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. 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

doi:10.1016/j.jhep.2011.04.021

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

School of Medicine

Research output: Contribution to journal › Article › peer-review

35 Scopus citations

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 language	English (US)
Pages (from-to)	313-319
Number of pages	7
Journal	Journal of Hepatology
Volume	56
Issue number	2
DOIs	https://doi.org/10.1016/j.jhep.2011.04.021
State	Published - Feb 2012

Keywords

GWAS
Hepatitis C
IL28B
ITPA
Neutropenia
Thrombocytopenia

ASJC Scopus subject areas

Hepatology

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10.1016/j.jhep.2011.04.021

Cite this

Thompson, A. J., Clark, P. J., Singh, A., Ge, D., Fellay, J., Zhu, M., Zhu, Q., Urban, T. J., Patel, K., Tillmann, H. L., Naggie, S., Afdhal, N. H., Jacobson, I. M., Esteban, R., Poordad, F., Lawitz, E. J., McCone, J., Shiffman, M. L., Galler, G. W., ... 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

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

@article{ba042853012c455aaaf274084b168e3a,

title = "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.",

keywords = "GWAS, Hepatitis C, IL28B, ITPA, Neutropenia, Thrombocytopenia",

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

note = "Funding Information: This study was funded by Schering-Plough Research Institute, Kenilworth, New Jersey. Dr. Thompson received funding support from the Duke Clinical Research Institute, a generous research gift from the Richard B. Boebel Family Fund, the National Health and Medical Research Council of Australia, the Gastroenterology Society of Australia and the Royal Australasian College of Physicians. Funding Information: Drs. McHutchison, Goldstein, Muir, Afdhal, Jacobson, Esteban, Poordad, Lawitz, McCone, Shiffman, King, Kwo, Patel and Sulkowski report having received research and grant support from Schering-Plough. Drs. McHutchison, Goldstein, Muir, Afdhal, Jacobson, Esteban, Poordad, Lawitz, Shiffman, Kwo, and Sulkowski have reported receiving consulting fees or acted in an advisory capacity for Schering-Plough. Drs. Noviello, Pedicone, Brass, Pedicone, and Albrecht are employees of Schering-Plough (now Merck & Co., Inc.) and are stock holders in this entity. Drs. Thompson, Goldstein, McHutchison, Ge, Fellay, Shianna, and Urban are co-inventors of a patent application based on the ITPA finding. ",

year = "2012",

month = feb,

doi = "10.1016/j.jhep.2011.04.021",

language = "English (US)",

volume = "56",

pages = "313--319",

journal = "Journal of Hepatology",

issn = "0168-8278",

publisher = "Elsevier",

number = "2",

}

TY - JOUR

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.

N1 - Funding Information: This study was funded by Schering-Plough Research Institute, Kenilworth, New Jersey. Dr. Thompson received funding support from the Duke Clinical Research Institute, a generous research gift from the Richard B. Boebel Family Fund, the National Health and Medical Research Council of Australia, the Gastroenterology Society of Australia and the Royal Australasian College of Physicians. Funding Information: Drs. McHutchison, Goldstein, Muir, Afdhal, Jacobson, Esteban, Poordad, Lawitz, McCone, Shiffman, King, Kwo, Patel and Sulkowski report having received research and grant support from Schering-Plough. Drs. McHutchison, Goldstein, Muir, Afdhal, Jacobson, Esteban, Poordad, Lawitz, Shiffman, Kwo, and Sulkowski have reported receiving consulting fees or acted in an advisory capacity for Schering-Plough. Drs. Noviello, Pedicone, Brass, Pedicone, and Albrecht are employees of Schering-Plough (now Merck & Co., Inc.) and are stock holders in this entity. Drs. Thompson, Goldstein, McHutchison, Ge, Fellay, Shianna, and Urban are co-inventors of a patent application based on the ITPA finding.

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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DO - 10.1016/j.jhep.2011.04.021

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JO - Journal of Hepatology

JF - Journal of Hepatology

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ER -

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

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