Genome-wide association study to characterize serum bilirubin elevations in patients with HCV treated with GS-9256, an HCV NS3 serine protease inhibitor

David Nelson, Eric M. Yoshida, Matthew S. Paulson, Paul N. Hengen, Dongliang Ge, Bittoo Kanwar, John McNally, Phillip S. Pang, G. Mani Subramanian, John G. McHutchison, Petr Urbanek, Eric Lawitz, Thomas J. Urban

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)679-686
Number of pages8
JournalAntiviral Therapy
Volume19
Issue number7
DOIs
StatePublished - 2014
Externally publishedYes

Fingerprint

Serine Proteinase Inhibitors
Genome-Wide Association Study
Bilirubin
Serum
GS-9256
Quantitative Trait Loci
Serine Proteases
Protease Inhibitors
Genetic Markers
Gene Frequency
Single Nucleotide Polymorphism
Genotype
Genome
Therapeutics

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases
  • Medicine(all)

Cite this

Genome-wide association study to characterize serum bilirubin elevations in patients with HCV treated with GS-9256, an HCV NS3 serine protease inhibitor. / Nelson, David; Yoshida, Eric M.; Paulson, Matthew S.; Hengen, Paul N.; Ge, Dongliang; Kanwar, Bittoo; McNally, John; Pang, Phillip S.; Subramanian, G. Mani; McHutchison, John G.; Urbanek, Petr; Lawitz, Eric; Urban, Thomas J.

In: Antiviral Therapy, Vol. 19, No. 7, 2014, p. 679-686.

Research output: Contribution to journalArticle

Nelson, D, Yoshida, EM, Paulson, MS, Hengen, PN, Ge, D, Kanwar, B, McNally, J, Pang, PS, Subramanian, GM, McHutchison, JG, Urbanek, P, Lawitz, E & Urban, TJ 2014, 'Genome-wide association study to characterize serum bilirubin elevations in patients with HCV treated with GS-9256, an HCV NS3 serine protease inhibitor', Antiviral Therapy, vol. 19, no. 7, pp. 679-686. https://doi.org/10.3851/IMP2747
Nelson, David ; Yoshida, Eric M. ; Paulson, Matthew S. ; Hengen, Paul N. ; Ge, Dongliang ; Kanwar, Bittoo ; McNally, John ; Pang, Phillip S. ; Subramanian, G. Mani ; McHutchison, John G. ; Urbanek, Petr ; Lawitz, Eric ; Urban, Thomas J. / Genome-wide association study to characterize serum bilirubin elevations in patients with HCV treated with GS-9256, an HCV NS3 serine protease inhibitor. In: Antiviral Therapy. 2014 ; Vol. 19, No. 7. pp. 679-686.
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T1 - Genome-wide association study to characterize serum bilirubin elevations in patients with HCV treated with GS-9256, an HCV NS3 serine protease inhibitor

AU - Nelson, David

AU - Yoshida, Eric M.

AU - Paulson, Matthew S.

AU - Hengen, Paul N.

AU - Ge, Dongliang

AU - Kanwar, Bittoo

AU - McNally, John

AU - Pang, Phillip S.

AU - Subramanian, G. Mani

AU - McHutchison, John G.

AU - Urbanek, Petr

AU - Lawitz, Eric

AU - Urban, Thomas J.

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N2 - 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.

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