Genetic determinants of mycophenolate-related anemia and leukopenia after transplantation

Pamala A. Jacobson, David Schladt, William S. Oetting, Robert Leduc, Weihau Guan, Arthur J. Matas, Vishal Lamba, Roslyn B. Mannon, Bruce A. Julian, Ajay Israni

Research output: Contribution to journalArticle

38 Scopus citations

Abstract

Background: Mycophenolate-related anemia and leukopenia are well-known toxicities after transplantation. Toxicity leads to dose reduction, addition of colony-stimulating factors or erythropoietin, or discontinuation of immunosuppressive therapy. The causes of and risk factors associated with toxicity are unclear. Methods: We studied the association between mycophenolate-related anemia and leukopenia and 2724 single nucleotide polymorphisms (SNP) in 978 patients undergoing living or deceased donor kidney transplant. Patients were followed up to time of first anemia (hemoglobin<10 gm/dL or hematocrit<30%) or first leukopenia (white blood cell [WBC] count <3000 cells/mm), which required clinical intervention in the first 6 months after transplant. Results: Anemia occurred in 87 (9.5%) subjects and leukopenia in 224 (22.9%). In single SNP analyses, none of the SNPs were associated with time to leukopenia at a false discovery rate (FDR) of 20%. However, SNPs from the IL12A, HUS, CYP2C8 genes were associated with time to anemia, allowing for an FDR of 20%. To assess the independence of these SNPs as predictors of anemia, we conducted a multi-SNP analysis including one SNP from each of the three genes. All three SNPs were associated with time to anemia, after adjusting for recipient age, weight, posttransplant dialysis and antiviral drug use, and stratifying by clinical center. Conclusion: Although these SNPs require validation in an independent population, our results suggest that genetics may play a role in risk of mycophenolate-related hematologic toxicity. This may ultimately provide for better management of maintenance immunosuppression and gives insights into potential mechanism(s) by which toxicity occurs.

Original languageEnglish (US)
Pages (from-to)309-316
Number of pages8
JournalTransplantation
Volume91
Issue number3
DOIs
StatePublished - Feb 15 2011

Keywords

  • Adverse effects
  • Anemia
  • Leukopenia
  • Mycophenolate
  • Mycophenolic acid
  • Pharmacogenetics
  • Pharmacogenomics
  • Toxicity
  • Transplantation

ASJC Scopus subject areas

  • Transplantation

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    Jacobson, P. A., Schladt, D., Oetting, W. S., Leduc, R., Guan, W., Matas, A. J., Lamba, V., Mannon, R. B., Julian, B. A., & Israni, A. (2011). Genetic determinants of mycophenolate-related anemia and leukopenia after transplantation. Transplantation, 91(3), 309-316. https://doi.org/10.1097/TP.0b013e318200e971