Rauch, A; Kutalik, Z; Descombes, P; Cai, T; Di Iulio, J; Mueller, T; Bochud, M; Battegay, M; Bernasconi, E; Borovicka, J; Colombo, S; Cerny, A; Dufour, J F; Furrer, H; Günthard, H F; Heim, M; Hirschel, B; Malinverni, R; Moradpour, D; Müllhaupt, B; Witteck, A; Beckmann, J S; Berg, T; Bergmann, S; Negro, F; Telenti, A; Bochud, P Y (2010). Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure: a genome-wide association study. Gastroenterology, 138(4):1338-1338-1345.e7 .
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BACKGROUND & AIMS: 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.
2010 AGA Institute. Published by Elsevier Inc. All rights reserved.
|Contributors:||Swiss Hepatitis C Cohort Study, Swiss HIV Cohort Study|
|Item Type:||Journal Article, refereed, original work|
|Communities & Collections:||04 Faculty of Medicine > University Hospital Zurich > Clinic for Infectious Diseases|
|DDC:||610 Medicine & health|
|Deposited On:||16 Jan 2011 17:45|
|Last Modified:||27 Nov 2013 22:10|
|Citations:||Web of Science®. Times Cited: 491|
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