Vinicius Tragante1, Daiane Hemerich1,2, Mohammad Alshabeeb3, Ingrid Brænne4, Harri Lempiäinen5, Riyaz S Patel6,7, Hester M den Ruijter8, Michael R Barnes7, Jason H Moore9, Heribert Schunkert10,11, Jeanette Erdmann4,12,13, Folkert W Asselbergs1,6,14,15. 1. Division of Heart and Lungs, Department of Cardiology (V.T., D.H., F.W.A.). 2. University Medical Center Utrecht, Utrecht University, The Netherlands. CAPES Foundation, Ministry of Education of Brazil, Brasília (D.H.). 3. Developmental Medicine Department, King Abdullah International Medical Research Center, King Saud Bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Riyadh, Kingdom of Saudi Arabia (M.A.). 4. Institute for Cardiogenetics, University of Lübeck, Germany (I.B., J.E.). 5. Genedata AG, Basel, Switzerland (H.L.). 6. Institute of Cardiovascular Science, University College London, United Kingdom (R.P., F.W.A.). Bart's Heart Centre, St Bartholomew's Hospital, London, United Kingdom (R.P.). 7. William Harvey Research Institute, Centre for Translational Bioinformatics, Barts and The London School of Medicine and Dentistry, Charterhouse Square, United Kingdom (M.R.B.). 8. Laboratory of Experimental Cardiology (H.M.d.R.). 9. Institute for Biomedical Informatics, University of Pennsylvania, Philadelphia (J.H.M.). 10. Deutsches Herzzentrum München, Technische Universität München, Germany (H.S.). 11. DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Germany (H.S.). 12. DZHK (German Research Center for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, Munich, Germany (J.E.). 13. University Heart Center Lübeck, Germany (J.E.). 14. Durrer Center for Cardiovascular Research, Netherlands Heart Institute, Utrecht (F.W.A.). 15. Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, United Kingdom (F.W.A.).
Abstract
BACKGROUND: Genome-wide association studies have identified multiple loci associated with coronary artery disease and myocardial infarction, but only a few of these loci are current targets for on-market medications. To identify drugs suitable for repurposing and their targets, we created 2 unique pipelines integrating public data on 49 coronary artery disease/myocardial infarction-genome-wide association studies loci, drug-gene interactions, side effects, and chemical interactions. METHODS: We first used publicly available genome-wide association studies results on all phenotypes to predict relevant side effects, identified drug-gene interactions, and prioritized candidates for repurposing among existing drugs. Second, we prioritized gene product targets by calculating a druggability score to estimate how accessible pockets of coronary artery disease/myocardial infarction-associated gene products are, then used again the genome-wide association studies results to predict side effects, excluded loci with widespread cross-tissue expression to avoid housekeeping and genes involved in vital processes and accordingly ranked the remaining gene products. RESULTS: These pipelines ultimately led to 3 suggestions for drug repurposing: pentolinium, adenosine triphosphate, and riociguat (to target CHRNB4, ACSS2, and GUCY1A3, respectively); and 3 proteins for drug development: LMOD1 (leiomodin 1), HIP1 (huntingtin-interacting protein 1), and PPP2R3A (protein phosphatase 2, regulatory subunit b-double prime, α). Most current therapies for coronary artery disease/myocardial infarction treatment were also rediscovered. CONCLUSIONS: Integration of genomic and pharmacological data may prove beneficial for drug repurposing and development, as evidence from our pipelines suggests.
BACKGROUND: Genome-wide association studies have identified multiple loci associated with coronary artery disease and myocardial infarction, but only a few of these loci are current targets for on-market medications. To identify drugs suitable for repurposing and their targets, we created 2 unique pipelines integrating public data on 49 coronary artery disease/myocardial infarction-genome-wide association studies loci, drug-gene interactions, side effects, and chemical interactions. METHODS: We first used publicly available genome-wide association studies results on all phenotypes to predict relevant side effects, identified drug-gene interactions, and prioritized candidates for repurposing among existing drugs. Second, we prioritized gene product targets by calculating a druggability score to estimate how accessible pockets of coronary artery disease/myocardial infarction-associated gene products are, then used again the genome-wide association studies results to predict side effects, excluded loci with widespread cross-tissue expression to avoid housekeeping and genes involved in vital processes and accordingly ranked the remaining gene products. RESULTS: These pipelines ultimately led to 3 suggestions for drug repurposing: pentolinium, adenosine triphosphate, and riociguat (to target CHRNB4, ACSS2, and GUCY1A3, respectively); and 3 proteins for drug development: LMOD1 (leiomodin 1), HIP1 (huntingtin-interacting protein 1), and PPP2R3A (protein phosphatase 2, regulatory subunit b-double prime, α). Most current therapies for coronary artery disease/myocardial infarction treatment were also rediscovered. CONCLUSIONS: Integration of genomic and pharmacological data may prove beneficial for drug repurposing and development, as evidence from our pipelines suggests.
Entities:
Keywords:
coronary artery disease; drug interactions; genome-wide association study; myocardial infarction; pharmacogenetics
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