![]() Previous studies have indicated that genetics may play a role in susceptibility to ACEi-associated ADRs. Clearly, better methods of patient–drug matching to minimize side effects would improve treatment. 9 Currently, clinicians have no way of predicting who will develop side effects prior to drug initiation, and trial-and-error switching is the only option in clinical practice. 6, 7 These ACEi-associated ADRs include a persistent dry cough (11%), 8 and more rarely, a potentially life-threatening angioedema (<1%). Although generally considered well-tolerated, 14–30% of patients discontinue treatment, mainly due to adverse drug reactions (ADRs). 1–5 At present, up to 40 million people are treated with ACEi worldwide. ACEi discontinuation was genetically correlated with important causes for cough, including gastro-esophageal reflux disease, allergic rhinitis, hay fever, and asthma, which indicates partly shared genetic underpinning between these traits.Ĭurrent guidelines recommend angiotensin-converting enzyme inhibitors (ACEis) as the standard of therapy for hypertension, chronic heart failure, diabetes, and chronic nephropathy. The ACEi discontinuation PRS was associated with ACEi-associated cough in a dose–response manner but not with ACEi-associated angioedema. Five of seven lead variants were associated with ACEi-associated cough, whereas none were associated with ACEi-associated angioedema. In total, seven genetic genome-wide loci were identified, of which six were previously unreported. A polygenetic risk score (PRS) based on ACEi discontinuation GWAS data was constructed and tested for association with ACEi-associated cough and angioedema in two population-based samples. To test for association with specific ACEi-associated ADRs, any genome-wide significant ( P < 5 × 10-8) ACEi discontinuation variants was tested for association with ACEi-associated cough and angioedema. Summary statistics from the individual cohorts were meta-analyzed with a fixed-effects model. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were computed for ACEi discontinuation risk by mixed model regression analysis. Controls were defined as persons who continued ACEi treatment for at least 1 year. Cases were defined as persons who switched from an ACEi treatment to an angiotensin receptor blocker. A genome-wide association study (GWAS) on ACEi discontinuation was conducted, including 33 959 ACEi-discontinuers and 44 041 controls. ![]()
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