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Polygenic Risk Score for ACE-Inhibitor-Associated Cough
Quick Takes
- ACEi discontinuation polygenic risk prediction can identify people at risk of developing ACEi-associated cough.
- This analysis highlights the potential of using information embedded in prescription patterns as a proxy for adverse drug reactions to maximize the yield of large biobanks with genetic data.
- If genotyping becomes standard-of-care in health care systems, integrating data on both genetic and nongenetic risk factors may facilitate more informed drug selection and improve drug adherence and compliance.
Study Questions:
What are the genetic sequence variants associated with angiotensin-converting enzyme inhibitor (ACEi) discontinuation and their association with ACEi-associated adverse drug reactions (ADRs)?
Methods:
The investigators conducted a genome-wide association study (GWAS) on ACEi discontinuation, including 33,959 ACEi-discontinuers and 44,041 controls. Cases were defined as persons who switched from an ACEi treatment to an angiotensin receptor blocker. Controls were defined as persons who continued ACEi treatment for ≥1 year. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were computed for ACEi discontinuation risk by mixed model regression analysis. Summary statistics from the individual cohorts were meta-analyzed with a fixed-effects model. To test for association with specific ACEi-associated ADRs, any genome-wide significant (p < 5 × 10-8) ACEi discontinuation variants were tested for association with ACEi-associated cough and angioedema. 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.
Results:
In total, seven genetic genome-wide loci were identified, of which six were previously unreported. The strongest association with ACEi discontinuation was at 20q13.3 (NTSR1; OR, 1.21; 95% CI, 1.17-1.24; p = 2.1 × 10-34). Five of seven lead variants were associated with ACEi-associated cough, whereas none were associated with ACEi-associated angioedema. The ACEi discontinuation PRS was associated with ACEi-associated cough in a dose-response manner but not with ACEi-associated angioedema. 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.
Conclusions:
The authors reported a strong association between ADR phenotype and ACEi-associated cough.
Perspective:
This study identified seven loci associated with ACEi discontinuation and found that ACEi discontinuation polygenic risk prediction can identify people at risk of developing ACEi-associated cough. Furthermore, this analysis highlights the potential of using information embedded in prescription patterns as a proxy for ADRs to maximize the yield of large biobanks with genetic data. Of note, considering the low single nucleotide polymorphism–based heritability (3.8%) noted here, environmental factors likely play a larger role than genetics in drug discontinuation. Therefore, if genotyping becomes standard-of-care in health care systems, integrating data on both genetic and nongenetic risk factors may facilitate more informed drug selection and improve drug adherence and compliance.
Clinical Topics: Arrhythmias and Clinical EP, Heart Failure and Cardiomyopathies, Prevention, Vascular Medicine, Genetic Arrhythmic Conditions, Acute Heart Failure
Keywords: Angioedema, Angiotensin-Converting Enzyme Inhibitors, Angiotensin Receptor Antagonists, Asthma, Cough, Drug-Related Side Effects and Adverse Reactions, Gastroesophageal Reflux, Genetics, Genome-Wide Association Study, Heart Failure, Medication Adherence, Primary Prevention, Rhinitis, Allergic, Risk Factors, Vascular Diseases
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