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

Jun Liu, Lies Lahousse, Michel G Nivard, Mariska Bot, Lianmin Chen, Jan Bert van Klinken, Carisha S Thesing, Marian Beekman, Erik Ben van den Akker, Roderick C Slieker, Eveline Waterham, Carla J H van der Kallen, Irene de Boer, Ruifang Li-Gao, Dina Vojinovic, Najaf Amin, Djawad Radjabzadeh, Robert Kraaij, Louise J M Alferink, Sarwa Darwish MuradAndré G Uitterlinden, Gonneke Willemsen, Rene Pool, Yuri Milaneschi, Diana van Heemst, H Eka D Suchiman, Femke Rutters, Petra J M Elders, Joline W J Beulens, Amber A W A van der Heijden, Marleen M J van Greevenbroek, Ilja C W Arts, Gerrit L J Onderwater, Arn M J M van den Maagdenberg, Dennis O Mook-Kanamori, Thomas Hankemeier, Gisela M Terwindt, Coen D A Stehouwer, Johanna M Geleijnse, Leen M 't Hart, P Eline Slagboom, Ko Willems van Dijk, Alexandra Zhernakova, Jingyuan Fu, Brenda W J H Penninx, Dorret I Boomsma, Ayşe Demirkan, Bruno H C Stricker, Cornelia M van Duijn

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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/).

Original languageEnglish
Pages (from-to)110-117
Number of pages8
JournalNature Medicine
Volume26
Issue number1
Early online date13 Jan 2020
DOIs
Publication statusPublished - Jan 2020

Funding

both within the framework of the Netherlands Genomics Initiative (NGI)/NWO (to A.M.J.M.v.d.M.) and by the FP7 EU project EUROHEADPAIN (grant no. 602633) (to A.M.J.M.v.d.M. and G.M.T.). NEO: the authors of the NEO study thank all individuals who participated, all participating general practitioners for inviting eligible participants and all research nurses for collection of the data. We thank the NEO study group—P. van Beelen, P. Noordijk and I. de Jonge—for coordination, laboratory and data management of the study. Genotyping in the NEO study was supported by Centre National de Génotypage (Paris, France), headed by J.-F. Deleuze. This study was supported by the participating departments, the Division and the Board of Directors of Leiden University Medical Center and by Leiden University, Research Profile Area Vascular and Regenerative Medicine. The study was also supported by the Netherlands Cardiovascular Research Initiative: an initiative with the support of the Dutch Heart Foundation (no. CVON2014-02 ENERGISE).

FundersFunder number
Centre National de Génotypage
Netherlands Genomics Initiative
Northern Gulf Institute
Seventh Framework Programme602633
Universiteit Leiden
HartstichtingCVON2014-02
Nederlandse Organisatie voor Wetenschappelijk Onderzoek
Leids Universitair Medisch Centrum

    Cohort Studies

    • Netherlands Twin Register (NTR)

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