Integration of epidemiologic, pharmacologic, genetic and gut microbiome data in a drug-metabolite atlas

  • Nat Med. 2020 Jan;26(1):110-117. doi: 10.1038/s41591-019-0722-x.
Jun Liu  1  2 ,  Lies Lahousse  3  4 ,  Michel G Nivard  5  6 ,  Mariska Bot  5  6 ,  Lianmin Chen  7  8 ,  Jan Bert van Klinken  9  10  11 ,  Carisha S Thesing  5  6 ,  Marian Beekman  12 ,  Erik Ben van den Akker  12  13  14 ,  Roderick C Slieker  6  15  16 ,  Eveline Waterham  17 ,  Carla J H van der Kallen  18  19 ,  Irene de Boer  20 ,  Ruifang Li-Gao  21 ,  Dina Vojinovic  3 ,  Najaf Amin  3 ,  Djawad Radjabzadeh  22 ,  Robert Kraaij  22 ,  Louise J M Alferink  23 ,  Sarwa Darwish Murad  23 ,  André G Uitterlinden  3  22 ,  Gonneke Willemsen  5  6 ,  Rene Pool  5  6 ,  Yuri Milaneschi  5  6 ,  Diana van Heemst  24 ,  H Eka D Suchiman  12 ,  Femke Rutters  6  15 ,  Petra J M Elders  6  25 ,  Joline W J Beulens  6  15 ,  Amber A W A van der Heijden  6  25 ,  Marleen M J van Greevenbroek  18  19 ,  Ilja C W Arts  19  26  27 ,  Gerrit L J Onderwater  20 ,  Arn M J M van den Maagdenberg  9  20 ,  Dennis O Mook-Kanamori  21  28 ,  Thomas Hankemeier  29  30 ,  Gisela M Terwindt  20 ,  Coen D A Stehouwer  18  19 ,  Johanna M Geleijnse  17 ,  Leen M 't Hart  6  12  15  16 ,  P Eline Slagboom  12 ,  Ko Willems van Dijk  9  10  31 ,  Alexandra Zhernakova  7 ,  Jingyuan Fu  7  8 ,  Brenda W J H Penninx  5  6 ,  Dorret I Boomsma  5  6 ,  Ayşe Demirkan  3  7  32 ,  Bruno H C Stricker  3  22  33 ,  Cornelia M van Duijn  34  35  36
Affiliations
  • 1. Department of Epidemiology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands. [email protected].
  • 2. Nuffield Department of Population Health, University of Oxford, Oxford, UK. [email protected].
  • 3. Department of Epidemiology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands.
  • 4. Department of Bioanalysis, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium.
  • 5. Department of Biological Psychology, Amsterdam University Medical Center, Vrije Universiteit, Amsterdam, the Netherlands.
  • 6. Amsterdam Public Health Research Institute, Amsterdam, the Netherlands.
  • 7. Department of Genetics, University Medical Center Groningen, Groningen, the Netherlands.
  • 8. Department of Pediatrics, University Medical Center Groningen, Groningen, the Netherlands.
  • 9. Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands.
  • 10. Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands.
  • 11. Department of Clinical Chemistry, Laboratory Genetic Metabolic Disease, Amsterdam University Medical Center, Amsterdam, the Netherlands.
  • 12. Department of Biomedical Data Sciences, section of Molecular Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.
  • 13. Department of Pattern Recognition and Bioinformatics, Delft University of Technology, Delft, the Netherlands.
  • 14. Leiden Computational Biology Center, Leiden University Medical Center, Leiden, the Netherlands.
  • 15. Department of Epidemiology and Biostatistics, Amsterdam University Medical Center, Vrije Universiteit, Amsterdam, the Netherlands.
  • 16. Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands.
  • 17. Division of Human Nutrition and Health, Wageningen University, Wageningen, the Netherlands.
  • 18. Department of Internal Medicine, Maastricht University, Maastricht, the Netherlands.
  • 19. School for Cardiovascular Diseases, Maastricht University, Maastricht, the Netherlands.
  • 20. Department of Neurology, Leiden University Medical Center, Leiden, the Netherlands.
  • 21. Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.
  • 22. Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, the Netherlands.
  • 23. Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands.
  • 24. Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.
  • 25. Department of General Practice and Elderly Care Medicine, Amsterdam University Medical Center, Vrije Universiteit, Amsterdam, the Netherlands.
  • 26. Department of Epidemiology, Maastricht University, Maastricht, the Netherlands.
  • 27. Maastricht Center for Systems Biology, Maastricht University, Maastricht, the Netherlands.
  • 28. Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, the Netherlands.
  • 29. Leiden Academic Center for Drug Research, Leiden University, Leiden, the Netherlands.
  • 30. Netherlands Metabolomics Center, Leiden, the Netherlands.
  • 31. Department of Internal Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, the Netherlands.
  • 32. Section of Statistical Multi-omics, Department of Clinical and Experimental Medicine, University of Surrey, Guildford, UK.
  • 33. Inspectorate of Healthcare, The Hague, the Netherlands.
  • 34. Department of Epidemiology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands. [email protected].
  • 35. Nuffield Department of Population Health, University of Oxford, Oxford, UK. [email protected].
  • 36. Leiden Academic Center for Drug Research, Leiden University, Leiden, the Netherlands. [email protected].
PMID: 31932804 DOI: 10.1038/s41591-019-0722-x
Abstract

Progress in high-throughput metabolic profiling provides unprecedented opportunities to obtain insights into the effects of drugs on human metabolism. The Biobanking BioMolecular Research Infrastructure of the Netherlands has constructed an atlas of drug-metabolite associations for 87 commonly prescribed drugs and 150 clinically relevant plasma-based metabolites assessed by proton nuclear magnetic resonance. The atlas includes a meta-analysis of ten cohorts (18,873 persons) and uncovers 1,071 drug-metabolite associations after evaluation of confounders including co-treatment. We show that the effect estimates of statins on metabolites from the cross-sectional study are comparable to those from intervention and genetic observational studies. Further data integration links Proton Pump inhibitors to circulating metabolites, liver function, hepatic steatosis and the gut microbiome. Our atlas provides a tool for targeted experimental pharmaceutical research and clinical trials to improve drug efficacy, safety and repurposing. We provide a web-based resource for visualization of the atlas (http://bbmri.researchlumc.nl/atlas/).