A genetic model of ivabradine recapitulates results from randomized clinical trials.

PloS One
M.-A. LegaultM.-P. Dube

Abstract

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. We used genetic association testing and Mendelian randomization to predict the effect of ivabradine and heart rate lowering on cardiovascular outcomes. 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 participa...Continue Reading

References

Jan 13, 2006·The New England Journal of Medicine·Raffaella MilanesiDario DiFrancesco
Jun 11, 2009·JAMA : the Journal of the American Medical Association·Pia R KamstrupBørge G Nordestgaard
May 1, 2012·Nature Genetics·Patrick T EllinorStefan Kääb
Jul 23, 2013·Circulation. Arrhythmia and Electrophysiology·Irene GrundvoldJohan Bodegard
Oct 12, 2013·Genetic Epidemiology·Stephen BurgessSimon G Thompson
Aug 26, 2014·Journal of the American College of Cardiology·Annalisa MilanoConnie R Bezzina
Sep 2, 2014·The New England Journal of Medicine·Kim FoxUNKNOWN SIGNIFY Investigators
Jun 8, 2015·International Journal of Epidemiology·Jack BowdenStephen Burgess
Aug 19, 2015·Statistical Methods in Medical Research·Stephen BurgessSimon G Thompson
May 18, 2018·Human Molecular Genetics·Gibran HemaniGeorge Davey Smith
Jun 13, 2018·Nature Genetics·Carolina RoselliPatrick T Ellinor
Jul 14, 2018·BMJ : British Medical Journal·Neil M DaviesGeorge Davey Smith
Aug 1, 2018·Nature Genetics·Jonas B NielsenCristen J Willer
Oct 12, 2018·Nature·Clare BycroftJonathan Marchini
Jan 19, 2020·Nature Communications·Stephen BurgessJoanna M M Howson

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Citations

Feb 3, 2021·Cardiovascular Drugs and Therapy·E F MagavernM Pirmohamed

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Software Mentioned

MR
HERMES
CARDIoGRAMplusC4D
UKB SOFT CAD CARDIoGRAMplusC4D MI Genetics
PRESSO
SIGNIFY
MendelianRandomization ” R
R
MEGASTROKE
CARDIoGRAMplusC4D SOFT + MiGen

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