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

Abstract

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 ≥80×10(9)/L and an absolute neutrophil count (ANC) ≥1500/mm(3). 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.

• Authors: Alexander J Thompson, Paul J Clark, Abanish Singh, Dongliang Ge, Jacques Fellay, Mingfu Zhu, Qianqian Zhu, Thomas J Urban, Keyur Patel, Hans L Tillmann, Susanna Naggie, Nezam H Afdhal, Ira M Jacobson, Rafael Esteban, Fred Poordad, Eric J Lawitz, Jonathan McCone, Mitchell L Shiffman, Greg W Galler, John W King, Paul Y Kwo, Kevin V Shianna, Stephanie Noviello, Lisa D Pedicone, Clifford A Brass, Janice K Albrecht, Mark S Sulkowski, David B Goldstein, John G McHutchison, Andrew J Muir
• Journal: Journal of hepatology (J Hepatol) Vol. 56 Issue 2 Pg. 313-9 (Feb 2012) ISSN: 1600-0641 [Electronic] Netherlands
• PMID: 21703177 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Chemical References

• Antiviral Agents
• Interferon alpha-2
• Interferon-alpha
• Recombinant Proteins
• Polyethylene Glycols
• Ribavirin
• Pyrophosphatases
• ITPA protein, human
• peginterferon alfa-2b
• peginterferon alfa-2a

Topics

• Adult
• Antiviral Agents (adverse effects)
• Female
• Genome-Wide Association Study
• Hepatitis C, Chronic (drug therapy, genetics)
• Humans
• Interferon alpha-2
• Interferon-alpha (adverse effects)
• Leukopenia (chemically induced, genetics)
• Linkage Disequilibrium
• Male
• Middle Aged
• Neutropenia (chemically induced, genetics)
• Polyethylene Glycols (adverse effects)
• Polymorphism, Single Nucleotide
• Pyrophosphatases (genetics)
• Recombinant Proteins (adverse effects)
• Ribavirin (adverse effects)
• Thrombocytopenia (chemically induced, genetics)