Association of a functional cytochrome P4504F2 haplotype with urinary 20-HETE and hypertension
Association of a functional cytochrome P4504F2 haplotype with urinary 20-HETE and hypertension
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功能性细胞色素 P4504F2 单倍型与尿 20-HETE 和高血压的关联
DOI：
10.1681/asn.2007060713
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发表时间：
2008-04-01
影响因子：
13.6
通讯作者：
Lu, Jingyu
中科院分区：
文献类型：
--
作者：
Liu, Hong;Zhao, Yanyan;Lu, Jingyu
细胞色素P450 4F 2（CYP 4F 2）催化花生四烯酸的ω-羟基化为20-羟基二十碳四烯酸（20-HETE），20-HETE是一种参与高血压发展的利钠和血管活性类二十碳酸。CYP 4F 2调控区基因变异、肾20-HETE形成和高血压之间的关系尚不清楚。本文报道了CYP 4F 2内含子调控区周围的7种遗传变异。这些变异中的四个使LIP成为两种常见的单倍型，Hap I（c.- 91T/c.- 48G/c.- 13T/c.+ 34T）和Hap II（c.- 91C/c.- 48C/c.- 13 C/c.+ 34 G）。Hap I包括一个主要的功能变体，c。91 T-> C，经报告基因分析和电泳迁移率变动分析鉴定。转染到HEK 293细胞中，Hap I构建体显示出更高的基础转录活性的趋势，并表现出比Hap II显著更大的LPS刺激活性;这些发现是两种构建体之间不同NF-κ B结合亲和力的结果。在体内，一项病例对照研究表明，Hap I的纯合性使中国人群患高血压的风险增加了一倍，即使在调整了年龄、性别和体重指数等风险因素后也是如此。这种关联在一项以家庭为基础的关联研究中得到证实。此外，Hap I与尿20-HETE升高相关。这些结果表明，CYP 4F 2调节区的功能变体增加了NF-κ B的结合亲和力，增加了高血压的风险，可能是通过调节20-HETE的产生。
Cytochrome P450 4F2 (CYP4F2) catalyzes the omega-hydroxylation of arachidonic acid to 20-hydroxyeicosatetraenoic acid (20-HETE), a natriuretic and vasoactive eicosanoid that participates in the development of hypertension. The relationship among CYP4F2 genetic variants in the regulatory region, formation of renal 20-HETE, and hypertension is unknown. Here are reported seven genetic variants around the CYP4F2 intronic regulatory region. Four of these variants made LIP two common haplotypes, Hap I (c.-91T/c.-48G/c.-13T/c.+34T) and Hap II (c.-91C/c.-48C/c.-13C/c.+34G). Hap I included a major functional variant, c.-91T -> C, which was identified by reporter assay and electrophoretic mobility shift assay. Transfected into HEK293 cells, the Hap I construct showed a trend toward higher basal transcriptional activity and exhibited significantly greater LPS-stimulated activity than Hap II; these findings were the result of different NF-kappa B binding affinity between the two constructs. In vivo, a case-control study demonstrated that homozygosity for Hap I doubled the risk for hypertension in a Chinese population, even after adjustment for risk factors including age, gender, and body mass index. This association was confirmed in a family-based association study. In addition, Hap I was associated with elevated urinary 20-HETE. These results indicate that a functional variant of the CYP4F2 regulatory region, which increases the binding affinity of NF-kappa B, increases the risk for hypertension, likely by modulating the production of 20-HETE.