Genome-wide association study of interferon-related cytopenia in chronic hepatitis C patients

Thompson, Alexander J.; Clark, Paul J.; Singh, Abanish; Ge, Dongliang; Fellay, Jacques; Zhu, Mingfu; Zhu, Qianqian; Urban, Thomas J.; Patel, Keyur; Tillmann, Hans L.; Naggie, Susanna; Afdhal, Nezam H.; Jacobson, Ira M.; Esteban, Rafael; Poordad, Fred; Lawitz, Eric J.; McCone, Jonathan; Shiffman, Mitchell L.; Galler, Greg W.; King, John W.; Kwo, Paul Y.; Shianna, Kevin V.; Noviello, Stephanie; Pedicone, Lisa D.; Brass, Clifford A.; Albrecht, Janice K.; Sulkowski, Mark S.; Goldstein, David B.; McHutchison, John G.; Muir, Andrew J.

doi:10.1016/j.jhep.2011.04.021

« Previous Next »Journal of Hepatology
Volume 56, Issue 2 , Pages 313-319, February 2012

Genome-wide association study of interferon-related cytopenia in chronic hepatitis C patients

Alexander J. Thompson
- Duke Clinical Research Institute, Duke University Medical Center, Durham, NC, USA
- These authors contributed equally to the work.
Paul J. Clark
- Duke Clinical Research Institute, Duke University Medical Center, Durham, NC, USA
- These authors contributed equally to the work.
Abanish Singh
- Center for Human Genome Variation, Duke University, Durham, NC, USA
- These authors contributed equally to the work.
Dongliang Ge
- Center for Human Genome Variation, Duke University, Durham, NC, USA
- These authors contributed equally to the work.
Jacques Fellay
- Center for Human Genome Variation, Duke University, Durham, NC, USA
Mingfu Zhu
- Center for Human Genome Variation, Duke University, Durham, NC, USA
Qianqian Zhu
- Center for Human Genome Variation, Duke University, Durham, NC, USA
Thomas J. Urban
- Center for Human Genome Variation, Duke University, Durham, NC, USA
Keyur Patel
- Duke Clinical Research Institute, Duke University Medical Center, Durham, NC, USA
Hans L. Tillmann
- Duke Clinical Research Institute, Duke University Medical Center, Durham, NC, USA
Susanna Naggie
- Duke Clinical Research Institute, Duke University Medical Center, Durham, NC, USA
Nezam H. Afdhal
- Beth Israel Deaconess Medical Centre, Boston, MA, USA
Ira M. Jacobson
- Weill Cornell Medical College, New York, NY, USA
Rafael Esteban
- Hospital General Universitario Valle de Hebron, CIBERehd del Instituto Carlos III, Barcelona, Spain
Fred Poordad
- Cedars-Sinai Medical Center, Los Angeles, CA, USA
Eric J. Lawitz
- Alamo Medical Research, San Antonio, TX, USA
Jonathan McCone
- Mt. Vernon Endoscopy Center, Alexandria, VA, USA
Mitchell L. Shiffman
- Liver Institute of Virginia, Newport News, VA, USA
Greg W. Galler
- Kelsey Research Foundation, Houston, TX, USA
John W. King
- Louisiana State University, Shreveport, LA, USA
Paul Y. Kwo
- Indiana University School of Medicine, Indianapolis, IN, USA
Kevin V. Shianna
- Center for Human Genome Variation, Duke University, Durham, NC, USA
Stephanie Noviello
- Schering-Plough Research Institute (now Merck, Inc.), USA
Lisa D. Pedicone
- Schering-Plough Research Institute (now Merck, Inc.), USA
Clifford A. Brass
- Schering-Plough Research Institute (now Merck, Inc.), USA
Janice K. Albrecht
- Schering-Plough Research Institute (now Merck, Inc.), USA
Mark S. Sulkowski
- Johns Hopkins University School of Medicine, Baltimore, MD, USA
David B. Goldstein
- Center for Human Genome Variation, Duke University, Durham, NC, USA
John G. McHutchison
- Duke Clinical Research Institute, Duke University Medical Center, Durham, NC, USA
Andrew J. Muir
- Duke Clinical Research Institute, Duke University Medical Center, Durham, NC, USA
- Corresponding author. Address: Duke Clinical Research Institute, Duke University Medical Center, 2400 Pratt Street, Terrace Level, Room 0311, Durham, NC 27701, USA. Tel.: +1 919 668 8557; fax: +1 919 668 7164.

Received 10 January 2011; received in revised form 10 March 2011; accepted 8 April 2011. published online 23 May 2011.

Background & Aims

Interferon-alfa (IFN)-related cytopenias are common and may be dose-limiting. We performed a genome wide association study on a well-characterized genotype 1 HCV cohort to identify genetic determinants of peginterferon-α (pegIFN)-related thrombocytopenia, neutropenia, and leukopenia.

Methods

1604/3070 patients in the IDEAL study consented to genetic testing. Trial inclusion criteria included a platelet (Pl) count ⩾80×10⁹/L and an absolute neutrophil count (ANC) ⩾1500/mm³. Samples were genotyped using the Illumina Human610-quad BeadChip. The primary analyses focused on the genetic determinants of quantitative change in cell counts (Pl, ANC, lymphocytes, monocytes, eosinophils, and basophils) at week 4 in patients >80% adherent to therapy (n=1294).

Results

6 SNPs on chromosome 20 were positively associated with Pl reduction (top SNP rs965469, p=10⁻¹⁰). These tag SNPs are in high linkage disequilibrium with 2 functional variants in the ITPA gene, rs1127354 and rs7270101, that cause ITPase deficiency and protect against ribavirin (RBV)-induced hemolytic anemia (HA). rs1127354 and rs7270101 showed strong independent associations with Pl reduction (p=10⁻¹², p=10⁻⁷) and entirely explained the genome-wide significant associations. We believe this is an example of an indirect genetic association due to a reactive thrombocytosis to RBV-induced anemia: Hb decline was inversely correlated with Pl reduction (r=−0.28, p=10⁻¹⁷) and Hb change largely attenuated the association between the ITPA variants and Pl reduction in regression models. No common genetic variants were associated with pegIFN-induced neutropenia or leucopenia.

Conclusions

Two ITPA variants were associated with thrombocytopenia; this was largely explained by a thrombocytotic response to RBV-induced HA attenuating IFN-related thrombocytopenia. No genetic determinants of pegIFN-induced neutropenia were identified.

Abbreviations: HCV, hepatitis C virus, pegIFN, pegylated-interferon-alfa, RBV, ribavirin, DARC, Duffy Antigen Receptor for Chemokines, IL28B, Iinterleukin 28B, ITPA, inosine triphosphatase gene, ITPase, inosine triphosphatase, ANC, absolute neutrophil count, Pl, platelet, Hb, hemoglobin, SNP, single nucleotide polymorphism, GWAS, genome-wide association study, BMI, body mass index, HA, hemolytic anemia, IFNLR, IFN-λ-receptor, IFNABR, IFN-α-receptor