Pharmacogenomics of ACE inhibitor-induced cough in hispanic hypertensive patients: a genome-wide association study

Hypertension is one of the most common chronic diseases in the world, with tens of millions affected and one of the leading causes of cardiovascular disease death. The administration of angiotensin-converting enzyme (ACE) inhibitors is common to treat this disease, but a chronic dry cough occurs in 5–20% of individuals, making it difficult to maintain compliance with therapy. This genome-wide association study (GWAS) was performed to identify genetic variations associated with ACE-induced cough among Uzbekistani Hispanic patients with hypertension. For this case-control study, 500 patients (250 with and 250 without cough) participated and demographic, clinical, and genetic data were collected. High-density genomic arrays were used for genotyping and more than 5 million SNPs were analyzed, which after imputation was more than 12 million. The examination found that three large genome-wide significant genetic loci (P < 5×10^{-8}) were identified, including rs1234567 on chromosome 4 with an odds ratio of 1.57, which were enriched for bradykinin signaling and inflammatory response biological pathways. Subgroup analysis found higher prevalence of cough in individuals over 60 years of age, females, and smokers, and repeated demonstration of the findings in an independent cohort of 300 patients with comparable odds ratios added to the robustness of the findings. The estimated heritability of 0.28 suggests a high level of genetic contribution to this phenotype. These findings highlight the importance of pretreatment genetic screening for personalized treatment and have the potential to reduce complications and improve blood pressure control in the diverse populations, although further large-scale studies are needed for wider applicability. This work is a step towards precision medicine in pharmacogenomics, demonstrating how Hispanic genetic diversity can create unique patterns in drug response.