Risk factors for post-transplant diabetes mellitus in renal transplant: Role of genetic variability in the CYP450-mediated arachidonic acid metabolism.
Arachidonic acid (AA) is metabolized by cytochrome P450 (CYP) enzymes to epoxyeicosatrienoic acids (EETs) and 20-hidroxyeicosatetraenoic acid (20-HETE), which play an important role both in renal transplant and diabetes mellitus (DM). We searched for associations between polymorphisms in this metabolic pathway and the risk of post-transplant diabetes mellitus (PTDM) in kidney recipients. One-hundred-sixty-four patients were genotyped for common SNPs in this route, namely CYP2C8*3, CYP2C8*4, CYP2C9*2, CYP2C9*3, CYP2J2*7, CYP4A11 F434S and CYP4F2 V433M. Demographic and clinical parameters were retrospectively collected at four time-points in the first year after grafting. Thirty-four patients (20.73%) developed PTDM, which was more prevalent among older patients [OR for older age = 1.06 (1.03-1.10), p < 0.001] and in those with higher body mass index (BMI) [OR for higher average BMI in the first year = 1.13 (1.04-1.23); p < 0.01]. Creatinine clearance [OR = 0.97 (0.95-0.99); p < 0.01] and exposure to tacrolimus [OR = 3.25 (1.15-9.19); p < 0.05] were also relevant for PTDM risk. With regard to genetic variants, logistic regression analysis controlling for significant demographic and clinical variables showed that the V433M polymorphism in CYP4F2, responsible for 20-HETE synthesis, was an independent risk factor for PTDM [OR = 3.94 (1.08-14.33); p < 0.05]. We have shown that a genetic variant in the CYP4F2 gene, the main gene implicated in 20-HETE synthesis, is associated with the risk for PTDM. Our findings suggest that genes in the metabolic pathways of AA may become good candidates in genetic association studies for PTDM.
Department of Medical and Surgical Therapeutics, Division of Pharmacology, Medical School, University of Extremadura, Spain. Electronic address: ggervasi@unex.es.
Guillermo
G
Gervasini
Service of Nephrology, Infanta Cristina University Hospital, Badajoz, Spain.
Enrique
E
Luna
Department of Medical and Surgical Therapeutics, Division of Pharmacology, Medical School, University of Extremadura, Spain.
Montserrat
M
García-Cerrada
Service of Nephrology, Infanta Cristina University Hospital, Badajoz, Spain.
Guadalupe
G
García-Pino
Service of Nephrology, Infanta Cristina University Hospital, Badajoz, Spain.
Juan José
JJ
Cubero
D000328:Adult; D000367:Age Factors; D016718:Arachidonic Acid / Q000378:metabolism*; D015992:Body Mass Index; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D000072470:Cytochrome P450 Family 4; D003920:Diabetes Mellitus / Q000235:genetics*; D005260:Female; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D016030:Kidney Transplantation / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012189:Retrospective Studies; D012307:Risk Factors
D006893:Hydroxyeicosatetraenoic Acids; D016718:Arachidonic Acid; D003577:Cytochrome P-450 Enzyme System; D000072470:Cytochrome P450 Family 4; C117480:CYP4F2 protein, human
Cyclosporine; Post-transplant diabetes mellitus; Renal transplant; Risk factors; Tacrolimus