Genome-Wide Association Study Identifies Variants Associated With Progression of Liver Fibrosis From HCV Infection
Etienne Patin
(1, 2)
,
Zoltán Kutalik
(3)
,
Julien Guergnon
(4)
,
Stéphanie Bibert
(5)
,
Bertrand Nalpas
(6)
,
Emmanuelle Jouanguy
(7)
,
Mona Munteanu
(8)
,
Laurence Bousquet
(9, 10)
,
Laurent Argiro
(11)
,
Philippe Halfon
(12)
,
Anne Boland
(13)
,
Beat Müllhaupt
(14)
,
David Semela
,
Jean-Francois Dufour
(15)
,
Markus H Heim
,
Darius Moradpour
(16)
,
Andreas Cerny
,
Raffaele Malinverni
,
Hans Hirsch
(17)
,
Gladys Martinetti
,
Vijayaprakash Suppiah
,
Graeme Stewart
,
David J Booth
(18)
,
Jacob George
,
Jean-Laurent Casanova
,
Christian Brechot
(19)
,
Charles M. Rice
(20)
,
Andrew H Talal
,
Ira M Jacobson
(21)
,
Marc Bourlière
(22)
,
Ioannis Théodorou
(23)
,
Thierry Poynard
(24)
,
Francesco Negro
,
Stanislas Pol
(10)
,
Pierre-Yves Bochud
,
Laurent Abel
1
Equipe Inserm U1163 -
Human genetics of infectious diseases: Complex predisposition
2 St. Giles Laboratory of Human Genetics of Infectious Diseases
3 Department of Medical Genetics
4 UPMC - Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie
5 Infectious Disease Service, Department of Internal Medicine
6 Service d'hépatologie médicale [CHU Cochin]
7 Inserm U980 - Génétique Humaine des Maladies Infectieuses
8 Biopredictive
9 UPD5 - Université Paris Descartes - Paris 5
10 IC UM3 (UMR 8104 / U1016) - Institut Cochin
11 GIMP - Génétique et immunologie des maladies parasitaires
12 Médecine générale
13 JACOB - Institut de Biologie François JACOB
14 University hospital of Zurich [Zurich]
15 University of Bern
16 Division of Gastroenterology and Hepatology
17 Institut für Medizinischediagnostik, Mikrobiologie
18 School of Life Sciences
19 Pathogénèse et traitement de l'hépatite fulminante et du cancer du foie
20 Rockefeller University [New York]
21 Weill Medical College of Cornell University [New York]
22 Service d'hépatologie et de gastroentérologie [Hôpital Saint-Joseph - Marseille]
23 Immunité et Infection
24 Service d'Hépato-Gastro-Entérologie [CHU Pitié-Salpêtrière]
2 St. Giles Laboratory of Human Genetics of Infectious Diseases
3 Department of Medical Genetics
4 UPMC - Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie
5 Infectious Disease Service, Department of Internal Medicine
6 Service d'hépatologie médicale [CHU Cochin]
7 Inserm U980 - Génétique Humaine des Maladies Infectieuses
8 Biopredictive
9 UPD5 - Université Paris Descartes - Paris 5
10 IC UM3 (UMR 8104 / U1016) - Institut Cochin
11 GIMP - Génétique et immunologie des maladies parasitaires
12 Médecine générale
13 JACOB - Institut de Biologie François JACOB
14 University hospital of Zurich [Zurich]
15 University of Bern
16 Division of Gastroenterology and Hepatology
17 Institut für Medizinischediagnostik, Mikrobiologie
18 School of Life Sciences
19 Pathogénèse et traitement de l'hépatite fulminante et du cancer du foie
20 Rockefeller University [New York]
21 Weill Medical College of Cornell University [New York]
22 Service d'hépatologie et de gastroentérologie [Hôpital Saint-Joseph - Marseille]
23 Immunité et Infection
24 Service d'Hépato-Gastro-Entérologie [CHU Pitié-Salpêtrière]
Etienne Patin
- Function : Author
- PersonId : 179015
- IdHAL : etienne-patin
- ORCID : 0000-0002-9911-4459
- IdRef : 132614553
Stéphanie Bibert
- Function : Author
- PersonId : 911123
Emmanuelle Jouanguy
- Function : Author
- PersonId : 756190
- ORCID : 0000-0002-7358-9157
- IdRef : 224367455
Anne Boland
- Function : Author
- PersonId : 757786
- ORCID : 0000-0001-8789-5676
David Semela
- Function : Author
Markus H Heim
- Function : Author
Andreas Cerny
- Function : Author
Raffaele Malinverni
- Function : Author
Gladys Martinetti
- Function : Author
Vijayaprakash Suppiah
- Function : Author
Graeme Stewart
- Function : Author
Jacob George
- Function : Author
- PersonId : 796850
- ORCID : 0000-0002-8421-5476
Jean-Laurent Casanova
- Function : Author
- PersonId : 756193
- ORCID : 0000-0002-7782-4169
- IdRef : 073388726
Andrew H Talal
- Function : Author
Thierry Poynard
- Function : Author
- PersonId : 881481
Francesco Negro
- Function : Author
Pierre-Yves Bochud
- Function : Author
Laurent Abel
- Function : Author
- PersonId : 929856
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 (Pcombined = 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 (Pcombined = 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.