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

<p><b>Objective:</b> 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.</p> <p><b>Methods:</b> In a cohort of 355 patients, we determined the presence of two polymorphisms, <i>CYP2C8*3</i> and <i>CYP2J2*7</i>, 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.</p> <p><b>Results:</b><i>CYP2J2*7</i> showed a statistical trend towards higher CV mortality (<i>p</i> = .06) and lower cardiac or cerebral event-free long-term survival (<i>p</i> = .05), whilst <i>CYP2C8*3</i> displayed a significant inverse association with the risk of CV event (hazard ratio [HR] = 0.34 [0.15–0.78], <i>p</i> = .01). The association of <i>CYP2J2*7</i> 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], <i>p</i> = .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), <i>p</i> = .007 and 0.26 (0.09–0.75), <i>p</i> = .012 for <i>CYP2J2*7</i> and <i>CYP2C8*3</i>, respectively.</p> <p><b>Conclusions:</b> Our results show, for the first time to our knowledge, that two SNPs in <i>CYP2C8</i> and <i>CYP2J2</i>, which synthesize EETs, may modify CV outcomes in renal transplant recipients, a population that is already at a high risk of suffering these events.</p>