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.