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(Hypertension. 2008;52:1142.)
© 2008 American Heart Association, Inc.

Original Articles

A Polymorphism Regulates CYP4A11 Transcriptional Activity and Is Associated With Hypertension in a Japanese Population

Ken Sugimoto; Hiroshi Akasaka; Tomohiro Katsuya; Koichi Node; Tomomi Fujisawa; Izumi Shimaoka; Osamu Yasuda; Mitsuru Ohishi; Toshio Ogihara; Kazuaki Shimamoto; Hiromi Rakugi

From the Department of Geriatric Medicine (K.S., T.K., T.F., I.S., O.Y., M.O., H.R.), Osaka University Graduate School of Medicine, Osaka, Japan; Second Department of Internal Medicine (H.A., K.S.), Sapporo Medical University, Sapporo, Japan; Cardiovascular and Renal Medicine (K.N.), Saga University Faculty of Medicine, Saga, Japan; and Osaka General Medical Center (T.O.), Osaka Prefectural Hospital Organization, Osaka, Japan.

Correspondence to Tomohiro Katsuya, Department of Geriatric Medicine, Osaka University Graduate School of Medicine, 2-2 #B6, Yamadaoka, Suita, Osaka 565-0871, Japan. E-mail katsuya{at}geriat.med.osaka-u.ac.jp

CYP4A11 oxidizes arachidonic acid to 20-hydroxyeicosatetraenoic acid, a metabolite with renovascular and tubular function in humans. A previous study demonstrated a significant association between the CYP4A11 gene polymorphism and hypertension; however, the precise mechanism of the association has not been clarified. To assess the involvement of CYP4A11 in the pathogenesis of hypertension, we sought to identify a functional polymorphism of CYP4A11 and examined its impact on predisposition to hypertension in the Tanno-Sobetsu Study. The –845A/G polymorphism was identified in the promoter region of CYP4A11 by direct sequencing. Luciferase expression driven by the promoter of CYP4A11 containing the wild-type –845GG genotype was 30% lower than expression with the variant –845AA genotype. Gel mobility shift assays with nuclear protein extracts showed specific binding to probes containing the variant –845GG. To assess the effect of CYP4A11 polymorphisms on hypertension, we also carried out a case-control study using 4 single nucleotide polymorphisms (–845A/G, –366C/T, 7119C/T, and 8590T/C) in the Tanno-Sobetsu Study. The odds ratio for hypertension in participants with the AG+GG genotype of –845A/G was 1.42 (P=0.008), and the odds ratio for hypertension of the TT genotype of 7119C/T was 1.37 (P=0.037) after adjusting for confounding factors. The haplotype-based case-control analysis using 4 single nucleotide polymorphisms revealed a significant haplotype (G-C-T-T) that was significantly associated with hypertension, with an odds ratio of 1.44 (P=0.006) after adjusting for confounding factors. We have identified a functional variant (–845A/G) of CYP4A11 that is significantly associated with hypertension and that appears to be a novel candidate for a predisposing factor for hypertension.

Key Words: genetics • hypertension • single nucleotide polymorphism (SNP) • CYP4A11 gene • renal circulation • transcription factor