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ITPA gene variants protect against anaemia in patients treated for chronic hepatitis C

Abstract

Chronic infection with the hepatitis C virus (HCV) affects 170 million people worldwide and is an important cause of liver-related morbidity and mortality1. The standard of care therapy combines pegylated interferon (pegIFN) alpha and ribavirin (RBV), and is associated with a range of treatment-limiting adverse effects2. One of the most important of these is RBV-induced haemolytic anaemia, which affects most patients and is severe enough to require dose modification in up to 15% of patients. Here we show that genetic variants leading to inosine triphosphatase deficiency, a condition not thought to be clinically important, protect against haemolytic anaemia in hepatitis-C-infected patients receiving RBV.

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Figure 1: Genomic overview of the 20q13 region including the genome-wide significant associated variants and the ITPA gene.
Figure 2: Two ITPA polymorphisms known to be responsible for inosine triphosphatase deficiency co-segregate with the rs6051702 C allele that strongly associates with protection against Hb reduction in European-Americans.
Figure 3: ITPA deficiency protects against clinically significant decline in Hb concentration induced by HCV anti-viral treatment.

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Acknowledgements

We are indebted to the IDEAL principal investigators, the study coordinators, nurses and patients involved in the study. We also thank E. Gustafson, P. Savino, D. Devlin, S. Noviello, M. Geffner, E. L. Heinzen, A. C. Need and E. T. Cirulli for their contributions to the study. This study was funded by the Schering-Plough Research Institute, Kenilworth, New Jersey. A.J.T. receives funding support from the National Health and Medical Research Council of Australia and the Gastroenterological Society of Australia.

Author Contributions J.F., A.J.T. and D.G. contributed equally. D.B.G., J.G.M., J.A., A.J.T. and J.F. defined the clinical phenotypes. J.F., A.J.T., D.G. and T.J.U. performed the statistical and bioinformatical analyses. K.V.S. performed the genotyping. C.E.G. and L.D.L. performed the sequencing experiments. P.Q., A.H.B., M.W., A.W., A.J.M., M.S., C.B. and J.A. collected and analysed the clinical data. A.J.M., M.S., J.G.M. and D.B.G designed the study. J.F., A.J.T. and D.B.G. wrote the manuscript with critical input from all authors.

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Correspondence to John G. McHutchison or David B. Goldstein.

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Competing interests

J.G.M. and D.B.G. received research and grant support from Schering-Plough. J.G.M., A.J.M., M.S. and D.B.G. received consulting fees or acted in an advisory capacity for Schering-Plough. P.Q., A.H.B., M.W., A.W., C.B. and J.A. are employees of Schering-Plough, and Schering-Plough filed a patent application based on these findings. J.F., A.J.T., D.G., K.V.S., C.E.G., T.J.U., C.B., J.A., J.G.M. and D.B.G. are inventors of a patent application based on these findings.

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Fellay, J., Thompson, A., Ge, D. et al. ITPA gene variants protect against anaemia in patients treated for chronic hepatitis C. Nature 464, 405–408 (2010). https://doi.org/10.1038/nature08825

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