Polymorphisms in CYP-mediated arachidonic acid routes affect the outcome of renal transplantation

• Published in: European journal of clinical investigation Vol. 45; no. 10; pp. 1060 - 1068
• Main Authors: Gervasini, Guillermo, García-Cerrada, Montserrat, Vergara, Esther, García-Pino, Guadalupe, Alvarado, Raul, Fernández-Cavada, Maria Jesús, Barroso, Sergio, Doblaré, Emilio, Cubero, Juan José
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.10.2015
• Subjects: Adult; Allografts - physiology; Arachidonic Acid - genetics; Arachidonic Acid - metabolism; Creatinine clearance; CYP450; Cytochrome P-450 Enzyme System - genetics; Cytochrome P-450 Enzyme System - metabolism; delayed graft function; Female; Genotype; Graft Survival; Homozygote; Humans; Kidney Diseases - genetics; Kidney Diseases - metabolism; Kidney Diseases - surgery; Kidney Transplantation; Male; Middle Aged; Polymorphism, Genetic - genetics; polymorphisms; renal transplant; Retrospective Studies; graft survival; Creatinine clearance; CYP450; polymorphisms; delayed graft function; renal transplant
• ISSN: 0014-2972; 1365-2362
• DOI: 10.1111/eci.12507

Background Arachidonic acid (AA) is metabolized by cytochrome P450 (CYP) enzymes to vasoactive metabolites (mainly epoxyeicosatrienoic acids) which are known to play a protective role against damaging processes that may occur after re‐oxygenation of the graft. We aimed to investigate whether the presence of functional polymorphisms along these metabolic routes may play a role in the outcome of renal transplantation. Design One‐hundred and forty Caucasian renal transplant recipients and 137 donors were included. We determined the presence of seven common functional polymorphisms in the five genes governing the CYP‐mediated AA metabolic pathway (CYP2C8, CYP2C9, CYP2J2, CYP4A11 and CYP4F2). Associations with parameters and events related to graft function and survival were retrospectively investigated throughout the first year after grafting. Results The CYP2J2*7 allele of the donor was significantly associated with higher risk for delayed graft function [OR = 4·40 (1·45–13·37), P < 0·01] and lower death‐censored graft survival [107·90 (84·19–131·62) vs. 176·89 (166·47–187·32) months for CYP2J2*1/*1 grafts; log‐rank P = 0·015]. In addition, patients whose donors carried the CYP4A11 434S variant of the F434S polymorphism displayed impaired creatinine clearance, with statistically significant differences vs. 434FF subjects throughout the whole period of study (P < 0·05, P < 0·01, P < 0·001 and P < 0·05 for 1 week, 1 month, 5 months and 1 year after grafting, respectively). Conclusions Taken together, these results indicate that variability in the CYP450 genes involved in the synthesis of eicosanoids from AA may have a significant impact on graft function and survival in renal transplantation.