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1 Physiology & Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, United States
2 Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
3 Genome Sciences, University of Washington, Seattle, Washington, United States
* To whom correspondence should be addressed. E-mail: dstec{at}physiology.umsmed.edu.
20-Hydroxyeciosatetranoic acid (20-HETE) plays an important role in the regulation of renal tubular and vascular function and a deficiency in the renal formation of 20-HETE has been linked to the development of hypertension. The cytochrome P450 4F2 (CYP4F2) gene encodes for the major CYP enzyme responsible for the synthesis of 20-HETE in the human kidney. We screened two human sampling panels (African- and European-Americans, n=24 and 23 individuals, respectively) using PCR and DNA resequencing to identify informative SNPs in the coding region of the CYP4F2 gene. Two non-synonymous SNPs that lead to amino acid changes at position 12 (W12G) and 433 (V433M), were identified. Both of these variants were found to be frequent in both African- and European-American sampling panels (9-21% minor allele frequency), and the W12G polymorphism exhibited extensive linkage disequilibrium with surrounding SNPs. In order to determine the functional significance of these mutations on the ability of the CYP4F2 enzyme to metabolize arachidonic acid and leukotriene B4 (LTB4), recombinant baculoviruses containing four different human CYP4F2 variants (i.e. W12/V433, W12/M433, G12/V433, G12/M433) were generated and the proteins expressed in Sf9 insect cells. The presence of the M433 allele, W12/M433 or G12/M433 decreased 20-HETE production to 56-66% of control. In contrast these variants had no effect on the w-hydroxylation of LTB4. These findings are the first to identify a functional variant in the human CYP4F2 gene that alters the production of 20-HETE.
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