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, 6 (7), e21854

Characterization of Serum Proteins Associated With IL28B Genotype Among Patients With Chronic Hepatitis C

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Characterization of Serum Proteins Associated With IL28B Genotype Among Patients With Chronic Hepatitis C

Derek D Cyr et al. PLoS One.

Abstract

Introduction: 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 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.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Quantile-Quantile plot showing the distribution of observed P values for IL28B rs12979860 genotype association with 110 metaproteins among chronic HCV patients to the expected distribution of P values under the null hypothesis.
The red point denotes the CBG metaprotein.
Figure 2
Figure 2. Expression level of CBG metaprotein by IL28B rs12979860 genotype in 41 Chronic HCV patients.
Filled circles represent non-responders (NR) to interferon treatment and open circles are from subjects who achieved sustained virologic response (SVR) to treatment.
Figure 3
Figure 3. CBG metaprotein peptide composition.
Each gray bar is a representation of the labeled protein. Red sections represent polypeptides from isotope groups that are in the factor and black sections represent polypeptides from the isotope groups that are identified in the data set but are not in the factor. Gray represents sections of the protein that are not identified in the data set. % Coverage is the percent of identified peptides from that protein that are in the factor and % Signature is the percent of the factor that comes from the associated protein.

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