title: Polymorphisms in CYP-mediated arachidonic acid routes affect the outcome of renal transplantation.
abstract: 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.
  
  
  METHODS
  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.
authors.affiliation: Department of Medical and Surgical Therapeutics, Division of Pharmacology, Medical School, University of Extremadura, Badajoz, Spain.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Gervasini
authors.affiliation: Department of Medical and Surgical Therapeutics, Division of Pharmacology, Medical School, University of Extremadura, Badajoz, Spain.
authors.forename: Montserrat
authors.initials: M
authors.lastname: García-Cerrada
authors.affiliation: Service of Immunology, Infanta Cristina University Hospital, Badajoz, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Vergara
authors.affiliation: Service of Nephrology, Infanta Cristina University Hospital, Badajoz, Spain.
authors.forename: Guadalupe
authors.initials: G
authors.lastname: García-Pino
authors.affiliation: Service of Nephrology, Infanta Cristina University Hospital, Badajoz, Spain.
authors.forename: Raul
authors.initials: R
authors.lastname: Alvarado
authors.affiliation: Service of Immunology, Infanta Cristina University Hospital, Badajoz, Spain.
authors.forename: Maria Jesús
authors.initials: MJ
authors.lastname: Fernández-Cavada
authors.affiliation: Service of Nephrology, Infanta Cristina University Hospital, Badajoz, Spain.
authors.forename: Sergio
authors.initials: S
authors.lastname: Barroso
authors.affiliation: Service of Nephrology, Infanta Cristina University Hospital, Badajoz, Spain.
authors.forename: Emilio
authors.initials: E
authors.lastname: Doblaré
authors.affiliation: Service of Immunology, Infanta Cristina University Hospital, Badajoz, Spain.
authors.forename: Juan José
authors.initials: JJ
authors.lastname: Cubero
mesh_terms: D000328:Adult; D064591:Allografts / Q000502:physiology; D016718:Arachidonic Acid / Q000235:genetics* / Q000378:metabolism; D000090762:Cytochrome P-450 CYP2J2; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005838:Genotype; D006085:Graft Survival; D006720:Homozygote; D006801:Humans; D007674:Kidney Diseases / Q000235:genetics / Q000378:metabolism / Q000601:surgery; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*; D012189:Retrospective Studies
chemical_list: C000717350:CYP2J2 protein, human; D016718:Arachidonic Acid; D003577:Cytochrome P-450 Enzyme System; D000090762:Cytochrome P-450 CYP2J2
keywords: CYP450; Creatinine clearance; delayed graft function; graft survival; polymorphisms; renal transplant