Real-world pharmacogenomics-guided antihypertensive treatment response in clinical practice underrepresented population: implications for precision prescribing and medication safety.

BACKGROUND: Pharmacogenomics-guided therapy is a promising approach for optimizing antihypertensive treatment response; however, robust real-world data from South Asian and particularly Pakistani populations remain scarce. Understanding genotype-drug response relationships in this underrepresented population is essential to inform context-specific precision prescribing strategies. OBJECTIVE: To evaluate associations between pharmacogenomics variants and antihypertensive therapy response using electronic health record (EHR) data from Khyber Pakhtunkhwa (KPK) patients, and to assess the incremental predictive value and practical limitations of genotype-based stratification in routine clinical care. METHODS: This retrospective cohort study analyzed 1,247 hypertensive patients treated at Kuwait Teaching Hospital (KTH), Peshawar, between January 2023 and August 2025. Hypertensive adults initiating antihypertensive monotherapy with at least 12 months of EHR follow-up and available genotyping results were included to minimize misclassification of treatment response. Five pharmacogenomics variants (CYP3A5 rs776746, ADD1 rs4961, NEDD4L rs4149601, ADRB1 rs1801253, and ACE rs4340) were genotyped using TaqMan assays. Primary outcomes were systolic blood pressure (SBP) reduction and target BP achievement (< 140/90 mmHg), analyzed using ANOVA, multivariable logistic regression, and receiver operating characteristic (ROC) curve analysis. Multiple testing was addressed using a Bonferroni-corrected significance threshold (α = 0.002) for variant-drug class associations, and model discrimination was internally validated using bootstrap resampling (1,000 iterations). RESULTS: Mean patient age was 63.1 ± 11.5 years; 661 (53.0%) were female. Baseline SBP/DBP were 157.1 ± 18.8/91.7 ± 11.1 mmHg. Calcium channel blockers (CCBs) produced greater SBP reduction than other classes (22.32 ± 8.78 vs. 19.68 ± 8.67 mmHg, t = 4.43, p = 1.0 × 10- 5; overall drug-class ANOVA F = 5.27, p = 3.3 × 10- 4, Bonferroni-significant). The CYP3A5 rs776746 *3/*3 genotype was associated with enhanced CCB response (23.96 ± 8.79 vs. 19.78 ± 8.17 mmHg, p = 9.7 × 10- 5), and the ADD1 rs4961 GG genotype with superior diuretic response (24.02 ± 8.84 vs. 17.66 ± 8.69 mmHg, p = 1.7 × 10- 6); both associations remained significant after Bonferroni correction. On direct recalculation from raw genotype counts, four of five variants deviated from Hardy-Weinberg equilibrium (CYP3A5 p = 0.0058, NEDD4L p = 0.0146, ADRB1 p < 0.0001, ACE p = 0.0379), while ADD1 remained in equilibrium (p = 0.554). In multivariable logistic regression, older age (aOR = 1.019, 95% CI 1.007-1.031), lower baseline SBP (aOR = 0.915, 95% CI 0.906-0.925), and absence of diabetes (aOR = 0.670 for diabetes, 95% CI 0.499-0.901) were independent predictors of target BP achievement; CCB therapy (aOR = 1.362, 95% CI 0.975-1.902) and favorable CYP3A5/ADD1 genotypes (aOR 1.14 each) showed positive but non-significant trends. The model achieved an AUC of 0.847, with a bootstrap-derived optimism-corrected AUC of 0.841 (95% CI 0.823-0.866). CONCLUSIONS: Real-world EHR data from Khyber Pakhtunkhwa reveal significant genotype-treatment response associations for CCB and diuretic therapy in an underrepresented South Asian population. However, the extensive Hardy-Weinberg disequilibrium observed across four of five variants indicates that population stratification and/or genotyping considerations must be more fully accounted for, and together with the observational design and lack of external validation, these findings should be regarded as hypothesis-generating rather than sufficient grounds for routine clinical implementation of pharmacogenomics-guided antihypertensive therapy.