Abstract P050: Loss-of-function Cyp4a11 Variants Are Associated With Apparent Treatment Resistant Hypertension Identified In Electronic Medical Records; In The VA Million Veteran’s Program And Vanderbilt’s BioVU

Abstract

Excessive dietary salt intake is common in patients with and salt-sensitivity contributes to the pathophysiology of resistant hypertension. Dietary salt intake regulates the excretion of 20-HETE and patients with salt-sensitive hypertension have a disrupted relationship between 20-HETE and sodium excretion. We hypothesized that rs1126742, a loss-of-function variant in the gene CYP4A11 encoding the enzyme responsible for the formation of 20-HETE, as well as a more common variant rs3890011, in partial linkage disequilibrium with rs1126742, would be associated with apparent-treatment resistant hypertension (ATRH). To test this hypothesis, we used the Department of Veteran Affairs Million Veterans Program dataset derived from electronic medical records. Patients with ATRH (cases, n=16,833), defined as uncontrolled BP of at least 140/90 mmHg despite the concurrent use of three antihypertensive medications including a thiazide diuretic or patients on four or more antihypertensive medications including a thiazide diuretic, and patients with controlled BP (controls, n=53,931) less than 135/90 mmHg on one or two antihypertensive medications were identified from the dataset using electronic algorithms. Within this population we found that there was a significant association between both rs1126742 and rs3890011 and ATRH (β=0.04, p=0.02; β=0.05, p<0.001, respectively). When we stratified the population by race, rs3890011 was significantly associated with ATRH in both whites and blacks (β=0.04, p<0.001 and β=0.06, p=0.02, respectively) while rs1126742 was associated with ATRH in blacks (β=0.07, p=0.01) but not whites. To validate these findings, we sought replication in an independent site, the Vanderbilt University Medical Center’s BioVU, a DNA databank linked with electronic medical records. We identified white patients with ATRH (n=2,998) and controlled hypertension (n=934), defined as patients with BP controlled to less than 140/90 mmHg by a single antihypertensive medication. The previous associations in whites were replicated; rs3890011 (β=0.43, p=0.02) was significantly associated with resistant hypertension while rs1126742 was not. Our findings support an association between these CYP4A11 loss-of-function variants and ATRH.