Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure: a genome-wide association study.
OBJECTIVE
Hepatitis C virus (HCV) induces chronic infection in 50% to 80% of infected persons; approximately 50% of these do not respond to therapy. We performed a genome-wide association study to screen for host genetic determinants of HCV persistence and response to therapy.


METHODS
The analysis included 1362 individuals: 1015 with chronic hepatitis C and 347 who spontaneously cleared the virus (448 were coinfected with human immunodeficiency virus [HIV]). Responses to pegylated interferon alfa and ribavirin were assessed in 465 individuals. Associations between more than 500,000 single nucleotide polymorphisms (SNPs) and outcomes were assessed by multivariate logistic regression.


RESULTS
Chronic hepatitis C was associated with SNPs in the IL28B locus, which encodes the antiviral cytokine interferon lambda. The rs8099917 minor allele was associated with progression to chronic HCV infection (odds ratio [OR], 2.31; 95% confidence interval [CI], 1.74-3.06; P = 6.07 x 10(-9)). The association was observed in HCV mono-infected (OR, 2.49; 95% CI, 1.64-3.79; P = 1.96 x 10(-5)) and HCV/HIV coinfected individuals (OR, 2.16; 95% CI, 1.47-3.18; P = 8.24 x 10(-5)). rs8099917 was also associated with failure to respond to therapy (OR, 5.19; 95% CI, 2.90-9.30; P = 3.11 x 10(-8)), with the strongest effects in patients with HCV genotype 1 or 4. This risk allele was identified in 24% of individuals with spontaneous HCV clearance, 32% of chronically infected patients who responded to therapy, and 58% who did not respond (P = 3.2 x 10(-10)). Resequencing of IL28B identified distinct haplotypes that were associated with the clinical phenotype.


CONCLUSIONS
The association of the IL28B locus with natural and treatment-associated control of HCV indicates the importance of innate immunity and interferon lambda in the pathogenesis of HCV infection.
Rauch
Andri
A
University Clinic of Infectious Diseases, University Hospital Bern and University of Bern, Bern, Switzerland. andri.rauch@insel.ch
Kutalik
Zoltán
Z
Descombes
Patrick
P
Cai
Tao
T
Di Iulio
Julia
J
Mueller
Tobias
T
Bochud
Murielle
M
Battegay
Manuel
M
Bernasconi
Enos
E
Borovicka
Jan
J
Colombo
Sara
S
Cerny
Andreas
A
Dufour
Jean-François
JF
Furrer
Hansjakob
H
Günthard
Huldrych F
HF
Heim
Markus
M
Hirschel
Bernard
B
Malinverni
Raffaele
R
Moradpour
Darius
D
Müllhaupt
Beat
B
Witteck
Andrea
A
Beckmann
Jacques S
JS
Berg
Thomas
T
Bergmann
Sven
S
Negro
Francesco
F
Telenti
Amalio
A
Bochud
Pierre-Yves
PY
D000328:Adult; D000368:Aged; D005260:Female; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006239:Haplotypes; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000235:genetics*; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage; D007372:Interferons; D007378:Interleukins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000008:administration & dosage; D020641:Polymorphism, Single Nucleotide; D011994:Recombinant Proteins; D012254:Ribavirin / Q000008:administration & dosage; D017211:Treatment Failure; D000095022:Interferon Lambda
D000077190:Interferon alpha-2; D016898:Interferon-alpha; D007372:Interferons; D007378:Interleukins; D011092:Polyethylene Glycols; D011994:Recombinant Proteins; D012254:Ribavirin; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C417083:peginterferon alfa-2b