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

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.