Functional variant of CYP4A11 20-hydroxyeicosatetraenoic acid synthase is associated with essential hypertension.
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.
Gainer
James V
JV
Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical School, Nashville, Tenn 37232-0146, USA.
Bellamine
Aouatef
A
Dawson
Elliott P
EP
Womble
Kristie E
KE
Grant
Sarah W
SW
Wang
Yarong
Y
Cupples
L Adrienne
LA
Guo
Chao-Yu
CY
Demissie
Serkalem
S
O'Donnell
Christopher J
CJ
Brown
Nancy J
NJ
Waterman
Michael R
MR
Capdevila
Jorge H
JH
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
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