A Pilot Randomized Study of NAT2 and YEATS4 Pharmacogenetic Return of Results in Adults with Hypertension and African Ancestry: The GUARDD ‐ US PGx Study

Almost half of individuals with hypertension fail to achieve recommended blood pressure (BP) goals. Pharmacogenetic gene‐drug interactions may alter the efficacy of antihypertensive agents. We conducted a multicenter randomized controlled sub‐study of participants ( N = 1874) with hypertension and self‐reported African ancestry to determine whether pharmacogenetic return of results (RoR) would improve systolic blood pressure (SBP) at 3 months. Participants were randomized to immediate pharmacogenetic RoR (intervention) or delayed RoR at trial completion (control). Clinical decision support conveyed recommendations for YEATS4 ‐guided thiazide diuretic selection and NAT2 ‐guided hydralazine dosing. Prespecified subgroup analyses included those with uncontrolled BP (baseline SBP ≥140 or DBP ≥90 mm Hg) and actionable genotypes. Immediate RoR did not improve SBP at 3 months in a broad population of hypertensive adults with controlled and uncontrolled SBP (covariate‐adjusted change in SBP between groups: −0.3 ± 0.74 mm Hg, 95% CI: −1.8, 1.2). In participants with an actionable YEATS4 genotype ( N = 867) predicting reduced thiazide efficacy, immediate RoR led to greater SBP reduction at 3 months (−2.46 mm Hg, 95% CI: −4.57 to −0.36). In participants with uncontrolled hypertension at baseline ( N = 659), immediate RoR led to a greater reduction in SBP (−2.9 ± 0.74 mm Hg, 95% CI: −5.6, −0.3). Although no SBP reduction was observed in the whole cohort, participants with an actionable YEATS4 genotype or uncontrolled BP who received immediate RoR had a significantly greater SBP improvement than those with delayed RoR. Future studies of antihypertensive pharmacogenetics should recruit individuals with uncontrolled BP and actionable genotypes.

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Journal
Clinical Pharmacology & Therapeutics
Published
2026-10-18
DOI
https://doi.org/10.1002/cpt.70527
Primary Topic
Pharmacogenetics and Drug Metabolism
Type
article
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article

A Pilot Randomized Study of NAT2 and YEATS4 Pharmacogenetic Return of Results in Adults with Hypertension and African Ancestry: The GUARDD ‐ US PGx Study

Todd C. Skaar, Khoa A. Nguyen, Paul Richard Dexter, Kady-Ann Steen-Burrell et al.
Clinical Pharmacology & Therapeutics
Pharmacogenetics and Drug Metabolism
article

A Pilot Randomized Study of NAT2 and YEATS4 Pharmacogenetic Return of Results in Adults with Hypertension and African Ancestry: The GUARDD ‐ US PGx Study

Todd C. Skaar, Khoa A. Nguyen, Paul Richard Dexter, Kady-Ann Steen-Burrell, Sabrina Clermont, Erica N. Elwood, Nandini Shroff, Girish N. Nadkarni, Dinushika Mohottige, Alexander Scott Parker, Rhonda M. Cooper‐DeHoff, Carol R. Horowitz, Hrishikesh Chakraborty, Michael T. Eadon, Kerri L. Cavanaugh, Emily J. Cicali, Larisa H. Cavallari, Philip E. Empey, Nita A. Limdi, Marc B. Rosenman, Mimsie Robinson, Julie Ann Johnson, Michelle A. Ramos, Christina M. Wyatt, Ronald Huang, the IGNITE Pragmatic Trials Network
article en

Abstract

Almost half of individuals with hypertension fail to achieve recommended blood pressure (BP) goals. Pharmacogenetic gene‐drug interactions may alter the efficacy of antihypertensive agents. We conducted a multicenter randomized controlled sub‐study of participants ( N = 1874) with hypertension and self‐reported African ancestry to determine whether pharmacogenetic return of results (RoR) would improve systolic blood pressure (SBP) at 3 months. Participants were randomized to immediate pharmacogenetic RoR (intervention) or delayed RoR at trial completion (control). Clinical decision support conveyed recommendations for YEATS4 ‐guided thiazide diuretic selection and NAT2 ‐guided hydralazine dosing. Prespecified subgroup analyses included those with uncontrolled BP (baseline SBP ≥140 or DBP ≥90 mm Hg) and actionable genotypes. Immediate RoR did not improve SBP at 3 months in a broad population of hypertensive adults with controlled and uncontrolled SBP (covariate‐adjusted change in SBP between groups: −0.3 ± 0.74 mm Hg, 95% CI: −1.8, 1.2). In participants with an actionable YEATS4 genotype ( N = 867) predicting reduced thiazide efficacy, immediate RoR led to greater SBP reduction at 3 months (−2.46 mm Hg, 95% CI: −4.57 to −0.36). In participants with uncontrolled hypertension at baseline ( N = 659), immediate RoR led to a greater reduction in SBP (−2.9 ± 0.74 mm Hg, 95% CI: −5.6, −0.3). Although no SBP reduction was observed in the whole cohort, participants with an actionable YEATS4 genotype or uncontrolled BP who received immediate RoR had a significantly greater SBP improvement than those with delayed RoR. Future studies of antihypertensive pharmacogenetics should recruit individuals with uncontrolled BP and actionable genotypes.

Clinical Pharmacology & Therapeutics
Northwestern University (US), Hasso Plattner Institute (DE), University of Pittsburgh (US), Duke University (US), American Association of Colleges of Pharmacy (US), University of Florida Health (US), Institute for Family Health (US), University of Alabama at Birmingham (US), University of Florida (US), Jacksonville University (US), VA Tennessee Valley Healthcare System (US), Child Health and Development Institute (US), Indiana University Indianapolis (US), UAB Medicine, Indiana University School of Medicine, The Ohio State University (US), Bethel University (US), Florida College (US), Icahn School of Medicine at Mount Sinai (US)
Openalex Percentile: Top 10%
Pharmacogenetics and Drug Metabolism
DOIOpen Access PDFOpenAlex
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