Association of a functional cytochrome P450 4F2 haplotype with urinary 20-HETE and hypertension.
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 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.-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-kappaB 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-kappaB, increases the risk for hypertension, likely by modulating the production of 20-HETE.
Liu
Hong
H
Department of Medical Genetics, China Medical University, No92, Bei Er Road, Shenyang, 110001, China. yyzhao@mail.cmu.edu.cn.
Zhao
Yanyan
Y
Nie
Dong
D
Shi
Jingpu
J
Fu
Lingyu
L
Li
Yan
Y
Yu
Dahai
D
Lu
Jingyu
J
D000328:Adult; D016022:Case-Control Studies; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D000072470:Cytochrome P450 Family 4; D005260:Female; D006239:Haplotypes; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000652:urine*; D006973:Hypertension / Q000235:genetics* / Q000652:urine*; D008297:Male; D008875:Middle Aged
D006893:Hydroxyeicosatetraenoic Acids; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D003577:Cytochrome P-450 Enzyme System; D000072470:Cytochrome P450 Family 4; C117480:CYP4F2 protein, human