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Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure: a genome-wide association study

Rauch, Andri
Kutalik, Zoltan
Cai, Tao
Di Iulio, Julia
Battegay, Manuel
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Published in Gastroenterology. 2010, vol. 138, no. 4, p. 1338-1345, 1345 e1331-1337
Abstract 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.
Keywords AdultAgedFemaleGenetic VariationGenome-Wide Association StudyGenotypeHaplotypesHepatitis C, Chronic/drug therapy/ geneticsHumansInterferon Alfa-2b/administration & dosageInterleukins/ geneticsMaleMiddle AgedPolyethylene Glycols/administration & dosagePolymorphism, Single NucleotideRibavirin/administration & dosageTreatment Failure
PMID: 20060832
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RAUCH, Andri et al. Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure: a genome-wide association study. In: Gastroenterology, 2010, vol. 138, n° 4, p. 1338-1345, 1345 e1331-1337. doi: 10.1053/j.gastro.2009.12.056 https://archive-ouverte.unige.ch/unige:7534

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Deposited on : 2010-06-21

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