Gene expression profiles associated with anemia and ITPA genotypes in patients with chronic hepatitis C

Aybike Birerdinc, Mike Estep, Maria Stepanova, Arian Afendi, V. Chandhoke, Ancha Baranova, Zobair M. Younossi

This is a collaborative project between

School of Systems Biology, College of Science,George Mason University, Fairfax, VA

Translational Reseach Institute, Inova Hospital, VA

Genetic variation of inosine triphosphatase (ITPA) causing an accumulation of inosine triphosphate (ITP) has been shown to protect patients against ribavirin (RBV)-induced anemia during treatment for chronic hepatitis C infection by genome-wide association study (GWAS). Recently, it was shown that ITP confers protection against RBV-induced ATP reduction by substituting for erythrocyte GTP, which is depleted by RBV, in the biosynthesis of ATP. Because patients with excess ITP appear largely protected against anemia, these results confirm that RBV-induced anemia is due primarily to the effect of the drug on GTP and consequently ATP levels in erythrocytes (Hitomi Y. et al., 2011).

Aim: To genotype CH-C patients for ITPA rs1127354 SNP (CC or CA) and associate treatment-induced anemia with gene expression profile and ITPA genotypes.

Methods: We used CH-C patients with available gene expression, clinical, laboratory data and whole blood samples. Using tetraprimer PCR rection, we determined ITPA rs1127354 genotypes (CC or CA). We used pre-treatment blood samples to assess expression of 153 genes previously implicated in host response to viral infections. The gene expression data were analyzed according to presence of anemia and ITPA genotypes.

The cohort with ITPA CA genotype revealed a distinct pattern of protection against anemia and a lower drop in hemoglobin. Six genes associated with treatment related anemia were involved in the response to hypoxia pathway, namely, HIF1A, AIF1, RHOC, PTEN, LCK, PDGFB. There was a substantial overlap between SVR-predicting and anemia-related genes. JAK-STAT pathway-related genes associated with SVR were not implicated in anemia. Therefore, we exclude the direct involvement of antiviral response in the development of anemia associated with PEG-IFN-RBV treatment. We have identified functional pathways associated with RBV-induced anemia by their baseline gene signatures. The hypoxia response pathway and the apoptosis/survival related gene network were differentially expressed CH-C patients with anemia.

RESULTS: are to be published soon