Pharmacogenetics of RAS-affecting AGT and ACE variants and the efficacy of Valsartan/HCTZ therapy.

Considerable inter-individual variability has been observed in the blood pressure response to valsartan/hydrochlorothiazide (Valsartan/HCTZ), and genetic differences within the renin-angiotensin system may contribute to this heterogeneity. This prospective cohort study included 354 hypertensive patients treated with Valsartan/HCTZ (80/12.5 mg or 160/12.5 mg). Baseline and 4-week BP measurements were recorded following standardized procedures, and five variants (AGT rs5050, rs5051, rs699, rs4762, and ACE I/D) were genotyped using PCR-based methods. Associations were evaluated through linear and multivariate regression, and multilocus interactions were examined using estimated marginal means. Overall, the cohort showed reductions of 23.2 ± 16.4 mmHg in SBP and 14.8 ± 10.9 mmHg in DBP. Among clinical factors, normal BMI was associated with greater reductions (22.9 ± 15.9; 15.5 ± 9.3 mmHg) compared with BMI ≥ 35 kg/m² (14.2 ± 17.3; 10.7 ± 11.4 mmHg). Hypertension-specific diets produced larger SBP decreases (25.6 ± 17.6 mmHg) than unrestricted diets (22.9 ± 16.3 mmHg). Increasing dose had only a modest additional effect. AGT rs5050 showed the strongest genetic association, with SBP decreasing by 26 mmHg in CA/CC carriers versus 13.4 mmHg in AA (p < 0.001). ACE I/D significantly affected DBP, with II carriers achieving 13.7 mmHg versus 8.0 mmHg in DD (p = 0.017). A significant AGT rs5050 × ACE I/D interaction revealed the greatest reduction in AC/II (20.6 ± 2.3 mmHg) and the lowest in AA/DD (3.80 ± 2.33 mmHg). These findings highlight meaningful multilocus effects and support the potential for genotype-guided antihypertensive therapy.