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

NAT2, YEATS4

YEATS4 genotype associated with reduced thiazide diuretic efficacy; NAT2 acetylation determining hydralazine dosing

This multicenter randomized sub-study enrolled 1,874 participants with hypertension and self-reported African ancestry, randomized to immediate pharmacogenetic return of results or delayed return at trial completion. Clinical decision support conveyed recommendations for YEATS4-guided thiazide diuretic selection and NAT2-guided hydralazine dosing. Immediate return did not improve systolic blood pressure at 3 months in the overall population (covariate-adjusted between-group change -0.3 ± 0.74 mm Hg, 95% CI -1.8 to 1.2). In prespecified subgroup analyses, carriers of an actionable YEATS4 genotype predicting reduced thiazide efficacy (n = 867) had a greater systolic reduction (-2.46 mm Hg, 95% CI -4.57 to -0.36), as did participants with uncontrolled hypertension at baseline (n = 659; -2.9 ± 0.74 mm Hg, 95% CI -5.6 to -0.3). The authors conclude that future trials should recruit patients with uncontrolled blood pressure and actionable genotypes.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The primary outcome is negative and must be reported as such: immediate return of pharmacogenetic results does not change blood pressure in an unselected hypertensive population. The gains seen in actionable YEATS4 carriers and in uncontrolled patients come from prespecified subgroups, so they are acceptable as hypothesis generation, but modest in size — 2 to 3 mm Hg — and over 3 months only. The main value of this trial is methodological: it indicates how a future antihypertensive pharmacogenetics trial should be recruited, in a population under-represented in this literature.

Analysis by Dr Thibaut Benquey