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.
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.
Authors: J Wang; J W Yang; A Zeevi; S A Webber; D M Girnita; R Selby; J Fu; T Shah; V Pravica; I V Hutchinson; G J Burckart Journal: Clin Pharmacol Ther Date: 2007-09-12 Impact factor: 6.875
Authors: E Link; S Parish; J Armitage; L Bowman; S Heath; F Matsuda; I Gut; M Lathrop; R Collins Journal: N Engl J Med Date: 2008-07-23 Impact factor: 91.245
Authors: Paul J Galiwango; Diego H Delgado; Raymond Yan; Stella Kozuszko; Robert Smith; Vivek Rao; Heather J Ross Journal: J Heart Lung Transplant Date: 2008-01 Impact factor: 10.247
Authors: Brian Van Ness; Christine Ramos; Majda Haznadar; Antje Hoering; Jeff Haessler; John Crowley; Susanna Jacobus; Martin Oken; Vincent Rajkumar; Philip Greipp; Bart Barlogie; Brian Durie; Michael Katz; Gowtham Atluri; Gang Fang; Rohit Gupta; Michael Steinbach; Vipin Kumar; Richard Mushlin; David Johnson; Gareth Morgan Journal: BMC Med Date: 2008-09-08 Impact factor: 8.775
Authors: Jean-Baptiste Woillard; Nicolas Picard; Antoine Thierry; Guy Touchard; Pierre Marquet Journal: Pharmacogenet Genomics Date: 2014-05 Impact factor: 2.089
Authors: William S Oetting; Baolin Wu; David P Schladt; Weihua Guan; Jessica van Setten; Brendan J Keating; David Iklé; Rory P Remmel; Casey R Dorr; Roslyn B Mannon; Arthur J Matas; Ajay K Israni; Pamala A Jacobson Journal: Transplantation Date: 2019-06 Impact factor: 4.939
Authors: W S Oetting; B Wu; D P Schladt; W Guan; R P Remmel; R B Mannon; A J Matas; A K Israni; P A Jacobson Journal: Pharmacogenomics J Date: 2017-11-21 Impact factor: 3.550
Authors: Malek Okour; Pamala A Jacobson; Mariam A Ahmed; Ajay K Israni; Richard C Brundage Journal: J Clin Pharmacol Date: 2018-01-12 Impact factor: 3.126
Authors: Ajay K Israni; Robert Leduc; Pamala A Jacobson; Winston Wildebush; Weihua Guan; David Schladt; Arthur J Matas; William S Oetting Journal: Clin Transplant Date: 2013-01-27 Impact factor: 2.863