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. and Muir, Andrew J. (2012) Genome-wide association study of interferon-related cytopenia in chronic hepatitis C patients. Journal of Hepatology, 56 2: 313-319. doi:10.1016/j.jhep.2011.04.021

Author 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.
Title Genome-wide association study of interferon-related cytopenia in chronic hepatitis C patients
Journal name Journal of Hepatology   Check publisher's open access policy
ISSN 0168-8278
Publication date 2012-02
Year available 2011
Sub-type Article (original research)
DOI 10.1016/j.jhep.2011.04.021
Open Access Status
Volume 56
Issue 2
Start page 313
End page 319
Total pages 7
Place of publication Amsterdam Netherlands
Publisher Elsevier BV
Language eng
Subject 2721 Hepatology
Formatted 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.

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).

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.

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.
Keyword GWAS
Hepatitis C
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Medicine Publications
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Citation counts: TR Web of Science Citation Count  Cited 26 times in Thomson Reuters Web of Science Article | Citations
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Created: Tue, 16 Sep 2014, 12:36:02 EST by Ms Kate Rowe on behalf of School of Medicine