Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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


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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

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.


  1. 1

    Lavanchy, D. The global burden of hepatitis. Liver Int. 29, 74–81 (2009)

    Article  Google Scholar 

  2. 2

    McHutchison, J. G. et al. Peginterferon α-2b or α-2a with ribavirin for treatment of hepatitis C infection. N. Engl. J. Med. 361, 580–593 (2009)

    CAS  Article  Google Scholar 

  3. 3

    Ge, D. et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature 461, 399–401 (2009)

    ADS  CAS  Article  Google Scholar 

  4. 4

    van Wijk, R. et al. HK Utrecht: missense mutation in the active site of human hexokinase associated with hexokinase deficiency and severe nonspherocytic hemolytic anemia. Blood 101, 345–347 (2003)

    CAS  Article  Google Scholar 

  5. 5

    de Vooght, K. M. K., van Solinge, W. W., van Wesel, A. C., Kersting, S. & van Wijk, R. First mutation in the red blood cell-specific promoter of hexokinase combined with a novel missense mutation causes hexokinase deficiency and mild chronic hemolysis. Haematologica 94, 1203–1210 (2009)

    CAS  Article  Google Scholar 

  6. 6

    Bonnefond, A. et al. A genetic variant in HK1 is associated with pro-anemic state and HbA1c but not other glycemic control related traits. Diabetes 58, 2687–2697 (2009)

    CAS  Article  Google Scholar 

  7. 7

    Peters, L. L. et al. Downeast anemia (dea), a new mouse model of severe nonspherocytic hemolytic anemia caused by hexokinase (HKI) deficiency. Blood Cells Mol. Dis. 27, 850–860 (2001)

    CAS  Article  Google Scholar 

  8. 8

    Ganesh, S. K. et al. Multiple loci influence erythrocyte phenotypes in the CHARGE Consortium. Nature Genet. 41, 1191–1198 (2009)

    CAS  Article  Google Scholar 

  9. 9

    Dickson, S. P., Wang, K., Kranz, I., Hakonarson, H. & Goldstein, D. B. Rare variants create synthetic genome-wide associations. PLoS Biol. 8, e1000294 (2010)

  10. 10

    Bierau, J., Lindhout, M. & Bakker, J. A. Pharmacogenetic significance of inosine triphosphatase. Pharmacogenomics 8, 1221–1228 (2007)

    CAS  Article  Google Scholar 

  11. 11

    Stocco, G. et al. Genetic polymorphism of inosine triphosphate pyrophosphatase is a determinant of mercaptopurine metabolism and toxicity during treatment for acute lymphoblastic leukemia. Clin. Pharmacol. Ther. 85, 164–172 (2009)

    CAS  Article  Google Scholar 

  12. 12

    Sumi, S. et al. Genetic basis of inosine triphosphate pyrophosphohydrolase deficiency. Hum. Genet. 111, 360–367 (2002)

    CAS  Article  Google Scholar 

  13. 13

    Cao, H. & Hegele, R. A. DNA polymorphisms in ITPA including basis of inosine triphosphatase deficiency. J. Hum. Genet. 47, 620–622 (2002)

    CAS  Article  Google Scholar 

  14. 14

    Arenas, M., Duley, J., Sumi, S., Sanderson, J. & Marinaki, A. The ITPA c.94C>A and g.IVS2+21A>C sequence variants contribute to missplicing of the ITPA gene. Biochim. Biophys. Acta 1772, 96–102 (2007)

    CAS  Article  Google Scholar 

  15. 15

    Stepchenkova, E. I. et al. Functional study of the P32T ITPA variant associated with drug sensitivity in humans. J. Mol. Biol. 392, 602–613 (2009)

    CAS  Article  Google Scholar 

  16. 16

    Shipkova, M., Lorenz, K., Oellerich, M., Wieland, E. & von Ahsen, N. Measurement of erythrocyte inosine triphosphate pyrophosphohydrolase (ITPA) activity by HPLC and correlation of ITPA genotype-phenotype in a Caucasian population. Clin. Chem. 52, 240–247 (2006)

    CAS  Article  Google Scholar 

  17. 17

    Atanasova, S. et al. Analysis of ITPA phenotype-genotype correlation in the Bulgarian population revealed a novel gene variant in exon 6. Ther. Drug Monit. 29, 6–10 (2007)

    CAS  Article  Google Scholar 

  18. 18

    Maeda, T. et al. Genetic basis of inosine triphosphate pyrophosphohydrolase deficiency in the Japanese population. Mol. Genet. Metab. 85, 271–279 (2005)

    CAS  Article  Google Scholar 

  19. 19

    The International HapMap Consortium. A haplotype map of the human genome. Nature 437, 1299–1320 (2005)

  20. 20

    Russmann, S., Grattagliano, I., Portincasa, P., Palmieri, V. O. & Palasciano, G. Ribavirin-induced anemia: mechanisms, risk factors and related targets for future research. Curr. Med. Chem. 13, 3351–3357 (2006)

    CAS  Article  Google Scholar 

  21. 21

    Fraser, J. H., Meyers, H., Henderson, J. F., Brox, L. W. & McCoy, E. E. Individual variation in inosine triphosphate accumulation in human erythrocytes. Clin. Biochem. 8, 353–364 (1975)

    CAS  Article  Google Scholar 

  22. 22

    Motulsky, A. G. Drug reactions enzymes, and biochemical genetics. J. Am. Med. Assoc. 165, 835–837 (1957)

    CAS  Article  Google Scholar 

  23. 23

    Goldstein, D. B. Common genetic variation and human traits. N. Engl. J. Med. 360, 1696–1698 (2009)

    CAS  Article  Google Scholar 

  24. 24

    Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007)

    CAS  Article  Google Scholar 

  25. 25

    Price, A. L. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nature Genet. 38, 904–909 (2006)

    CAS  Article  Google Scholar 

  26. 26

    Whitlock, M. C. Combining probability from independent tests: the weighted Z-method is superior to Fisher’s approach. J. Evol. Biol. 18, 1368–1373 (2005)

    CAS  Article  Google Scholar 

  27. 27

    Ge, D. et al. WGAViewer: software for genomic annotation of whole genome association studies. Genome Res. 18, 640–643 (2008)

    CAS  Article  Google Scholar 

Download references


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.

Author information



Corresponding authors

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

Ethics declarations

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.

Supplementary information

Supplementary Information

This file contains Supplementary Notes I-IV, Supplementary Tables 1-6 and Supplementary References. (PDF 446 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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).

Download citation

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing