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 Urbánek; Eric Lawitz; Thomas J Urban

doi:10.3851/imp2747

journal article Oct 01, 2013

Genome-Wide Association Study to Characterize Serum Bilirubin Elevations in Patients with HCV Treated with Gs-9256, An HCV Ns3 Serine Protease Inhibitor

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 Urbánek Eric Lawitz Thomas J Urban

Antiviral Therapy Vol. 19 No. 7 pp. 679-686 · SAGE Publications

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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.

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References

28

[1]

10.1053/j.gastro.2011.08.051

[2]

Yang J., Yang C., Mathias A. In vitro inhibition of hepatic bilirubin transporters by the HCV NS3 protease inhibitor GS-9451 and in vivo correlation in healthy subjects. 47th Annual Meeting of the European Association for the Study of the Liver. 18–22 April 2012, Barcelona, Spain. Abstract 1216. 10.1016/s0168-8278(12)61228-8

[3]

Huisman M.T., Snoeys J., Monbaliu J., Martens M., Sekar V., Raoof A. In vitro studies investigating the mechanism of interaction between TMC435 and hepatic transporters. 61st Annual Meeting of the American Association for the Study of Liver Diseases. 29 October–2 November 2010, Boston, MA, USA. Abstract 278.

[4]

10.1016/j.cbi.2004.08.008

[5]

Guidance for Industry. Drug-Induced Liver Injury: Premarketing Clinical Evaluation. Department of Health and Human Services. (Updated July 2009. Accessed 26 February 2013.) Available from http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM174090.pdf.

[6]

10.1038/nature08825

[7]

10.1038/ejhg.2011.206

[8]

10.1093/hmg/ddp202

[9]

10.1093/hmg/ddp203

[10]

10.2133/dmpk.dmpk-11-rv-099

[11]

10.1124/dmd.104.001909

[12]

10.1007/s00280-008-0864-x

[13]

10.1016/j.ctrv.2008.05.002

[14]

10.1002/hep.24744

[15]

Tong L., Mwangi J., Roy A. In vitro studies on the potential for the hepatitis C virus protease inhibitors GS-9256 and GS-9451 to affect bilirubin elimination. 46th Annual Meeting of the European Association for the Study of the Liver. 30 March–3 April 2011, Berlin, Germany. Abstract 1232. 10.1016/s0168-8278(11)61234-8

[16]

Sane R., Podila L., Mathur K. Mechanisms of isolated unconjugated hyperbilirubinemia induced by the HCV NS3/4A protease inhibitor BI201335. 46th Annual Meeting of the European Association for the Study of the Liver. 30 March–3 April 2011, Berlin, Germany. Abstract 1236. 10.1016/s0168-8278(11)61238-5

[17]

Nelson D.R., Lawitz E., Bain V. High SVR12 with 16 weeks of tegobuvir and GS-9256 with peginterferon-alfa 2a and ribavirin in treatment-naive genotype 1 HCV patients. 47th Annual Meeting of the European Association for the Study of the Liver. 18–22 April 2012, Barcelona, Spain. Abstract 12. 10.1016/s0168-8278(12)60026-9

[18]

PLINK: A Tool Set for Whole-Genome Association and Population-Based Linkage Analyses

Shaun Purcell, Benjamin Neale, Kathe Todd-Brown et al.

The American Journal of Human Genetics 10.1086/519795

[19]

10.1093/bioinformatics/bth457

[20]

10.1038/nrg2344

[21]

Principal components analysis corrects for stratification in genome-wide association studies

Alkes L Price, Nick J Patterson, Robert M Plenge et al.

Nature Genetics 10.1038/ng1847

[22]

10.1002/hep.26276

[23]

Fried M., Poordad F., Zeuzem S. Safety and tolerability of TMC435 in combination with peginterferon alpha-2a and ribavirin for treatment of HCV genotype 1 infection in treatment-naive and -experienced patients (PILLAR and ASPIRE trials). 63rd Annual Meeting of the American Association for the Study of Liver Diseases. 9–13 November 2012, Boston, MA, USA. Abstract 769.

[24]

Poordad F., Fried M., Zeuzem S. Efficacy and tolerability of TMC435 150 mg once daily with peginterferon alpha-2a and ribavirin for treatment of HCV genotype 1 infection in patients with Metavir score F3 and F4 (PILLAR and ASPIRE trials). 63rd Annual Meeting of the American Association for the Study of Liver Diseases. 9–13 November 2012, Boston, MA, USA. Abstract 83.

[25]

10.1074/jbc.m103792200

[26]

10.1097/01.fpc.0000170913.73780.5f

[27]

10.1056/nejmoa0801936

[28]

10.1038/nature08309

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References

Details

Published: Oct 01, 2013
Vol/Issue: 19(7)
Pages: 679-686
License: View

Authors

D

David Nelson

Department of Medicine, University of Florida, Gainesville, FL, USA

E

Eric M Yoshida

Department of Medicine, University of British Columbia, Vancouver, BC, Canada

M

Matthew S Paulson