Abstract 749: A New Candidate Gene of Essential Hypertension: CYP4A11 Gene, Regulating a 20-Hydroxyeicosatetraenoic Acid Production
Background: The CYP4A11, ω/ω-1 hydroxylase, oxidizes arachidonic acid to 20-hydroxyeicosatetraenoic acid (20-HETE) which is a metabolite with renovascular and tubular function in human. Even though previous association study suggested the association between a polymorphism (T8590C) of CYP4A11 gene and hypertension, the precise mechanism of the association hasn’t been clarified yet. To assess the functional implications of CYP4A11 gene in the pathogenesis of hypertension, we carried out a large genetic epidemiological study in Japan, the Tanno Sobetsu Study.
Methods and Results: The consequence of the minor allele frequency and the estimation of the linkage disequilibrium among SNPs of CYP4A11 gene is that we decided to use two polymorphisms, A-845G (allele frequency was 0.22) in promoter region and T8590C (allele frequency was 0.347) in exon11. The subjects who gave the informed consent for genetic analysis (n=1514) were recruited from the participants of the Tanno Sobetsu Study. After adjustment of confounding factors (age, sex and BMI), A-845G polymorphism was significantly associated with the prevalence of hypertension and the estimated odds ratio with G allele for hypertension was 1.66 (95%CI: 1.12–2.47). The significance of the association was stronger in male then in female. On the other hand, there was no association between T8590C polymorphism and hypertension. The luciferase activity of constructs containing -845GG genotype of CYP4A11 promoter was 41% higher than that with the -845AA genotype (p=0.02). Gel mobility shift assay showed a specific binding of the -845GG genotype to nuclear protein extracts.
Conclusions: We identified a functional variant (A-845G) in the promoter of CYP4A11, and revealed the significant association with hypertension. A-845G polymorphism of CYP4A11 is new candidate of genetic predisposing factor for hypertension via modulation of the ’third arachidonate cascade’.