PI-046 - GENOME WIDE ASSOCIATION STUDY OF APPARENT TREATMENT RESISTANT HYPERTENSION (ATRH): INSIGHTS FROM THE ALL OF US RESEARCH PROGRAM.

Background: aTRH is defined as uncontrolled blood pressure (BP) while using ≥3 antihypertensive classes or controlled BP while using ≥4 antihypertensive classes. We have previously characterized patients with aTRH in the United States in the All of Us Research Program.

Methods: We conducted a genome-wide association study for aTRH in All of Us participants, comparing aTRH with stable controlled hypertension (SCH, BP control at ≥80% of encounters on ≤2 antihypertensives), using data from the global diversity array. Logistic regression was used to adjust for age, sex, body mass index, heart failure, diabetes and chronic kidney disease. Analyses were conducted by ancestry in African Americans (AA) and European Americans (EA). Single-nucleotide polymorphisms (SNPs) with a P< 5x10-6 were further evaluated for validation in the other ancestry group at P≤0.05 with consistent direction of effect.

Results: ~1.1 million SNPs were tested in 3,369 aTRH and 5,828 SCH AAs, and 5,196 aTRH and 19,056 SCH EAs. The top signal in EAs was rs62279645 in the intron of P3H2; prolyl 3-hydroxylase 2, with the T allele associated with increased risk of aTRH in EAs (OR [OR], 1.44; 95% CI, 1.27–1.63; P=5.93x10-7). This signal validated with a consistent direction and nominal significance in AAs (OR, 1.19; 95% CI, 0.996-1.41; P=0.05). We also observed one additional locus with suggestive significance in EAs (P < 5x10-6) and a trend in AAs (P < 0.10, and consistent direction of effect). The T allele of rs73028640 near ATP1B1, ATPase Na+/K+ transporting subunit beta 1, was associated with increased risk of aTRH (EAs: OR, 1.34; 95% CI, 1.19-1.52; P=1.28x10-6) and marginal validation in AAs (OR, 1.12; 95% CI, 0.99-1.27; P=0.07). Additionally, top signals across ancestry groups were rs680168 near BUB1p1; mitotic checkpoint serine/threonine kinase pseudogene 1 (EAs: OR, 1.11; 95% CI=1.052-1.179, P=7.37x10-6, AAs: OR, 1.06; 95% CI= 0.99-1.13, P=0.12) and rs933744 near TBX5; T-box transcription factor 5 (EAs: OR, 0.78; 95% CI= 0.70-0.86, P=6.92x10-6, AAs: OR,0.76; 95% CI= 0.55-1.07, P=0.11).

Conclusion: Prior studies have shown that the P3H2 enzyme facilitates altered collagen-IV hydroxylation which has been implicated in hypertension pathophysiology, through its effects on vascular homeostasis and renal function. Our results suggest that this gene may also influence aTRH.