Polygenic Risk Score for ACE-Inhibitor-Associated Cough
- 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.
What are the genetic sequence variants associated with angiotensin-converting enzyme inhibitor (ACEi) discontinuation and their association with ACEi-associated adverse drug reactions (ADRs)?
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.
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.
The authors reported a strong association between ADR phenotype and ACEi-associated cough.
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.
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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