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

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. KingPaul 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

Research output: Contribution to journalArticle

35 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)313-319
Number of pages7
JournalJournal of Hepatology
Volume56
Issue number2
DOIs
StatePublished - Feb 2012

Fingerprint

Genome-Wide Association Study
Chronic Hepatitis C
Interferons
Blood Platelets
Ribavirin
Neutropenia
Thrombocytopenia
Single Nucleotide Polymorphism
Hemolytic Anemia
Leukopenia
Interferon-alpha
Neutrophils
Chromosomes, Human, Pair 20
Thrombocytosis
Basophils
Linkage Disequilibrium
Lymphocyte Count
Genetic Testing
Platelet Count
Eosinophils

Keywords

  • GWAS
  • Hepatitis C
  • IL28B
  • ITPA
  • Neutropenia
  • Thrombocytopenia

ASJC Scopus subject areas

  • Hepatology

Cite this

Thompson, A. J., Clark, P. J., Singh, A., Ge, D., Fellay, J., Zhu, M., ... Muir, A. J. (2012). Genome-wide association study of interferon-related cytopenia in chronic hepatitis C patients. Journal of Hepatology, 56(2), 313-319. https://doi.org/10.1016/j.jhep.2011.04.021

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.

In: Journal of Hepatology, Vol. 56, No. 2, 02.2012, p. 313-319.

Research output: Contribution to journalArticle

Thompson, AJ, Clark, PJ, Singh, A, Ge, D, Fellay, J, Zhu, M, Zhu, Q, Urban, TJ, Patel, K, Tillmann, HL, Naggie, S, Afdhal, NH, Jacobson, IM, Esteban, R, Poordad, F, Lawitz, EJ, McCone, J, Shiffman, ML, Galler, GW, King, JW, Kwo, PY, Shianna, KV, Noviello, S, Pedicone, LD, Brass, CA, Albrecht, JK, Sulkowski, MS, Goldstein, DB, McHutchison, JG & Muir, AJ 2012, 'Genome-wide association study of interferon-related cytopenia in chronic hepatitis C patients', Journal of Hepatology, vol. 56, no. 2, pp. 313-319. https://doi.org/10.1016/j.jhep.2011.04.021
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. / Genome-wide association study of interferon-related cytopenia in chronic hepatitis C patients. In: Journal of Hepatology. 2012 ; Vol. 56, No. 2. pp. 313-319.
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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.",
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T1 - Genome-wide association study of interferon-related cytopenia in chronic hepatitis C patients

AU - Thompson, Alexander J.

AU - Clark, Paul J.

AU - Singh, Abanish

AU - Ge, Dongliang

AU - Fellay, Jacques

AU - Zhu, Mingfu

AU - Zhu, Qianqian

AU - Urban, Thomas J.

AU - Patel, Keyur

AU - Tillmann, Hans L.

AU - Naggie, Susanna

AU - Afdhal, Nezam H.

AU - Jacobson, Ira M.

AU - Esteban, Rafael

AU - Poordad, Fred

AU - Lawitz, Eric J.

AU - McCone, Jonathan

AU - Shiffman, Mitchell L.

AU - Galler, Greg W.

AU - King, John W.

AU - Kwo, Paul Y.

AU - Shianna, Kevin V.

AU - Noviello, Stephanie

AU - Pedicone, Lisa D.

AU - Brass, Clifford A.

AU - Albrecht, Janice K.

AU - Sulkowski, Mark S.

AU - Goldstein, David B.

AU - McHutchison, John G.

AU - Muir, Andrew J.

PY - 2012/2

Y1 - 2012/2

N2 - 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.

AB - 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.

KW - GWAS

KW - Hepatitis C

KW - IL28B

KW - ITPA

KW - Neutropenia

KW - Thrombocytopenia

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