A Single Nucleotide Polymorphism in the CYP4F2 but not CYP4A11 Gene Is Associated With Increased 20-HETE Excretion and Blood Pressure

Abstract

Abstract-Arachidonic acid is a major fatty acid that can be metabolized by the cytochrome P450 enzyme to a number of bioactive eicosanoids. A major metabolite of this oxidation is 20-hydroxyeicosatetraenoic acid, which acts as a potent vasoconstrictor. However, in the kidney, its vasoconstrictor actions can be offset by its natriuretic properties. A guanine-to-adenine polymorphism in the CYP4F2 gene was associated with a reduction in 20-hydroxyeicosatetraenoic acid production in vitro. A thymidine-to-cytosine polymorphism in the CYP4A11 gene reduced catalytic activity by Ͼ50% in vitro and was associated with hypertension. The aim was to determine whether these 2 mutations are associated with urinary 20-hydroxyeicosatetraenoic acid excretion and blood pressure in humans. For the CYP4F2, 51% were homozygous for the G allele, 40% were carriers, and 9% were homozygous for the A allele. For CYP4A11, 72% were homozygous for the T allele, 25% were carriers, and 3% were homozygous for the C allele. The CYP4F2 GA/AA genotype was significantly associated with an increase in both 20-hydroxyeicosatetraenoic acid excretion and systolic blood pressure. The CYP4A11 CC/TC genotype was significantly associated with a reduction in 20-hydroxyeicosatetraenoic acid excretion but was not associated with blood pressure. We have demonstrated for the first time in humans that polymorphisms of the CYP4F2 and CYP4A11 genes have opposite effects on 20-hydroxyeicosatetraenoic acid excretion. The positive association between the CYP4F2 GA/AA genotype and both systolic blood pressure and 20-hydroxyeicosatetraenoic acid excretion strengthens a role for 20-hydroxyeicosatetraenoic acid in the modulation of blood pressure. A rachidonic acid is a major membrane fatty acid that can be metabolized by the cytochrome P450 (CYP450) enzymes to a range of bioactive compounds. These compounds are thought to play a central role in the regulation of blood pressure (BP), vascular tone, and renal function. 1,2 Within the vasculature, the CYP450 enzymes belonging to the 2-gene family (CYP 2B, 2C8, 2C9, 2C10, and 2J2) are responsible for the production of epoxides, whereas the -hydroxylases belonging to the CYP 4A and 4F families are involved in the production of hydroxyeicosatetraenoic acids (HETEs). 3,4 Animal studies have previously shown that disruption of the murine Cyp450 4a14 gene results in hypertension, possibly via increased expression of Cyp4a12. 5 20-HETE has been shown to play a role in vasoconstriction and renal salt handling in the spontaneously hypertensive rat. 2,6 -8 In humans, 20-HETE has been shown to play a role in regulation of natriuresis in salt-sensitive and salt-resistant hypertension, 9 and we have previously demonstrated a significant association between urinary 20-HETE excretion and both hypertension and endothelial dysfunction. 10 Paradoxically, within the kidney, 20-HETE can have either prohypertensive or antihypertensive actions, depending on its site of production. In the renal tubule, 20-HETE inhibits tubular sodium reabsorpti...

Interaction among <i>CYP2C8</i>, <i>EPHX2</i>, and <i>CYP4A11</i> Gene Variants Significantly Increases the Risk for Ischemic Stroke in Chinese Populations

“…Apart from the rs9333025 variant, there were no significant differences in association with IS identified for other variants using a singlelocus analytical approach. These results were consistent with those of some previous studies 29,34,35) and in contrast to some others 20,22,[25][26][27][28][36][37][38] . For instance, Gschwendtner et al have reported that genetic variations in the EPHX2 gene are associated with IS risk, an association that has been described as predominantly mediated by large-vessel disease 36) .…”

“…Similarly, Zhang et al have reported that the EPHX2 860A allele is associated with a significantly reduced risk of IS 37) . In addition, Ward et al have reported that a single polymorphism in the CYP4F2 gene is associated with increased 20-HETE 38) . Some studies also have reported that CYP4F2 polymorphisms are associated with IS risk [25][26][27][28] .…”

“…CYPderived EETs and 20-HETE regulate sodium transport and blood pressure 52) . Some previous studies have shown that these genetic variants are associated with hypertension through the regulation of sodium transport and CYP metabolites 38,52,53) . All of these previous observations support the hypothesis that the three-factor interaction affects IS pathogenesis.…”

20-HETE is Associated with Unfavorable Outcomes in Subarachnoid Hemorrhage Patients

“…25,26 Interpretation of our results is complicated by the discrepant in vitro/in vivo findings on the effect of CYP4F3*3 on 20-HETE levels, which despite decreased activity in vitro have shown increased 20-HETE concentrations in the urine of patients. 16,27 With respect to CYP4A11, our genetic analysis showed that patients with the variant g.4207G-allele located in the promoter region of CYP4A11 showed 43% lower mean 20-HETE CSF levels. In silico models predicted that this SNP will lower CYP4A11 transcriptional activity.…”

Lack of an association between TSC gene Arg904Gln polymorphisms and essential hypertension risk based on a meta-analysis

“…Many candidate genes have been reported to be involved in essential hypertension susceptibility, including TSC, NEDD4L (Luo et al, 2009), CYP4F2 (Ward et al, 2008), EMILIN 1 (Shimodaira et al, 2010), ATP2B1 (Tabara et al, 2010), apelin-AGTRL1 system (Niu et al, 2010), and so on. Several studies suggest that TSC plays a major role in sodium and chloride re-absorption in the distal convoluted tubule, accounting for a significant proportion of the total renal sodium re-absorption (Plotkin et al, 1996;Matsuo et al, 2004).…”