Abstract 094: Gain-of-function EPHX2 Variant rs41507953 Is Associated With Acute Kidney Injury Following Cardiac Surgery
Acute kidney injury (AKI) affects 20-30% of patients following cardiac surgery and predicts increased mortality. Murine models suggest that epoxyeicosatrienoic acids (EETs) protect against renal ischemia/reperfusion injury, a contributor to AKI following cardiac surgery. Soluble epoxide hydrolase (sEH), encoded by EPHX2, hydrolyzes EETs to less active DHETs. We tested the hypothesis that a gain-of-function EPHX2 variant, rs41507953, is associated with AKI following cardiac surgery.
We first studied 371 cardiac surgery patients (67.3% male, mean age 65.6±12.9years and BMI 28.5±6.17kg/m2) enrolled in a clinical trial in which DNA was collected. Ninety-eight patients (26.4%) developed AKI, defined by AKIN criteria. Rs41507953 genotypes were in Hardy-Weinberg equilibrium (AA:AG:GG=297:68:6). There was a significant association between the gain-of-function “G” allele and AKI, p=0.006. Adjusting for known risk factors for AKI including estimated glomerular filtration rate (eGFR), age, sex, race, history of diabetes, BMI, and use of cardiopulmonary bypass the rs41507953 “G” allele remained independently associated with higher rates of AKI [OR=2.09 (95%CI 1.132-3.848, p=0.018). We replicated this association between the rs41507953 “G” allele and AKI in another cohort of 800 cardiac surgery patients.
To assess the association between the rs41507953 “G” allele and sEH activity we measured 9,10 or 12,13-dihydroxyoctadecanoic acid/9,10 or 12,13-epoxyoctadecanoic acid (DiHOME/EpOME) ratios, measures of sEH activity, in plasma collected from 26 AA and 5 AG individuals in the original cohort. sEH activity was highest in plasma collected post-protamine administration. The 12,13 DiHOME/EpOME and the total DiHOME/EpOME ratios post-protamine were significantly greater in the AG vs. the AA genotype group, 11.66±12.91 vs. 2.32±3.03 (p=0.002) and 28.35±47.79 vs. 4.03±7.96 (p=0.014), respectively.
An EPHX2 variant with increased sEH activity is associated with AKI following cardiac surgery. Pharmacologic inhibition of the sEH enzyme might protect patients from AKI following cardiac surgery.
Author Disclosures: M.M. Shuey: None. F.T. Billings: None. S. Wei: None. G.L. Milne: None. N.J. Brown: None.
- © 2015 by American Heart Association, Inc.