Association of ACE I/D polymorphism with blood pressure response to valsartan-hydrochlorothiazide combination therapy in hypertensive patients from Khyber Pakhtunkhwa, Pakistan

Background Interindividual variability in antihypertensive response may be partly explained by genetic variation. The angiotensin-converting enzyme insertion/deletion polymorphism (ACE I/D; rs1799752) has been associated with variable response to renin-angiotensin-aldosterone system-targeting therapies, but evidence for valsartan-hydrochlorothiazide (Val-HCTZ) combination therapy remains limited, particularly in South Asian populations.Methods In this multicenter prospective cohort study, 645 hypertensive patients from Khyber Pakhtunkhwa, Pakistan, receiving fixed-dose Val-HCTZ were enrolled; 627 were included in the final analysis after excluding 18 patients with poor adherence (<80%) followed for 3 months. ACE I/D genotyping was performed by polymerase chain reaction with confirmatory testing. The primary analysis evaluated blood pressure reduction across ACE I/D genotypes using regression models adjusted for age, sex, and body mass index. Achievement of target blood pressure (<140/90 mmHg) was analyzed as a secondary outcome.Results Genotype distribution was in Hardy-Weinberg equilibrium (p = 0.171). Blood pressure reduction differed across genotypes, with the most favorable response observed in DD carriers, an intermediate response in II carriers, and the least favorable response in ID carriers. In the primary analysis of continuous blood pressure reduction, ID carriers showed significantly less reduction compared to II carriers (ΔSBP: adjusted β = -11.2, 95% CI: −16.8 to −5.6, p = 0.002; ΔDBP: adjusted β = −7.4, 95% CI: −11.9 to −2.9, p = 0.004). DD carriers showed greater observed reduction compared to II carriers, but this was not statistically significant (ΔSBP: adjusted β = +1.8, 95% CI: −4.2 to +7.8, p = 0.561; ΔDBP: adjusted β = +0.5, 95% CI: −4.1 to +5.1, p = 0.823). In the secondary analysis, response rates were 90.6% for DD, 75.8% for II, and 40.8% for ID.Conclusion ACE I/D genotype was associated with variation in blood pressure response to fixed-dose Val-HCTZ therapy in this Pakistani cohort, with the most robust finding being poorer response among ID carriers. These findings support further investigation of ACE I/D as a candidate pharmacogenetic marker in genotype-stratified and interventional studies.