Hypertension & P450 w/w-1 Hykdroxylases and Epoxygenases

高血压

• 批准号: 7459644
• 负责人: MICHAEL R WATERMAN
• 金额: $ 20.66万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7459644
• 关键词: Address; African American; Alkane 1-monooxygenase; Amino Acids; Arachidonic Acids; Attention; Bibliography; Biometry; Boston; CYP4A11 gene; Candidate Disease Gene; Caucasians; Caucasoid Race; Cytochrome P450; DNA; Data; Data Analyses; Data Reporting; Drops; Female; Framingham Heart Study; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Ghana; Grant; Haplotypes; Human; Human Genetics; Human Genome; Hydroxylation; Hypertension; Individual; Introns; Investigation; Kidney; Link; Mixed Function Oxygenases; Mus; Nucleic Acid Regulatory Sequences; Phenotype; Population; Proteins; Public Health Schools; Sampling; Secure; Testing; United States National Institutes of Health; Universities; Variant; Wages; Work; cohort; experience; male; normotensive; professor; programs

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.

在先前的授予期间，该计划项目支持的研究建立了CYP4A14基因与高血压之间的小鼠之间的联系。此处报告的初步数据表明，人类CYP4A11基因与高血压之间的联系也存在。我们已经确定人类基因组中有两个，很可能只有两个CYP4A基因（CYP4A11和CYP4A22）。 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，并且不会产生功能性蛋白质，表明如果人类中高血压和CYP4A之间存在关联，则通过CYP4A11。我们已经检查了390个个体，120名非裔美国人和270名高加索人的CYP4A11基因的外显子序列，这两组均在正常性和高血压之间分布。发现一种变体（F434）与高加索群体中的高血压统计相关，但在非裔美国人群体中无关。在P4504A11蛋白中更改该氨基酸可将花生四烯酸羟化酶活性降低60％。在当前的提案中，我们将使用更大的人群（Framingham心脏研究）来统计确认当地队列的初步结果。 Framingham研究产生了广泛的表型数据，这将有助于确定与该变体相关的表型。我们使用该队列的priminary数据表明在高血压中的关联 高加索男性，而不是女性。我们还将在非裔美国人队列（AASK）和加纳队列中研究这种变体。还将检查CYP4A11的5'-regulatory区域 多态性也是其内含子。将仔细检查来自CYP4A11的数据以识别 与高血压的单倍型关联。最后，我们将对人肾脏中的另一个丰富的CYP基因进行多态性发现，CYP2C8。我们认为，我们的初步数据清楚地将CYP4A11作为用于研究高血压的候选基因。有大量证据表明，花生四烯酸羟基化和去氧化与高血压有关，这进一步强调了这些研究的重要性。