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

Abstract

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.

Keywords:

• Epoxyeicosatrienoic acids
• cardiovascular disease
• genetic polymorphisms
• renal transplant
• CYP450

Transparency

Declaration of funding

This work has been supported in part by grant PI15/00804 from Instituto de Salud Carlos III, Madrid (Spain), the Association for the Study and Prevention of Renal Diseases (ASEPER), Badajoz (Spain) by grant IB16014 from Fando Europeo de Desarrolle Regional (FEDER) and by grant GR15012 from Junta de Extremadura, Consejería de Economía, Comercio e Innovación, Merida, Spain. The funding sources were not involved in study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the article for publication.

Author contributions: G.G. wrote the manuscript and designed research, E.L. and S.M.-Z. performed statistical analyses; G.G.-P. and L.A. collected clinical and demographic parameters on transplant recipients; J.J.C. helped with research design and the clinical evaluation of patients.

Declaration of financial and other relationships

J.J.C. has disclosed that he is the president of the Association for the Study and Prevention of Renal Diseases (ASEPER), which partly financed the study. ASEPER is a non-commercial organization without any link with commercial companies. G.G., E.L., G.G.-P., L.A. and S.M.-Z. have disclosed that they have no significant relationships with or financial interests in any commercial companies related to this study or article.

CMRO peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgements

The authors want to thank the patients included in the study and the technical and human support provided by the Facility of Bioscience Applied Techniques of SAIUEx (financed by UEX, Junta de Extremadura, MICINN, FEDER and FSE). No assistance in the preparation of this article is to be declared.