in separate GWA studies of HCV clearance.

RESULTS:

In the combined cohort of 2342 HCV-infected patients, the SNPs rs16851720 (in the total sample) and rs4374383 (in patients who received blood transfusions) were associated with fibrosis progression (P(combined) = 8.9 × 10(-9) and 1.1 × 10(-9), respectively). The SNP rs16851720 is located within RNF7, which encodes an antioxidant that protects against apoptosis. The SNP rs4374383, together with another replicated SNP, rs9380516 (P(combined) = 5.4 × 10(-7)), were linked to the functionally related genes MERTK and TULP1, which encode factors involved in phagocytosis of apoptotic cells by macrophages.

CONCLUSIONS:

Our GWA study identified several susceptibility loci for HCV-induced liver fibrosis; these were linked to genes that regulate apoptosis. Apoptotic control might therefore be involved in liver fibrosis.

PMID:
22841784
PMCID:
PMC3756935
DOI:
10.1053/j.gastro.2012.07.097
[Indexed for MEDLINE]
Free PMC Article

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