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Association of a Functional Cytochrome P450 4F2 Haplotype with Urinary 20-HETE and Hypertension

Hong Liu^*, Yanyan Zhao^*, Dong Nie^*, Jingpu Shi, Lingyu Fu, Yan Li^*, Dahai Yu^* and Jingyu Lu^*

Departments of ^* Medical Genetics and Clinical Epidemiology, China Medical University, Shenyang, China

Correspondence: Prof. Yanyan Zhao, Department of Medical Genetics, China Medical University, No92, Bei Er Road, Shenyang, 110001, China. Phone: +86-24-23257322; Fax: +86-24-23257322; E-mail: yyzhao{at}mail.cmu.edu.cn

Received for publication June 27, 2007. Accepted for publication November 19, 2007.

Cytochrome P450 4F2 (CYP4F2) catalyzes the -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 up 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.–91TC, 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-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-B, increases the risk for hypertension, likely by modulating the production of 20-HETE.

Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673