| Title: | A genetic model of ivabradine recapitulates results from randomized clinical trials |
| Journal: | PLOS ONE |
| Published: | 21 Jul 2020 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/32692755/ |
| DOI: | https://doi.org/10.1371/journal.pone.0236193 |
| URL: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0236193&type=printable |
Publication 3458
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Abstract
BACKGROUND: Naturally occurring human genetic variants provide a valuable tool to identify drug targets and guide drug prioritization and clinical trial design. Ivabradine is a heart rate lowering drug with protective effects on heart failure despite increasing the risk of atrial fibrillation. In patients with coronary artery disease without heart failure, the drug does not protect against major cardiovascular adverse events prompting questions about the ability of genetics to have predicted those effects. This study evaluates the effect of a variant in HCN4, ivabradine's drug target, on safety and efficacy endpoints.</p>
METHODS: We used genetic association testing and Mendelian randomization to predict the effect of ivabradine and heart rate lowering on cardiovascular outcomes.</p>
RESULTS: Using data from the UK Biobank and large GWAS consortia, we evaluated the effect of a heart rate-reducing genetic variant at the HCN4 locus encoding ivabradine's drug target. These genetic association analyses showed increases in risk for atrial fibrillation (OR 1.09, 95% CI: 1.06-1.13, P = 9.3 ×10-9) in the UK Biobank. In a cause-specific competing risk model to account for the increased risk of atrial fibrillation, the HCN4 variant reduced incident heart failure in participants that did not develop atrial fibrillation (HR 0.90, 95% CI: 0.83-0.98, P = 0.013). In contrast, the same heart rate reducing HCN4 variant did not prevent a composite endpoint of myocardial infarction or cardiovascular death (OR 0.99, 95% CI: 0.93-1.04, P = 0.61).</p>
CONCLUSION: Genetic modelling of ivabradine recapitulates its benefits in heart failure, promotion of atrial fibrillation, and neutral effect on myocardial infarction.</p>
20 Keywords
- Adult
- Aged
- Alleles
- Cardiovascular Diseases
- Endpoint Determination
- Female
- Genetic Variation
- Genome-Wide Association Study
- Heart Rate
- Humans
- Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
- Ivabradine
- Male
- Mendelian Randomization Analysis
- Middle Aged
- Models, Genetic
- Muscle Proteins
- Potassium Channels
- Randomized Controlled Trials as Topic
- Risk Factors
11 Authors
- Marc-André Legault
- Johanna Sandoval
- Sylvie Provost
- Amina Barhdadi
- Louis-Philippe Lemieux Perreault
- Sonia Shah
- R. Thomas Lumbers
- Simon de Denus
- Benoit Tyl
- Jean-Claude Tardif
- Marie-Pierre Dubé
1 Application
| Application ID | Title |
|---|---|
| 20168 | Pharmacogenomic study using the UK Biobank data |
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