Functional Variant of CYP4A11 20-Hydroxyeicosatetraenoic Acid Synthase Is Associated With Essential Hypertension

Abstract

Background-The CYP4A11 arachidonic acid monooxygenase oxidizes endogenous arachidonic acid (AA) to 20-hydroxyeicosatetraenoic acid (20-HETE), a metabolite with renovascular and tubular functions. Mice with targeted disruption of Cyp4a14, a murine homologue of CYP4A11, have severe hypertension. We combined molecular and biochemical approaches to identify a functional variant of the CYP4A11 20-HETE synthase and determine its association with hypertensive status in 2 independent human populations. Methods and Results-A thymidine-to-cytosine polymorphism at nucleotide 8590 resulted in a phenylalanine-to-serine substitution at amino acid 434. Expression of cDNA with serine 434 resulted in a protein with a significantly reduced AA and lauric acid metabolizing activity. In a population of 512 whites from Tennessee, the age, body mass index, and gender-adjusted OR of having hypertension attributable to the 8590C variant was 2.31 (95% CI 1.41 to 3.78) compared with the reference 8590TT genotype. In subjects from the Framingham Heart Study, the adjusted ORs of hypertension associated with the 8590C variant were 1.23 (CI 0.94 to 1.59; nϭ1538) in all subjects and 1.33 (CI 1.01 to 1.77; nϭ1331) when subjects with diabetes were excluded. No association of the variant with hypertension was detected in a population of 120 blacks. Conclusions-We

Association of the T8590C Polymorphism of CYP4A11 With Hypertension in the MONICA Augsburg Echocardiographic Substudy

“…The less frequent 8590C genotype, which corresponds to the 434S variant on protein level, affects the catalytic activity of the 20-HETE synthase through a loss-of-function mechanism. 10 This variant was associated weakly with hypertension in the Framingham Offspring Cohort. Similar results were obtained in white participants of the Tennessee Cohort.…”

“…8,9 Recently, CYP4A11 but not CYP4A22 was identified as the functional active protein that catalyzes the metabolism of arachidonic acid to 20-HETE in humans. 10 Screening for genetic variants revealed a cytosine for thymidine transition at nucleotide 8590 in exon 11, which results in a nonsynonymous phenylalanine to serine substitution at residue 434 of CYP4A11. The less frequent 8590C genotype, which corresponds to the 434S variant on protein level, affects the catalytic activity of the 20-HETE synthase through a loss-of-function mechanism.…”

“…Subgroup analyses in these studies including blacks within the Tennessee Cohort did not show significant association, most likely because of insufficient power. 10 This initial weak positive evaluation requires verification in an independent cohort to reduce the chance of being false-positive. Furthermore, the present analysis within the population-based MONICA (MONitoring trends and determinants In CArdiovascular disease) Augsburg echocardiographic substudy sample intends to evaluate the potential impact of the CYP4A11 T8590C polymorphism on echocardiographic parameters of left ventricular (LV) function and geometry.…”

Regulation of Human Cytochrome P450 4F2 Expression by Sterol Regulatory Element-binding Protein and Lovastatin

“…Selective disruption of the murine Cyp4a10 (6) and Cyp4a14 (7) genes leads to hypertensive phenotypes that are thought to reflect changes in renal 20-HETE production arising through distinct mechanisms. Interestingly, an allelic variant encodes a human CYP4A11 with reduced catalytic activity that is associated with an increased risk for hypertension in studies of three independent cohorts (8,9). P450s 4F2 and 4F3B are highly similar in amino acid sequence and display overlapping catalytic activity profiles.…”

Cytochromes P450: Roles in Diseases

“…1B). 20-HETE regulates salt and water balance in this organ; therefore, a mutation in CYP4A11 (F434S) profoundly reducing 20-HETE biosynthesis was found in three different cohorts of individuals with elevated blood pressure (essential hypertension; MIM 145500) (91)(92)(93)(94). Elevated blood pressure was more significant in males than in females in an African-American cohort, suggesting androgen regulation of CYP4A11 transcription (94).…”