Association of CYP4A11 Variants with Resistant Hypertension

CYP4A11 变异与难治性高血压的关联

• 批准号: 9189886
• 负责人: Megan Marie Shuey
• 金额: $ 2.82万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 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/9189886
• 关键词: Academic Medical Centers; Acids; Adult; African; African American; Algorithms; Alleles; Amiloride; Antihypertensive Agents; Arachidonic Acids; Area; Attenuated; Bioinformatics; Blood Pressure; CYP4A11 gene; Cardiovascular system; Chronic; Chronic Kidney Failure; Communication; Computerized Medical Record; Congestive Heart Failure; Cytochrome P450; DNA; DNA Databases; Data; Distal; Diuretics; Drug resistance; Enzymes; Epithelial; European; Evaluation; Experimental Designs; Foundations; Funding; Future; Genetic Variation; Genotype; Hospitals; Hydroxyeicosatetraenoic Acids; Hydroxylation; Hypertension; Individual; Institution; Kidney; Knowledge; Lead; Link; Linkage Disequilibrium; Location; Mentorship; Mixed Function Oxygenases; Molecular; Myocardial Infarction; National Research Service Awards; Nephrons; Patients; Pharmaceutical Preparations; Pharmacogenetics; Phenotype; Population; Population Heterogeneity; Records; Research; Research Personnel; Research Technics; Resistant Hypertension; Sampling; Sodium; Sodium Channel; Spironolactone; Testing; Thiazide Diuretics; Training; Treatment Step; Variant; abstracting; base; blood pressure regulation; career; case control; epithelial Na+ channel; hypertension control; loss of function; meetings; member; novel; novel therapeutics; predicting response; programs; repository; response; salt sensitive; therapeutic development; vasoconstriction

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.

项目摘要/摘要 尽管具有降压药的足够治疗，但包括利尿剂在内的药物在8.4％至17.5％之间 患有高血压的成年人的血压不受控制，耐药性高血压（RH）。 rh是 与心血管和慢性肾脏疾病率提高有关。小说的识别 这种情况下的机制对于发现新的药物策略至关重要。一 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-羟基二乙酸二烯酸（20-HETE）。 20-Hete具有亲和抗 高血压作用取决于表达的位置，即在脉管系统中或肾单位中 CYP4A11基因中的变体与各种血压升高有关 种群以及对利尿剂的差异反应。 因此，我假设CYP4A11功能丧失变体将与RH相关 对特定利尿剂的反应减弱。在AIM I中，使用生物信息学方法，我将测试 CYP4A11功能丧失变体RS1126742和RS3890011的假设与RH IN有关 使用范德比尔特的DNA数据库在范德比尔特大学医学中心接受治疗的患者 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功能丧失变体与对利尿剂的衰减有关 降压治疗，特别是在规定的42,110名成人受试者中的螺内酯 Biovu的螺内酯。鉴定与RH或减弱降压反应的关联和 CYP4A11的变体可能提出一种潜在的分子机制，以便将来评估高血压 研究。此外，拟议项目的结果可能会导致新的药物遗传学策略以优化 RH患者的治疗。 除了强大的研究计划外，还举例说明 研究领域，NRSA资金的收到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。这些机会 对于我从事学术机构独立研究人员的职业至关重要。