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Post-Transplant Events

The hemochromatosis C282Y allele: a risk factor for hepatic veno-occlusive disease after hematopoietic stem cell transplantation

Bone Marrow Transplantation volume 35, pages 1155–1164 (2005)Cite this article

Summary:

Hepatic veno-occlusive disease (HVOD) is a serious complication of hematopoietic stem cell transplantation (HSCT). Since the liver is a major site of iron deposition in HFE-associated hemochromatosis, and iron has oxidative toxicity, we hypothesized that HFE genotype might influence the risk of HVOD after myeloablative HSCT. We determined HFE genotypes in 166 HSCT recipients who were evaluated prospectively for HVOD. We also tested whether a common variant of the rate-limiting urea cycle enzyme, carbamyl-phosphate synthetase (CPS), previously observed to protect against HVOD in this cohort, modified the effect of HFE genotype. Risk of HVOD was significantly higher in carriers of at least one C282Y allele (RR=3.7, 95% CI 1.2–12.1) and increased progressively with C282Y allelic dose (RR=1.7, 95% CI 0.4–6.8 in heterozygotes; RR=8.6, 95% CI 1.5–48.5 in homozygotes). The CPS A allele, which encodes a more efficient urea cycle enzyme, reduced the risk of HVOD associated with HFE C282Y. We conclude that HFE C282Y is a risk factor for HVOD and that CPS polymorphisms may counteract its adverse effects. Knowledge of these genotypes and monitoring of iron stores may facilitate risk-stratification and testing of strategies to prevent HVOD, such as iron chelation and pharmacologic support of the urea cycle.

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Acknowledgements

We are indebted to the patients who took part in this study. We also thank colleagues (Drs John Greer, Steven Wolff, Richard Stein, Stephen Brandt, and Stacey Goodman) and staff in the Vanderbilt Bone Marrow Transplant Program for their support of these studies. Funding support was provided by USPHS grants ES-09915 (MLS), HS-55198 (BWC), CA-92313 (MLS and BWC), a GCRC award (RR00095) to Vanderbilt University (DWB). This study was supported by USPHS grants ES-09915 (MLS), HS-55198 (BWC), CA-92313 (MLS and BWC), and a GCRC award (RR00095) to Vanderbilt University (DWB). Support was also provided by the VA TN Valley Healthcare System Geriatric Research, Education and Clinical Center (GRECC), the HSR&D Targeted Research Enhancement Program (TREP), the VA National Quality Scholars Fellowship Program, and the TN Valley VA Clinical Research Training Center of Excellence (CRCoE).

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Authors and Affiliations

  1. Division of General Internal Medicine and Public Health, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA

    A R Kallianpur, T Speroff & R S Dittus

  2. Department of Molecular Physiology and Biophysics, University Medical Center, Nashville, TN, USA

    L D Hall, J L Haines & M L Summar

  3. Division of Medical Genetics, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA

    M Yadav & M L Summar

  4. Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA

    D W Byrne

  5. Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA

    B W Christman

  6. Center for Health Services Research, Veterans Affairs Medical Center, Nashville, TN, USA

    A R Kallianpur, T Speroff & R S Dittus

  7. General Clinical Research Center, Vanderbilt University Medical Center, Nashville, TN, USA

    D W Byrne

  8. Center for Human Genetics Research, Vanderbilt University Medical Center, Nashville, TN, USA

    J L Haines & M L Summar

  9. Department of Preventive Medicine, Vanderbilt University Medical Center, Nashville, TN, USA

    T Speroff

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  1. A R Kallianpur
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Correspondence to A R Kallianpur.

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Kallianpur, A., Hall, L., Yadav, M. et al. The hemochromatosis C282Y allele: a risk factor for hepatic veno-occlusive disease after hematopoietic stem cell transplantation. Bone Marrow Transplant 35, 1155–1164 (2005). https://doi.org/10.1038/sj.bmt.1704943

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