| Summary: | Genes in the epoxygenase pathway of arachidonic acid metabolism leading to vasoactive eicosanoids, mainly 20-hydroxyeicosatetraenoic (20-HETE) and epoxyeicosatrienoic (EETs) acids, have been related to glucose-induced renal damage in preclinical reports. We genotyped 1088 diabetic kidney disease (DKD) patients and controls for seven polymorphisms in five genes (<i>CYP2C8</i>, <i>CYP2J2</i>, <i>CYP4F2</i>, <i>CYP4A11</i>, and <i>EPHX2</i>) along this metabolic route and evaluated their effect on DKD risk, clinical outcomes, and the plasma/urine levels of eicosanoids measured by LC/MS/MS and immunoenzymatic assays. The <i>CYP4F2</i> 433M variant allele was associated with lower incidence of DKD (OR = 0.65 (0.48–0.90), <i>p</i> = 0.008), whilst the <i>CYP2C8*3/*3</i> genotype was related to increased risk (OR = 3.21 (1.05–9.87), <i>p</i> = 0.036). Patients carrying the 433M allele also showed lower eGFR [median and interquartile range vs. wildtype carriers: 30.8 (19.8) and 33.0 (23.2) mL/min/1.73 m<sup>2</sup>, <i>p</i> = 0.037). Finally, the 433VM/MM variant genotypes were associated with lower urinary levels of 20-HETE compared with 433VV (3.14 (0.86) vs. 8.45 (3.69) ng/mg Creatinine, <i>p</i> = 0.024). Our results indicate that the <i>CYP4F2</i> V433M polymorphism, by decreasing 20-HETE levels, may play an important role in DKD.
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