Pharmacogenetics of Resistant Hypertension: Leveraging the Electronic Medical Record

Abstract

Patients with resistant hypertension have uncontrolled blood pressure despite concurrent treatment with three or more antihypertensive medications including a thiazide diuretic. Compared to patients with controlled hypertension, resistant hypertensive patients are at an increased risk for myocardial infarction, stroke, and renal disease. Despite these risks, the pathophysiology underlying resistant hypertension remains poorly understood and very few novel antihypertensive medications have been discovered to treat the condition. We hypothesized that we could use electronic medical records (EMRs) to identify patients with resistant hypertension for use in epidemiologic and genetic studies.

Using the Vanderbilt University Medical Center (VUMC) EMRs we identified patients with resistant hypertension. Consistent with previous clinical studies, the prevalence of resistant hypertension in the EMR-derived populations was greater among African Americans compared to European Americans, and patients with resistant hypertension were significantly older, heavier, more likely to have chronic kidney disease stage three, and had a higher incidence of type 2 diabetes mellitus than patients with controlled hypertension. We also identified significant differences in the pharmacologic treatment of resistant hypertension in African Americans and European Americans in an academic medical center .

To demonstrate the potential for EMR-derived resistant hypertension populations to be used in genetic studies, we used the Department of Veteran Affairs Million Veterans Program database to test for an association between two loss-of-function variants in CYP4A11 and resistant hypertension. We determined there was a significant association between the two CYP4A11 variants, rs1126742 and rs3890011, and resistant hypertension (β=0.04, p=0.02; β=0.05, p<0.001, respectively).

Finally, using the VUMC EMR-derived resistant hypertension population we developed an algorithm to determine the blood pressure response to spironolactone. We determined that approximately 29% of patients with resistant hypertension do not respond to spironolactone. Higher blood pressure and changes in serum sodium, potassium and creatinine were associated with the blood pressure response to spironolactone, consistent with spironolactone’s mechanism of action to block the mineralocorticoid receptor and decrease activity of the epithelial sodium channel.