Abstract 018: Whole Genome Sequence Analysis Of Apparent Treatment Resistant Hypertension Status In Participants From The Trans-omics For Precision Medicine Program
Authors: Armstrong Nicole D , Irvin Marguerite M , Srinivasasainagendra Vinodh , Smith Jennifer A , Kelly Tanika N , Franceschini Nora , Assimes Themistocles L , Beitelshees Amber L , Montasser May , Guo Xiuqing , Chen Yii-Der Ida , Redline Susan , Mathias Rasika , Morrison Alanna C , Lange Leslie , Kenny Eimear , Psaty Bruce , Arnett Donna K 
Published: April 2022

Background:
Apparent treatment-resistant hypertension (aTRH) is characterized by the use of four or more antihypertensive classes to achieve blood pressure (BP) control. The estimated prevalence of aTRH from population-based studies is ~12-15% among adults with hypertension (HTN). Individuals with aTRH have an increased risk for cardiovascular events compared to those individuals with controlled HTN.

Hypothesis:
We hypothesize that identifying the genetic contributors to aTRH may provide insight on its etiology.

Methods:
We conducted case-control single-variant and gene-based analyses of aTRH among individuals treated for HTN from 13 TOPMed cohorts with whole-genome sequencing data. Cases were defined as individuals treated for HTN taking three different antihypertensive classes, with average BP ≥ 140/90 mmHg, or four or more medications regardless of BP level (n=2,616; 68% African Ancestry, AA). A normotensive control group (n=6,062; 42% AA) was defined as individuals with BP <140/90 mmHg. A second control group comprised individuals who were treatment responsive on one antihypertensive medication with BP <140/90 mmHg (n=26,356; 29% AA). We performed logistic regression with kinship adjustment using the
S
calable and
A
ccurate Implementation of
Ge
neralized mixed models (SAIGE) and adjusted for age, sex, and genetic ancestry. We assessed variants using SKAT-O within EPACTS in a rare-variant, gene-based analysis. Gene-based tests were stratified by functional impact of variants (e.g. high or high-moderate), as well as race (AA, European Ancestry (EA), and race-combined) for each case-control model. We used a Bonferroni correction to correct for multiple testing.

Results:
An intronic variant (rs142681624) in
ZFHX3
(p=2.44E-08) exceeded the significance threshold in the case vs treatment responsive control analysis in the AA stratum. The variant was replicated in AAs from the Genetics of Hypertension Associated Treatments (GenHAT) study (p=0.016) with the same direction of effect. In the gene-based analyses in the EA stratum,
ERG
was statistically significant in the case vs normotensive control analysis (32 variants/ 27 singletons, p=2.22E-14) and marginally significant in the case vs treatment responsive control analysis (16 singletons; p=7.69E-06).

Conclusions:
We identified and replicated a
ZFHX3 v
ariant from our single-variant analysis in AAs.
ZFHX3
has been implicated in atrial fibrillation, systolic BP, hydrochlorothiazide-induced metabolic effects, and ischemic stroke. Gene-based tests in EAs identified
ERG
as a gene of interest. The
ERG
intronic variant rs117870289 has been previously associated with diastolic BP, pulse pressure, and coronary artery disease. The 16 singletons were not in LD with rs117870289. Additional work validating these loci is warranted to determine whether these regions influence the pathobiology of aTRH.