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

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

来源：Hypertension, 2008, 52(6): 1142-1148.

DOI：10.1161/HYPERTENSIONAHA.108.114082

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

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. (Hypertension. 2008;52:1142-1148.)

• 出版日期2008-12