Functional variant of CYP4A11 20-hydroxyeicosatetraenoic acid synthase is associated with essential hypertension.

Gainer JV, Bellamine A, Dawson EP, Womble KE, Grant SW, Wang Y, Cupples LA, Guo CY, Demissie S, O'Donnell CJ, Brown NJ, Waterman MR, Capdevila JH
Circulation. 2005 111 (1): 63-9

PMID: 15611369 · DOI:10.1161/01.CIR.0000151309.82473.59

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.

MeSH Terms (34)

Adult African Continental Ancestry Group Aged Alleles Amino Acid Substitution Arachidonic Acid Blood Pressure Codon Cohort Studies Comorbidity Cytochrome P-450 CYP4A Cytochrome P-450 Enzyme System DNA Mutational Analysis European Continental Ancestry Group Female Gene Frequency Genetic Predisposition to Disease Genetic Variation Genotype Humans Hydroxyeicosatetraenoic Acids Hypertension Introns Kidney Lauric Acids Male Middle Aged Multifactorial Inheritance Mutagenesis, Insertional Mutation, Missense Point Mutation Sequence Deletion Tennessee United States

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