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

JOURNAL OF HEPATOLOGY

卷:56

Article

Thompson, Alexander J.¹  Clark, Paul J.¹  Singh, Abanish²  Ge, Dongliang²  Fellay, Jacques²  Zhu, Mingfu²  Zhu, Qianqian²  Urban, Thomas J.²  Patel, Keyur¹  Tillmann, Hans L.¹  Naggie, Susanna¹  Afdhal, Nezam H.³  Jacobson, Ira M.⁴  Esteban, Rafael⁵  Poordad, Fred⁶  Lawitz, Eric J.⁷  McCone, Jonathan⁸  Shiffman, Mitchell L.⁹  Galler, Greg W.¹⁰  King, John W.¹¹  Kwo, Paul Y.¹²  Shianna, Kevin V.²  Noviello, Stephanie¹³  Pedicone, Lisa D.¹³  Brass, Clifford A.¹³  Albrecht, Janice K.¹³  Sulkowski, Mark S.¹⁴  Goldstein, David B.²  McHutchison, John G.¹  Muir, Andrew J.¹ 

[1] Duke Univ, Med Ctr, Duke Clin Res Inst, 2400 Pratt St,Terrace Level,Room 0311, Durham, NC 27701 USA

[2] Duke Univ, Ctr Human Genome Variat, Durham, NC 27701 USA

[3] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA

[4] Weill Cornell Med Coll, New York, NY USA

[5] Hosp Gen Univ Valle Hebron, Inst Carlos III, CIBERehd, Barcelona, Spain

[6] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA

[7] Alamo Med Res, San Antonio, TX USA

[8] Mt Vernon Endoscopy Ctr, Alexandria, VA USA

[9] Liver Inst Virginia, Newport News, VA USA

[10] Kelsey Res Fdn, Houston, TX USA

[11] Louisiana State Univ Hlth Sci Ctr, Shreveport, LA 71105 USA

[12] Indiana Univ Sch Med, Indianapolis, IN USA

[13] Merck Inc, Whitehouse Stn, NJ USA

[14] Johns Hopkins Univ, Sch Med, Baltimore, MD USA

关键词: GWAS;    ITPA;    Thrombocytopenia;    Hepatitis C;    Neutropenia;    IL28B;   

DOI  :  10.1016/j.jhep.2011.04.021

来源: Elsevier

【 摘 要 】

Background 82 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-alpha, (pegIFN)-related thrombocytopenia, neutropenia, and leukopenia. Methods: 1604/3070 patients in the IDEAL study consented to genetic testing. Trial inclusion criteria included a platelet (PI) count >= 80 x 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 (PI, 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 PI 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 PI reduction (p = showed strong independent associations with PI 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 PI reduction (r = -0.28, p = 10(-17)) and Hb change largely attenuated the association between the ITPA variants and PI 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. (C) 2011 Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver.

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