Genetic determinants of mycophenolate-related anemia and leukopenia after transplantation.
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.


CONCLUSIONS
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.
Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA. jacob117@umn.edu
Pamala A
PA
Jacobson
David
D
Schladt
William S
WS
Oetting
Robert
R
Leduc
Weihau
W
Guan
Arthur J
AJ
Matas
Vishal
V
Lamba
Roslyn B
RB
Mannon
Bruce A
BA
Julian
Ajay
A
Israni
D000328:Adult; D000368:Aged; D000740:Anemia / Q000139:chemically induced* / Q000453:epidemiology / Q000235:genetics; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics; D065727:Cytochrome P-450 CYP2C8; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000627:therapeutic use; D053765:Interleukin-12 Subunit p35 / Q000235:genetics; D016030:Kidney Transplantation; D007970:Leukopenia / Q000139:chemically induced* / Q000453:epidemiology / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011446:Prospective Studies; D012307:Risk Factors
D018797:Cell Cycle Proteins; C549605:HUS1 protein, human; C508858:IL12A protein, human; D007166:Immunosuppressive Agents; D053765:Interleukin-12 Subunit p35; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8; D009173:Mycophenolic Acid