title: 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.
  
  
  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.
authors.affiliation: Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical School, Nashville, Tenn 37232-0146, USA.
authors.forename: James V
authors.initials: JV
authors.lastname: Gainer
authors.forename: Aouatef
authors.initials: A
authors.lastname: Bellamine
authors.forename: Elliott P
authors.initials: EP
authors.lastname: Dawson
authors.forename: Kristie E
authors.initials: KE
authors.lastname: Womble
authors.forename: Sarah W
authors.initials: SW
authors.lastname: Grant
authors.forename: Yarong
authors.initials: Y
authors.lastname: Wang
authors.forename: L Adrienne
authors.initials: LA
authors.lastname: Cupples
authors.forename: Chao-Yu
authors.initials: CY
authors.lastname: Guo
authors.forename: Serkalem
authors.initials: S
authors.lastname: Demissie
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: O'Donnell
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Brown
authors.forename: Michael R
authors.initials: MR
authors.lastname: Waterman
authors.forename: Jorge H
authors.initials: JH
authors.lastname: Capdevila
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D019943:Amino Acid Substitution; D016718:Arachidonic Acid / Q000378:metabolism; D044383:Black People / Q000235:genetics; D001794:Blood Pressure / Q000235:genetics / Q000502:physiology*; D003062:Codon / Q000235:genetics; D015331:Cohort Studies; D015897:Comorbidity; D042926:Cytochrome P-450 CYP4A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000502:physiology; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000096:biosynthesis*; D006973:Hypertension / Q000201:enzymology / Q000208:ethnology / Q000235:genetics*; D007438:Introns / Q000235:genetics; D007668:Kidney / Q000201:enzymology; D007850:Lauric Acids / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020412:Multifactorial Inheritance; D016254:Mutagenesis, Insertional; D020125:Mutation, Missense; D017354:Point Mutation; D017384:Sequence Deletion; D013714:Tennessee / Q000453:epidemiology; D014481:United States / Q000453:epidemiology; D044465:White People / Q000235:genetics; D001741:Black or African American
chemical_list: D003062:Codon; D006893:Hydroxyeicosatetraenoic Acids; D007850:Lauric Acids; C030358:lauric acid; D016718:Arachidonic Acid; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D003577:Cytochrome P-450 Enzyme System; C465478:CYP4A11 protein, human; C471051:CYP4A22 protein, human; D042926:Cytochrome P-450 CYP4A