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Characterization of serum proteins associated with IL28B genotype among patients with chronic hepatitis C.

ABSTRACT: INTRODUCTION:Polymorphisms near the IL28B gene (e.g. rs12979860) encoding interferon ?3 have recently been associated with both spontaneous clearance and treatment response to pegIFN/RBV in chronic hepatitis C (CHC) patients. The molecular consequences of this genetic variation are unknown. To gain further insight into IL28B function we assessed the association of rs12979860 with expression of protein quantitative traits (pQTL analysis) generated using open-platform proteomics in serum from patients. METHODS:41 patients with genotype 1 chronic hepatitis C infection from the Duke Liver Clinic were genotyped for rs12979860. Proteomic profiles were generated by LC-MS/MS analysis following immunodepletion of serum with MARS14 columns and trypsin-digestion. Next, a latent factor model was used to classify peptides into metaproteins based on co-expression and using only those peptides with protein identifications. Metaproteins were then analyzed for association with IL28B genotype using one-way analysis of variance. RESULTS:There were a total of 4,186 peptides in the data set with positive identifications. These were matched with 253 proteins of which 110 had two or more associated, identified peptides. The IL28B treatment response genotype (rs12979860_CC) was significantly associated with lower serum levels of corticosteroid binding globulin (CBG; p?=?9.2×10(-6)), a major transport protein for glucocorticoids and progestins. Moreover, the CBG metaprotein was associated with treatment response (p?=?0.0148), but this association was attenuated when both IL28B genotype and CBG were included in the model, suggesting that the CBG association may be independent of treatment response. CONCLUSIONS:In this cohort of chronic hepatitis C patients, IL28B polymorphism was associated with serum levels of corticosteroid binding globulin, a major transporter of cortisol, however, CBG does not appear to mediate the association of IL28B with treatment response. Further investigation of this pathway is warranted to determine if it plays a role in other comorbidities of HCV-infection.

SUBMITTER: Cyr DD

PROVIDER: S-EPMC3130042 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Characterization of serum proteins associated with IL28B genotype among patients with chronic hepatitis C.

Cyr Derek D DD Lucas Joseph E JE Thompson J Will JW Patel Keyur K Clark Paul J PJ Thompson Alexander A Tillmann Hans L HL McHutchison John G JG Moseley M Arthur MA McCarthy Jeanette J JJ

PloS one 20110705 7

<h4>Introduction</h4>Polymorphisms near the IL28B gene (e.g. rs12979860) encoding interferon λ3 have recently been associated with both spontaneous clearance and treatment response to pegIFN/RBV in chronic hepatitis C (CHC) patients. The molecular consequences of this genetic variation are unknown. To gain further insight into IL28B function we assessed the association of rs12979860 with expression of protein quantitative traits (pQTL analysis) generated using open-platform proteomics in serum f ...[more]

PMID: 21750736

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Project description:UNLABELLED:Genetic variation in the IL28B (interleukin 28B; interferon lambda 3) region has been associated with sustained virological response (SVR) rates in patients with chronic hepatitis C (CHC) who were treated with peginterferon-? and ribavirin. We hypothesized that IL28B polymorphism is associated with intrahepatic expression of interferon-stimulated genes (ISGs), known to influence treatment outcome. IL28B genotyping (rs12979860) and whole-genome RNA expression were performed using liver biopsies from 61 North American patients with CHC. After correction for multiple testing (false discovery rate < 0.10), 164 transcripts were found to be differentially expressed by IL28B-type. The interferon signaling pathway was the most enriched canonical pathway differentially expressed by IL28B-type (P < 10(-5)), with most genes showing higher expression in livers of individuals carrying the poor-response IL28B-type. In 25 patients for which treatment response data were available, IL28B-type was associated with SVR (P = 0.0054). ISG expression was also associated with SVR; however, this was not independent of IL28B-type. Analysis of miR-122 expression in liver biopsies showed reduced miR-122 levels associated with poorer treatment outcome, independently of IL28B-type. No association was observed between IL28B-type and levels of liver IL28B or IL28A messenger RNA expression. IL28B protein sequence variants associated with rs12979860 were therefore investigated in vitro: no differences in ISG induction or inhibition of HCV replication were observed in Huh7.5 cells. CONCLUSION:The good response IL28B variant was strongly associated with lower level ISG expression. The results suggest that IL28B genotype may explain the relationship between hepatic ISG expression and HCV treatment outcome, and this is independent of miR-122 expression. IL28B-type was not associated with intrahepatic IL28B messenger RNA expression in vivo. Further investigation of the precise molecular mechanism(s) by which IL28B genetic variation influences HCV outcomes is warranted.

Dataset Information

Characterization of serum proteins associated with IL28B genotype among patients with chronic hepatitis C.

Publications

Characterization of serum proteins associated with IL28B genotype among patients with chronic hepatitis C.

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