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 Murad; André 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

doi:10.1038/s41591-019-0722-x

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 language	English
Pages (from-to)	110-117
Number of pages	8
Journal	Nature Medicine
Volume	26
Issue number	1
Early online date	13 Jan 2020
DOIs	https://doi.org/10.1038/s41591-019-0722-x
Publication status	Published - 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).

Funders	Funder number
Centre National de Génotypage
Netherlands Genomics Initiative
Northern Gulf Institute
Seventh Framework Programme	602633
Universiteit Leiden
Hartstichting	CVON2014-02
Nederlandse Organisatie voor Wetenschappelijk Onderzoek
Leids Universitair Medisch Centrum

Cohort Studies

Netherlands Twin Register (NTR)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Integration of epidemiologic pharmacologic genetic and gut microbiome data in a drugmetabolite atlasFinal published version, 9.99 MBLicence: Article 25fa Dutch Copyright Act

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Liu, J., Lahousse, L., Nivard, M. G., Bot, M., Chen, L., van Klinken, J. B., Thesing, C. S., Beekman, M., van den Akker, E. B., Slieker, R. C., Waterham, E., van der Kallen, C. J. H., de Boer, I., Li-Gao, R., Vojinovic, D., Amin, N., Radjabzadeh, D., Kraaij, R., Alferink, L. J. M., ... van Duijn, C. M. (2020). Integration of epidemiologic, pharmacologic, genetic and gut microbiome data in a drug-metabolite atlas. Nature Medicine, 26(1), 110-117. https://doi.org/10.1038/s41591-019-0722-x

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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/).",

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

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doi = "10.1038/s41591-019-0722-x",

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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 2020, 'Integration of epidemiologic, pharmacologic, genetic and gut microbiome data in a drug-metabolite atlas', Nature Medicine, vol. 26, no. 1, pp. 110-117. https://doi.org/10.1038/s41591-019-0722-x

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AU - Liu, Jun

AU - Lahousse, Lies

AU - Nivard, Michel G

AU - Bot, Mariska

AU - Chen, Lianmin

AU - van Klinken, Jan Bert

AU - Thesing, Carisha S

AU - Beekman, Marian

AU - van den Akker, Erik Ben

AU - Slieker, Roderick C

AU - Waterham, Eveline

AU - van der Kallen, Carla J H

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AU - Amin, Najaf

AU - Radjabzadeh, Djawad

AU - Kraaij, Robert

AU - Alferink, Louise J M

AU - Murad, Sarwa Darwish

AU - Uitterlinden, André G

AU - Willemsen, Gonneke

AU - Pool, Rene

AU - Milaneschi, Yuri

AU - van Heemst, Diana

AU - Suchiman, H Eka D

AU - Rutters, Femke

AU - Elders, Petra J M

AU - Beulens, Joline W J

AU - van der Heijden, Amber A W A

AU - van Greevenbroek, Marleen M J

AU - Arts, Ilja C W

AU - Onderwater, Gerrit L J

AU - van den Maagdenberg, Arn M J M

AU - Mook-Kanamori, Dennis O

AU - Hankemeier, Thomas

AU - Terwindt, Gisela M

AU - Stehouwer, Coen D A

AU - Geleijnse, Johanna M

AU - 't Hart, Leen M

AU - Slagboom, P Eline

AU - van Dijk, Ko Willems

AU - Zhernakova, Alexandra

AU - Fu, Jingyuan

AU - Penninx, Brenda W J H

AU - Boomsma, Dorret I

AU - Demirkan, Ayşe

AU - Stricker, Bruno H C

AU - van Duijn, Cornelia M

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

Abstract

Funding

Cohort Studies

UN SDGs

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