title: Characterization of serum proteins associated with IL28B genotype among patients with chronic hepatitis C.
abstract: BACKGROUND
  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.
authors.affiliation: Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Derek D
authors.initials: DD
authors.lastname: Cyr
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Lucas
authors.forename: J Will
authors.initials: JW
authors.lastname: Thompson
authors.forename: Keyur
authors.initials: K
authors.lastname: Patel
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Clark
authors.forename: Alexander
authors.initials: A
authors.lastname: Thompson
authors.forename: Hans L
authors.initials: HL
authors.lastname: Tillmann
authors.forename: John G
authors.initials: JG
authors.lastname: McHutchison
authors.forename: M Arthur
authors.initials: MA
authors.lastname: Moseley
authors.forename: Jeanette J
authors.initials: JJ
authors.lastname: McCarthy
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D001798:Blood Proteins / Q000032:analysis*; D002853:Chromatography, Liquid; D015331:Cohort Studies; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D019698:Hepatitis C, Chronic / Q000097:blood* / Q000235:genetics*; D006801:Humans; D007372:Interferons; D007378:Interleukins / Q000235:genetics*; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D040901:Proteomics / Q000379:methods; D014156:Transcortin / Q000032:analysis; D000095022:Interferon Lambda
chemical_list: D001798:Blood Proteins; D007372:Interferons; D007378:Interleukins; D014156:Transcortin; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C534935:SERPINA6 protein, human