Integration of epidemiologic, pharmacologic, genetic and gut microbiome data in a drug-metabolite atlas.
Liu J., Lahousse L., Nivard MG., Bot M., Chen L., van Klinken JB., Thesing CS., Beekman M., van den Akker EB., Slieker RC., Waterham E., van der Kallen CJH., de Boer I., Li-Gao R., Vojinovic D., Amin N., Radjabzadeh D., Kraaij R., Alferink LJM., Murad SD., Uitterlinden AG., Willemsen G., Pool R., Milaneschi Y., van Heemst D., Suchiman HED., Rutters F., Elders PJM., Beulens JWJ., van der Heijden AAWA., van Greevenbroek MMJ., Arts ICW., Onderwater GLJ., van den Maagdenberg AMJM., Mook-Kanamori DO., Hankemeier T., Terwindt GM., Stehouwer CDA., Geleijnse JM., 't Hart LM., Slagboom PE., van Dijk KW., Zhernakova A., Fu J., Penninx BWJH., Boomsma DI., Demirkan A., Stricker BHC., van Duijn CM.
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/).