title: Genome-wide association study to characterize serum bilirubin elevations in patients with HCV treated with GS-9256, an HCV NS3 serine protease inhibitor.
abstract: BACKGROUND
  Protease inhibitors for the treatment of HCV can cause mild and reversible elevations of unconjugated bilirubin. We sought to characterize genetic determinants of bilirubin elevations using a genome-wide approach among patients with genotype 1 HCV who received combination therapy that included GS-9256, a novel potent inhibitor of HCV NS3 serine protease, as part of a Phase IIb trial.
  
  
  METHODS
  Of the 200 patients sampled, 176 had confirmed European ancestry and were included in the analysis. Infinium HumanOmni5BeadChip (Illumina, Inc., San Diego, CA, USA) was used for genotyping. A categorical analysis of low (grade 0-1) versus high (grade 2-4) bilirubin toxicity grade and a quantitative trait locus mapping of peak bilirubin concentrations was performed.
  
  
  RESULTS
  A total of 4,466,809 genetic markers were analysed. No single variant showed a statistically significant association with observed bilirubin elevations in this patient population. In a targeted analysis of single nucleotide polymorphisms in genes known to be involved in bilirubin transport, no significant differences in allele frequency between high and low bilirubin toxicity grade were observed.
  
  
  CONCLUSIONS
  These results indicate that risk for bilirubin elevation in patients receiving GS-9256 is unlikely to be strongly influenced by common genetic variants with large effects. The current study cannot rule out a role for common variants of weak effect, or a more complex model, including multiple contributing factors, such as rare variants and as yet unidentified environmental influences.
authors: Department of Medicine, University of Florida, Gainesville, FL, USA.
authors: David
authors: D
authors: Nelson
authors: Eric M
authors: EM
authors: Yoshida
authors: Matthew S
authors: MS
authors: Paulson
authors: Paul N
authors: PN
authors: Hengen
authors: Dongliang
authors: D
authors: Ge
authors: Bittoo
authors: B
authors: Kanwar
authors: John
authors: J
authors: McNally
authors: Phillip S
authors: PS
authors: Pang
authors: G Mani
authors: GM
authors: Subramanian
authors: John G
authors: JG
authors: McHutchison
authors: Petr
authors: P
authors: Urbanek
authors: Eric
authors: E
authors: Lawitz
authors: Thomas J
authors: TJ
authors: Urban
mesh_terms: D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001663:Bilirubin / Q000097:blood*; D019295:Computational Biology; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects / Q000378:metabolism*; D006526:Hepatitis C / Q000097:blood* / Q000188:drug therapy / Q000235:genetics*; D006801:Humans; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D027361:Organic Anion Transporters / Q000235:genetics; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics; D010456:Peptides, Cyclic / Q000494:pharmacology / Q000627:therapeutic use*; D010597:Pharmacogenetics; D010641:Phenotype; D010721:Phosphinic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D020641:Polymorphism, Single Nucleotide; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors; D055815:Young Adult; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D001663:Bilirubin; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; D010456:Peptides, Cyclic; D010721:Phosphinic Acids; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D017361:Viral Nonstructural Proteins; C571665:GS-9256; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C503999:SLCO1B1 protein, human; C421209:SLCO1B3 protein, human