Genetic variation in IL28B Is Associated with Chronic Hepatitis C and Treatment Failure - A Genome-Wide Association Study

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Gastroenterology. 2010 Jan 7. [Epub ahead of print]

Genetic variation in IL28B Is Associated with Chronic Hepatitis C and Treatment

Failure - A Genome-Wide Association Study.

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 JF, Furrer H,

Günthard HF, Heim M, Hirschel B, Malinverni R, Moradpour D, Müllhaupt B, Witteck

A, Beckmann JS, Berg T, Bergmann S, Negro F, Telenti A, Bochud PY; Swiss

Hepatitis C and HIV Cohort Studies.

University Clinic of Infectious Diseases, University Hospital Bern and

University of Bern, Switzerland.

BACKGROUND & AIMS:: The hepatitis C virus (HCV) induces chronic infection in

50%-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 that

spontaneously cleared the virus (448 were co-infected with HIV). Responses to

pegylated interferon-alpha 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 rs8099917minor allele was

associated with progression to chronic HCV infection (OR=2.31, 95% confidence

interval [CI]=1.74-3.06, P=6.07*10-9). The association was observed in HCV

mono-infected (OR=2.49, 95% CI=1.64-3.79, P=1.96*10-5) and HCV/HIV co-infected

individuals (OR=2.16, 95% CI=1.47-3.18, P=8.24*10-5). rs8099917 was also

associated with failure to respond to therapy (OR=5.19, 95% CI=2.90-9.30, P=

3.11*10-8), with the strongest effects in patients with HCV genotypes 1 or 4.

This risk allele was identified in 24% of individuals with spontaneous HCV

clearance, 32% of chronically infected patients that responded to therapy, and

58% that did not respond (P=3.2*10-10). Re-sequencing 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. AGA

Institute. Published by Elsevier Inc. All rights reserved.

PMID: 20060832 [PubMed - as supplied by publisher]