Interferon gamma receptor 2 gene variants are associated with liver fibrosis in patients with chronic hepatitis C infection.
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 gamma receptor 2 gene (IFNGR2) were significantly associated with liver fibrosis in both the prospective and the retrospective samples. The strongest association (p=8x10(-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=9x10(-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 IFNgamma in the development of liver fibrosis that may pave the way for new treatments.
Nalpas
Bertrand
B
Unité d'Hépatologie, Institut National de la Santé et de la Recherche Médicale, U567, Hôpital Cochin, Paris, France.
Lavialle-Meziani
Roubila
R
Plancoulaine
Sabine
S
Jouanguy
Emmanuelle
E
Nalpas
Antoine
A
Munteanu
Mona
M
Charlotte
Frederic
F
Ranque
Brigitte
B
Patin
Etienne
E
Heath
Simon
S
Fontaine
Hélène
H
Vallet-Pichard
Anaïs
A
Pontoire
Dominique
D
Bourlière
Marc
M
Casanova
Jean-Laurent
JL
Lathrop
Mark
M
Bréchot
Christian
C
Poynard
Thierry
T
Matsuda
Fumihiko
F
Pol
Stanislas
S
Abel
Laurent
L
D000328:Adult; D000368:Aged; D018450:Disease Progression; D004812:Epidemiologic Methods; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D019698:Hepatitis C, Chronic / Q000150:complications*; D006801:Humans; D015810:Linkage Disequilibrium; D008103:Liver Cirrhosis / Q000235:genetics* / Q000821:virology*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D017471:Receptors, Interferon / Q000235:genetics*; D055815:Young Adult
C086185:IFNGR2 protein, human; D017471:Receptors, Interferon