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

Publication ,  Journal Article
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 ...
Published in: J Hepatol
February 2012

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.

Duke Scholars

Published In

J Hepatol

DOI

EISSN

1600-0641

Publication Date

February 2012

Volume

56

Issue

2

Start / End Page

313 / 319

Location

Netherlands

Related Subject Headings

  • Thrombocytopenia
  • Ribavirin
  • Recombinant Proteins
  • Pyrophosphatases
  • Polymorphism, Single Nucleotide
  • Polyethylene Glycols
  • Neutropenia
  • Middle Aged
  • Male
  • Linkage Disequilibrium
 

Citation

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MLA
NLM
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. J Hepatol, 56(2), 313–319. https://doi.org/10.1016/j.jhep.2011.04.021
Thompson, Alexander J., Paul J. Clark, Abanish Singh, Dongliang Ge, Jacques Fellay, Mingfu Zhu, Qianqian Zhu, et al. “Genome-wide association study of interferon-related cytopenia in chronic hepatitis C patients.J Hepatol 56, no. 2 (February 2012): 313–19. https://doi.org/10.1016/j.jhep.2011.04.021.
Thompson AJ, Clark PJ, Singh A, Ge D, Fellay J, Zhu M, et al. Genome-wide association study of interferon-related cytopenia in chronic hepatitis C patients. J Hepatol. 2012 Feb;56(2):313–9.
Thompson, Alexander J., et al. “Genome-wide association study of interferon-related cytopenia in chronic hepatitis C patients.J Hepatol, vol. 56, no. 2, Feb. 2012, pp. 313–19. Pubmed, doi: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. Genome-wide association study of interferon-related cytopenia in chronic hepatitis C patients. J Hepatol. 2012 Feb;56(2):313–319.
Journal cover image

Published In

J Hepatol

DOI

EISSN

1600-0641

Publication Date

February 2012

Volume

56

Issue

2

Start / End Page

313 / 319

Location

Netherlands

Related Subject Headings

  • Thrombocytopenia
  • Ribavirin
  • Recombinant Proteins
  • Pyrophosphatases
  • Polymorphism, Single Nucleotide
  • Polyethylene Glycols
  • Neutropenia
  • Middle Aged
  • Male
  • Linkage Disequilibrium