Hypertension & P450 w/w-1 Hykdroxylases and Epoxygenases

在上一个资助期内，该项目支持的研究在小鼠中建立了Cyp4a14基因与高血压之间的联系。本文报道的初步数据表明，人类CYP4A11基因与高血压之间也存在联系。我们已经确定，有两个，最有可能只有两个CYP4A基因（CYP4A11和CYP4A22）在人类基因组中。CYP4A11使用月桂酸或花生四烯酸作为底物。我们发现CYP4A22基因在肾脏中表达非常低，并且不产生功能性蛋白质，这表明如果人类高血压与CYP4A之间存在关联，则是通过CYP4A11。我们研究了390个人，120名非洲裔美国人和270名高加索人，两组平均分布在血压正常和高血压之间的CYP4A11基因的外显子序列。发现一种变异体（F434S）与高加索人组的高血压有统计学相关性，但与非洲裔美国人组无关。改变P4504A11蛋白中的这种氨基酸可使花生四烯酸羟化酶活性降低60%。在目前的提案中，我们将使用更大的人群（心脏病研究）来统计确认我们当地队列的初步结果。Fracket研究产生了大量的表型数据，这将有助于确定与该变体相关的表型。我们对这一队列的初步数据表明， 白人男性但不是女性我们还将在非洲裔美国人队列（AASK）和来自加纳的队列中研究这种变体。还将检查CYP4A11的5 '调控区， 多态性，其内含子也是。将仔细检查CYP4A11的数据，以确定 单倍型与高血压的关系最后，我们将对人类肾脏中另一个丰富的CYP2C8基因进行多态性发现。我们相信，我们的初步数据清楚地建立CYP4A11作为一个候选基因的高血压调查。大量证据表明花生四烯酸羟基化和花生四烯酸氧化与高血压有关，这进一步强调了这些研究的重要性。

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.