Hypertension & P450 w/w-1 Hykdroxylases and Epoxygenases

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During the previous granting period studies supported by this Program Project established a link in the mouse between the Cyp4a14 gene and hypertension. Preliminary data reported here suggests that a link between the human CYP4A11 gene and hypertension also exists. We have established that there are two, and most likely only two CYP4A genes (CYP4A11 and CYP4A22) in the human genome. CYP4A11 uses either lauric acid or arachidonic acid as substrate. We have found that the CYP4A22 gene is very poorly expressed in kidney and does not produce a functional protein, indicating that if there is association between hypertension and CYP4A in humans, it is through CYP4A11. We have examined the exonic sequence of the CYP4A11 gene in 390 individuals, 120 African Americans and 270 Caucasians, both groups equally distributed between normotensive and hypertensive. A variant (F434S) is found to be statistically associated with hypertension in the Caucasian group but not in the African American group. Changing this amino acid in the P4504A11 protein reduces arachidonic acid hydroxylase activity by 60%. In the current proposal we will use a much larger population (Framingham Heart Study) to statistically confirm the preliminary results from our local cohort. The Framingham Study has generated extensive phenotypic data which will be helpful in determining the phenotype associated with this variant. Our prliminary data with this cohort indicates association in hypertension in Caucasian males but not females. We will also study this variant in an African-American cohort (AASK) and cohorts from Ghana. The 5'-regulatory region of CYP4A11 will also be examined for polymorphisms as will its introns. This data from CYP4A11 will be carefully examined to identify haplotype associations with hypertension. Finally, we will carry out polymorphism discovery on the other abundant CYP gene in human kidney, CYP2C8. We believe that our preliminary data clearly establish CYP4A11 as a candidate gene for investigation of hypertension. There is considerable evidence that arachidonic acid hydroxylation and expoxidation are related to hypertension which further emphasizes the importance of these studies.