ACE inhibitors (ACEIs) are a cornerstone in the treatment of hypertension and cardiovascular disorders, yet a notable side effect is dry cough, affecting roughly 5%–35% of patients and often resulting in treatment discontinuation. This study sought to uncover genetic variants that may predispose individuals to ACEI-related cough and to examine how these variants correlate with ACE enzyme levels in a multi-ethnic hypertensive cohort from the UAE. Participants were selected from the UAE-based EmHeart Study (n = 900), focusing on individuals receiving ACEI therapy. In this retrospective, multi-center analysis, 107 patients were included, comprising 35 individuals who developed a cough and 72 who did not. Genotyping targeted ACE rs1799752 I/D, BDKRB2 rs1799722 (C>T), and four KCNIP4 variants (rs7675300 C>A, rs1495509 T>C, rs7661530 T>C, and rs16870989 T>A). ACE plasma concentrations were measured using a sandwich ELISA to explore functional associations. Statistical analysis indicated that the ACE rs1799752 I/D genotype, evaluated under an over-dominant model, was significantly associated with cough in patients on ACEIs (p = 0.046), after controlling for sex. Similarly, individuals homozygous for the T allele at KCNIP4 rs7661530 showed a higher likelihood of developing cough compared with carriers of C/T or C/C genotypes (p = 0.035). No meaningful associations were observed for BDKRB2 rs1799722 or the other KCNIP4 variants. Plasma ACE levels were notably lower in the cough group than in non-cough patients (p = 0.0014), and subgroup analysis revealed that this difference was significant within the I/D genotype (p = 0.0061) but not among D/D or I/I genotypes. These findings provide evidence that ACEI-induced cough is linked to the ACE rs1799752 I/D genotype and reduced ACE plasma concentrations. This study is the first in the UAE and broader Middle East to analyze these variants collectively in relation to ACEI-induced cough. Although constrained by a limited cohort size, the results offer valuable insight into genetic susceptibility to ACEI-related adverse effects among hypertensive patients.
