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 ?-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.
One in three adults worldwide suffers from high blood pressure, and for some of these individuals traditional treatment is ineffective. I will study a population of individuals with uncontrolled blood pressure defined as having resistant hypertension to determine if variation in the CYP4A11 gene relates to their elevated blood pressure and the lack of response to traditional treatment. My results will lay the foundation for future studies to develop new drugs to treat blood pressure and to tailor blood pressure medications based on an individual's genotype and his or her predicted response to a specific medication.
| Chaugai, Sandip; Dickson, Alyson L; Shuey, Megan M et al. (2018) Co-Prescription of Strong CYP1A2 Inhibitors and the Risk of Tizanidine-Associated Hypotension: A Retrospective Cohort Study. Clin Pharmacol Ther : |
