Published Online
on December 20, 2004

A more recent version of this article appeared on January 4, 2005

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Submitted on June 25, 2004
Revised on August 24, 2004
Accepted on September 27, 2004

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

James V. Gainer MD, Aouatef Bellamine PhD, Elliott P. Dawson , Kristie E. Womble , Sarah W. Grant , Yarong Wang , L. Adrienne Cupples PhD, Chao-Yu Guo MS, Serkalem Demissie PhD, MPH, Christopher J. O’Donnell MD, MPH, Nancy J. Brown MD, Michael R. Waterman PhD^*, and Jorge H. Capdevila PhD

From the Department of Medicine, Divisions of Clinical Pharmacology (J.V.G., N.J.B.) and Nephrology (Y.W., J.H.C.) and the Department of Biochemistry (A.B., M.R.W.), Vanderbilt University Medical School, Nashville, Tenn; BioVentures Inc (E.P.D., K.E.W., S.W.G.), Murfreesboro, Tenn; Department of Biostatistics (L.A.C., C.-Y.G., S.D.), Boston University School of Public Health, Boston, Mass; and National Heart, Lung, and Blood Institute/Framingham Heart Study (C.J.O.), Framingham, Mass.

^* To whom correspondence should be addressed. E-mail: michael.waterman{at}vanderbilt.edu.

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; n=1538) in all subjects and 1.33 (CI 1.01 to 1.77; n=1331) when subjects with diabetes were excluded. No association of the variant with hypertension was detected in a population of 120 blacks.

Conclusions--We identified a variant of the human CYP4A11 (T8590C) that encodes for a monooxygenase with reduced 20-HETE synthase activity. The association of the T8590C variant with hypertension supports its role as a polygenic determinant of blood pressure control in humans, and results obtained from the large population database suggest that the relevance of the variant may vary according to hypertension comorbidity.

Key words: genetics • hypertension, renal • lipids • metabolism

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