Association of CYP4A11 Variants with Resistant Hypertension

CYP4A11 变异与难治性高血压的关联

基本信息

批准号：
9336690
负责人：
Megan Marie Shuey
金额：
$ 2.87万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9336690
关键词：
Academic Medical Centers Acids Adult African African American Algorithms Alleles Antihypertensive Agents Arachidonic Acids Area Attenuated Bioinformatics Blood Pressure CYP4A11 gene Cardiovascular system Chronic Kidney Failure Communication Computerized Medical Record Congestive Heart Failure Cytochrome P450 DNA DNA Databases Data Distal Diuretics Drug resistance Enzymes European Evaluation Experimental Designs Foundations Funding Future Genetic Variation Genotype Hospitals Hydroxyeicosatetraenoic Acids Hydroxylation Hypertension Individual Institution Knowledge Lead Link Linkage Disequilibrium Location Mentorship Mixed Function Oxygenases Molecular Myocardial Infarction National Research Service Awards Nephrons Patients Pharmaceutical Preparations Pharmacogenetics Pharmacology Phenotype Population Population Heterogeneity Records Research Research Personnel Research Technics Resistant Hypertension Sampling Sodium Spironolactone Testing Thiazide Diuretics Training Treatment Step Variant base blood pressure regulation career case control epithelial Na+ channel hypertension control loss of function member new therapeutic target novel novel therapeutics predicting response programs repository response salt sensitive hypertension therapeutic development vasoconstriction

项目摘要

Project Summary/Abstract Despite adequate treatment with antihypertensive, medications including a diuretic, between 8.4% and 17.5% of adults with hypertension continue to have uncontrolled blood pressure, resistant hypertension (RH). RH is associated with increased rates of cardiovascular and chronic kidney diseases. Identification of novel mechanisms underlying this condition is essential for the discovery of new pharmacological strategies. One potential mechanism involves the cytochrome P450 enzyme CYP4A11, responsible for the ω-hydroxylation of arachidonic acid to form 20-hydroxyeicosatetraienoic acid (20-HETE). 20-HETE has both pro- and anti- hypertensive actions depending on the location of expression, i.e. in the vasculature or in the nephron, respectively. Variants in the CYP4A11 gene have been associated with elevated blood pressure in various populations as well as differential responses to diuretics. I, therefore, hypothesize that CYP4A11 loss-of-function variants will be associated with RH due to attenuated responses to specific diuretics. In Aim I, using a bioinformatics approach I will test the hypothesis that CYP4A11 loss-of-function variants, rs1126742 and rs3890011, are associated with RH in patients treated at Vanderbilt University Medical Center using Vanderbilt's DNA databank linked to electronic medical records, BioVU. In Aim II, I will again use a bioinformatics approach to test the hypothesis that CYP4A11 loss-of-function variants are associated with an attenuated response to diuretic antihypertensive therapies, specifically spironolactone among the 42,110 adult subjects prescribed spironolactone in BioVU. Identification of associations with RH or attenuated antihypertensive response and CYP4A11 variants may suggest a potential molecular mechanism for hypertension to be evaluated in future studies. Further, the results of the proposed project may lead to new pharmacogenetic strategies to optimize therapy for patients with RH. In addition to a strong research program, exemplified by an established mentorship team of experts in relevant research areas, the receipt of NRSA funding will bolster my training by providing opportunities to expand my knowledge of experimental design, research techniques, and scientific communication. These opportunities are essential to my pursuit of a career as an independent researcher at an academic institution.

项目概要/摘要尽管接受了充分的抗高血压治疗，但仍有 8.4% 至 17.5% 的患者接受了包括利尿剂在内的药物治疗成人高血压患者的血压持续不受控制，称为难治性高血压 (RH)。与心血管和慢性肾脏疾病发病率增加相关的新发现。这种情况的潜在机制对于发现新的药理学策略至关重要。潜在机制涉及细胞色素 P450 酶 CYP4A11，负责 ω-羟基化花生四烯酸形成 20-羟基二十碳四烯酸 (20-HETE)，具有亲和抗作用。高血压作用取决于表达位置，即在脉管系统或肾单位中， CYP4A11 基因的变异分别与多种血压升高有关。人群以及对利尿剂的不同反应。因此，我认为 CYP4A11 功能丧失变体将与 RH 相关，因为对特定利尿剂的减弱反应在目标 I 中，我将使用生物信息学方法测试假设 CYP4A11 功能丧失变异体 rs1126742 和 rs3890011 与 RH 相关范德比尔特大学医学中心使用范德比尔特 DNA 数据库治疗的患者电子病历，BioVU。在 Aim II 中，我将再次使用生物信息学方法来检验假设。 CYP4A11 功能丧失变异与利尿剂反应减弱有关 42,110 名成人受试者接受了抗高血压治疗，特别是螺内酯 BioVU 中螺内酯与 RH 或抗高血压反应减弱的关联的鉴定 CYP4A11变异可能提示未来评估高血压的潜在分子机制此外，拟议项目的结果可能会导致新的药物遗传学策略的优化。 RH 患者的治疗。除了强大的研究计划外，还包括相关领域的专家指导团队研究领域，获得 NRSA 资助将通过提供扩展我的机会来加强我的培训实验设计、研究技术和科学交流的知识。对于我作为学术机构独立研究员的职业追求至关重要。