Multi-institutional Study of Outcomes After Pediatric Heart Transplantation: Candidate Gene Polymorphism Analysis of ABCC2.
OBJECTIVE
Earlier studies have indicated that the pharmacokinetics of mycophenolic acid (MPA) is influenced by polymorphisms of ABCC2, which encodes for the membrane transporter MRP2. The ABCC2 rs717620 A allele has been associated with enterohepatic recirculation of MPA, and our previous work had correlated the discontinuance of MPA with this allele in pediatric heart transplant patients. Therefore, we hypothesized that the ABCC2 rs717620 A allele would be associated with poorer outcomes including rejection with hemodynamic compromise (RHC), graft failure, and death in the pediatric heart transplant (PHTx) population receiving MPA.


METHODS
PHTx recipients from 6 institutions in the Pediatric Heart Transplantation Study (PHTS) from the period of 1993-2009, receiving MPA therapy, were genotyped for ABCC2 rs717620. Genotyping was accomplished by direct sequencing. Demographic and outcome data were limited to the data routinely collected as part of the PHTS and included RHC and mortality.


RESULTS
Two hundred ninety patients were identified who received MPA at some point post transplantation, of which 200 carried the GG genotype, 81 carried the AG genotype, and 9 carried the AA genotype. Follow-up time after transplantation was 6 years. RHC occurred in 76 patients and 18 patients died. In the 281 patients followed up more than 1 year, late RHC (>1 year post transplantation) occurred in 42 patients. While both RHC and late RHC were associated with the ABCC2 rs717620 GG genotype (hazard ratios: 1.80 and 4.57, respectively, p<0.05) in all patients, this association was not significant in PHTx patients receiving only MPA as the antiproliferative agent from the time of transplant (n=142).


CONCLUSIONS
ABCC2 rs717620 polymorphisms varied within racial groups. As a candidate gene assessment, the ABCC2 rs717620 AG and AA genotypes may be associated with improved, rather than poorer, RHC in PHTx patients receiving MPA therapy. ABCC2 rs717620 polymorphisms should be included in any expanded pharmacogenomic analysis of outcomes after pediatric heart transplantation.
Pediatric Clinical Pharmacology Staff, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland.
Gilbert J
GJ
Burckart
Medical Pharmacology Section, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
William D
WD
Figg
Department of Epidemiology.
Maria M
MM
Brooks
Pediatric Clinical Pharmacology Staff, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland.
Dionna J
DJ
Green
Medical Pharmacology Section, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
Sarah M
SM
Troutman
Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania.
Robert
R
Ferrell
Department of Pediatrics, Loma Linda University, Loma Linda University Children's Hospital, Loma Linda, California.
Richard
R
Chinnock
Department of Pediatrics, Division of Cardiology, Washington University School of Medicine, St Louis Children's Hospital, St Louis, Missouri.
Charles
C
Canter
Department of Pediatrics, Division of Cardiology, Columbia University, New York Presbyterian Hospital, New York, New York.
Linda
L
Addonizio
Department of Pediatrics, Division of Cardiology, Stanford University, Lucile Packard Children's Hospital, Palo Alto, California.
Daniel
D
Bernstein
Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama.
James K
JK
Kirklin
Department of Pathology, Thomas E Starzl Transplant Institute.
David
D
Naftel
Medical Pharmacology Section, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
Douglas K
DK
Price
Medical Pharmacology Section, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
Tristan M
TM
Sissung
Department of Pathology, Thomas E Starzl Transplant Institute.
Diana M
DM
Girnita
Department of Pathology, Thomas E Starzl Transplant Institute.
Adriana
A
Zeevi
Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee.
Steven A
SA
Webber
ABCC2 polymorphisms; heart transplantation; mycophenolic acid; pediatrics; pharmacogenetics; rejection