Association between CYP4A11 and EPHX2 genetic polymorphisms and chronic kidney disease progression in hypertensive patients

Miguel A Suárez-Santisteban; Gracia Santos-Díaz; Vanesa García-Bernalt; Ana M Pérez-Pico; Esther Mingorance; Raquel Mayordomo; Pedro Dorado

doi:10.1016/j.nefroe.2024.01.020

Association between CYP4A11 and EPHX2 genetic polymorphisms and chronic kidney disease progression in hypertensive patients

Nefrologia (Engl Ed). 2024 Mar 5:S2013-2514(24)00037-3. doi: 10.1016/j.nefroe.2024.01.020. Online ahead of print.

Authors

Miguel A Suárez-Santisteban¹, Gracia Santos-Díaz², Vanesa García-Bernalt³, Ana M Pérez-Pico⁴, Esther Mingorance⁵, Raquel Mayordomo⁶, Pedro Dorado⁷

Affiliations

¹ Biosanitary University Research Institute (INUBE), University of Extremadura, Badajoz, Spain; Service of Nephrology, Virgen del Puerto Hospital, Plasencia, Spain.
² Biosanitary University Research Institute (INUBE), University of Extremadura, Badajoz, Spain.
³ Service of Nephrology, Virgen del Puerto Hospital, Plasencia, Spain.
⁴ Department of Nursing, University of Extremadura, Plasencia, Spain.
⁵ Department of Nursing, University of Extremadura, Merida, Spain.
⁶ Department of Anatomy, Cellular Biology and Zoology, University of Extremadura, Plasencia, Spain.
⁷ Biosanitary University Research Institute (INUBE), University of Extremadura, Badajoz, Spain; Department of Medical and Surgical Therapeutics, University of Extremadura, Badajoz, Spain. Electronic address: pdorado@unex.es.

PMID: 38448299
DOI: 10.1016/j.nefroe.2024.01.020

Abstract

Background: There are evidence indicating that some metabolites of arachidonic acid produced by cytochromes P450 (CYP) and epoxide hydroxylase (EPHX2), such as hydroxyeicosatetraenoic acids (HETEs), epoxyeicosatrienoic acids (EETs) or dihydroxyeicosatrienoic acids (DHETEs), play an important role in blood pressure regulation and they could contribute to the development of hypertension (HT) and kidney damage. Therefore, the main aim of the study was to evaluate whether the genetic polymorphisms of CYP2C8, CYP2C9, CYP2J2, CYP4F2, CYP4F11 and EPHX2, responsible for the formation of HETEs, EETs and DHETEs, are related to the progression of impaired renal function in a group of patients with hypertension.

Methods: 151HT patients from a hospital nephrology service were included in the study. Additionally, a group of 87 normotensive subjects were involved in the study as control group. For HT patients, a general biochemistry analysis, estimated glomerular filtration rate and genotyping for different CYPs and EPHX2 variant alleles was performed.

Results: CYP4A11 rs3890011, rs9332982 and EPHX2 rs41507953 polymorphisms, according to the dominant model, presented a high risk of impaired kidney function, with odds ratios (OR) of 2.07 (1.00-4.32; P=0.049) 3.02 (1.11-8.23; P=0.030) and 3.59 (1.37-9.41; P=0.009), respectively, and the EPHX2 rs1042032 polymorphism a greater risk according to the recessive model (OR=6.23; 95% CI=1.50-25.95; P=0.007). However, no significant differences in allele frequencies between HT patients and in normotensive subjects for any of the SNP analysed. In addition, the patients with diagnosis of dyslipidemia (n=90) presented higher frequencies of EPHX2 K55R (rs41507953) and *35A>G (rs1042032) variants than patients without dyslipidemia, 4% vs. 14% (P=0.005) and 16 vs. 27% (P=0.02), respectively.

Conclusions: In this study has been found higher odds of impaired renal function progression associated with rs3890011 and rs9332982 (CYP4A11) and rs41507953 and rs1042032 (EPHX2) polymorphisms, which may serve as biomarkers for improve clinical interventions aimed at avoiding or delaying, in chronic kidney disease patients, progress to end-stage kidney disease needing dialysis or kidney transplant.

Keywords: CYP; CYPs; Chronic kidney disease; EPHX2; Eicosanoides; Eicosanoids; Enfermedad renal crónica; Hipertensión; Hypertension; Progresión; Progression.