Polymorphisms in genes involved in vasoactive eicosanoid synthesis affect cardiovascular risk in renal transplant recipients

Objective: Arachidonic acid metabolism by cytochrome P450 (CYP) epoxygenases leads to epoxyeicosatrienoic acids (EETs), which are eicosanoids with vasodilator and anti-inflammatory properties. We aim to determine whether genetic variability in these routes may contribute to cardiovascular (CV) risk in renal transplant recipients. Methods: In a cohort of 355 patients, we determined the presence of two polymorphisms, CYP2C8*3 and CYP2J2*7, known to affect eicosanoid levels. Associations with CV mortality, CV event-free long-term survival and graft survival were retrospectively investigated by logistic regression models. Results:CYP2J2*7 showed a statistical trend towards higher CV mortality (p = .06) and lower cardiac or cerebral event-free long-term survival (p = .05), whilst CYP2C8*3 displayed a significant inverse association with the risk of CV event (hazard ratio [HR] = 0.34 [0.15-0.78], p = .01). The association of CYP2J2*7 with CV mortality became significant when the analysis was restrained to 316 patients without a history of CV events prior to transplantation (HR = 15.72 [2.83-91.94], p = .005). In this subgroup of patients both single nucleotide polymorphisms (SNPs) were significantly associated with event-free survival. HR values were 5.44 (1.60-18.51), p=.007 and 0.26 (0.09-0.75), p = .012 for CYP2J2*7 and CYP2C8*3, respectively. Conclusions: Our results show, for the first time to our knowledge, that two SNPs in CYP2C8 and CYP2J2, which synthesize EETs, may modify CV outcomes in renal transplant recipients, a population that is already at a high risk of suffering these events.