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

J. Liu; L. Lahousse; M.G. Nivard; M. Bot; L.M. Chen; J.B. van Klinken; C.S. Thesing; M. Beekman; E.B. van den Akker; R.C. Slieker; E. Waterham; C.J.H. van der Kallen; I. de Boer; R.F. Li-Gao; D. Vojinovic; N. Amin; D. Radjabzadeh; R. Kraaij; L.J.M. Alferink; S.D. Murad; A.G. Uitterlinden; G. Willemsen; R. Pool; Y. Milaneschi; D. van Heemst; H.E.D. Suchiman; F. Rutters; P.J.M. Elders; J.W.J. Beulens; A.A.W.A. van der Heijden; M.M.J. van Greevenbroek; I.C.W. Arts; G.L.J. Onderwater; A.M.J.M. van den Maagdenberg; D.O. Mook-Kanamori; T. Hankemeier; G.M. Terwindt; C.D.A. Stehouwer; J.M. Geleijnse; L.M. 't Hart; P.E. Slagboom; K.W. van Dijk; A. Zhernakova; J.Y. Fu; B.W.J.H. Penninx; D.I. Boomsma; A. Demirkan; B.H.C. Stricker; C.M. van Duijn

doi:10.1038/s41591-019-0722-x

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

J. Liu^*, L. Lahousse, M.G. Nivard, M. Bot, L.M. Chen, J.B. van Klinken, C.S. Thesing, M. Beekman, E.B. van den Akker, R.C. Slieker, E. Waterham, C.J.H. van der Kallen, I. de Boer, R.F. Li-Gao, D. Vojinovic, N. Amin, D. Radjabzadeh, R. Kraaij, L.J.M. Alferink, S.D. MuradA.G. Uitterlinden, G. Willemsen, R. Pool, Y. Milaneschi, D. van Heemst, H.E.D. Suchiman, F. Rutters, P.J.M. Elders, J.W.J. Beulens, A.A.W.A. van der Heijden, M.M.J. van Greevenbroek, I.C.W. Arts, G.L.J. Onderwater, A.M.J.M. van den Maagdenberg, D.O. Mook-Kanamori, T. Hankemeier, G.M. Terwindt, C.D.A. Stehouwer, J.M. Geleijnse, L.M. 't Hart, P.E. Slagboom, K.W. van Dijk, A. Zhernakova, J.Y. Fu, B.W.J.H. Penninx, D.I. Boomsma, A. Demirkan, B.H.C. Stricker, C.M. van Duijn^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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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	20
Journal	Nature Medicine
Volume	26
Issue number	1
DOIs	https://doi.org/10.1038/s41591-019-0722-x
Publication status	Published - 1 Jan 2020

Keywords

circulating metabolites
design
diabetes-mellitus
magnetic-resonance metabolomics
mendelian randomization
obesity
population
profiles
risk
serum metabolome
POPULATION
PROFILES
DESIGN
SERUM METABOLOME
RISK
MENDELIAN RANDOMIZATION
CIRCULATING METABOLITES
DIABETES-MELLITUS
MAGNETIC-RESONANCE METABOLOMICS
OBESITY

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10.1038/s41591-019-0722-x

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Cite this

Liu, J., Lahousse, L., Nivard, M. G., Bot, M., Chen, L. M., 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. F., 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

@article{91bc7071be344f97b22892f606e6a18f,

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

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/).",

keywords = "circulating metabolites, design, diabetes-mellitus, magnetic-resonance metabolomics, mendelian randomization, obesity, population, profiles, risk, serum metabolome, POPULATION, PROFILES, DESIGN, SERUM METABOLOME, RISK, MENDELIAN RANDOMIZATION, CIRCULATING METABOLITES, DIABETES-MELLITUS, MAGNETIC-RESONANCE METABOLOMICS, OBESITY",

author = "J. Liu and L. Lahousse and M.G. Nivard and M. Bot and L.M. Chen and {van Klinken}, J.B. and C.S. Thesing and M. Beekman and {van den Akker}, E.B. and R.C. Slieker and E. Waterham and {van der Kallen}, C.J.H. and {de Boer}, I. and R.F. Li-Gao and D. Vojinovic and N. Amin and D. Radjabzadeh and R. Kraaij and L.J.M. Alferink and S.D. Murad and A.G. Uitterlinden and G. Willemsen and R. Pool and Y. Milaneschi and {van Heemst}, D. and H.E.D. Suchiman and F. Rutters and P.J.M. Elders and J.W.J. Beulens and {van der Heijden}, A.A.W.A. and {van Greevenbroek}, M.M.J. and I.C.W. Arts and G.L.J. Onderwater and {van den Maagdenberg}, A.M.J.M. and D.O. Mook-Kanamori and T. Hankemeier and G.M. Terwindt and C.D.A. Stehouwer and J.M. Geleijnse and {'t Hart}, L.M. and P.E. Slagboom and {van Dijk}, K.W. and A. Zhernakova and J.Y. Fu and B.W.J.H. Penninx and D.I. Boomsma and A. Demirkan and B.H.C. Stricker and {van Duijn}, C.M.",

note = "Funding Information: We acknowledge all participants included in the cohorts. We also acknowledge the BBMRI Metabolomics Consortium (see Supplementary Information, http://www.bbmri. nl/omics-metabolomics/) funded by BBMRI-NL, a research infrastructure financed by the Dutch government through the Netherlands Organisation for Scientific Research (NWO) (grant nos. 184.021.007 and 184033111). This work is part of the CardioVasculair Onderzoek Nederland (CVON 2012-03), the Common mechanisms and pathways in Stroke and Alzheimer{\textquoteright}s disease (CoSTREAM) project (www.costream.eu, grant agreement no. 667375), the Memorabel program (project no. 733050814), Netherlands X-omics Research Infrastructure and U01-AG061359 NIA. The full list of funding information for each cohort can be found in the cohort acknowledgements below. J.L., C.M.v.D. and A.D. benefitted from exchange grants from the Personalized pREvention of Chronic DIseases consortium (no. H2020-MSCA-RISE-2014). A.D. is supported by the Dutch Science Organization (ZonMW-VENI, grant no. 2015). L.C. is supported by a joint PhD fellowship from China Scholarship Council (no. 201708320268) and University of Groningen. M.G.N. is supported by Royal Netherlands Academy of Science Professor Award (no. PAH/6635) to D.I.B. D.O.M.-K. is supported by the ZonMW-VENI (grant no. 916.14.023). B.H.C.S. received a grant from TransQST (no. 116030-2; IMI2). D.R. is funded by an Erasmus MC mRACE grant (Profiling of the human gut microbiome). Cohort acknowledgements, ERF: we are grateful to all study participants and their relatives, general practitioners and neurologists for their contributions and to P. Veraart for her help in genealogy, J. Vergeer for supervision of the laboratory work and P. Snijders for his help in data collection. ERF was supported by the Consortium for Systems Biology (NCSB), both within the framework of the Netherlands Genomics Initiative (NGI)/NWO). The ERF study as a part of European Special Populations Research Network (EUROSPAN) was supported by European Commission FP6 STRP, grant no. 018947 (LSHG-CT-2006-01947) and also received funding from the European Community{\textquoteright}s Seventh Framework Programme (FP7/2007-2013)/grant agreement no. HEALTH-F4-2007-201413 by the European Commission under the program {\textquoteleft}Quality of Life and Management of the Living Resources{\textquoteright} of the 5th Framework Programme (no. QLG2-CT-2002-01254), as well as the FP7 project EUROHEADPAIN (no. 602633). High-throughput analysis of ERF data was supported by a joint grant from NWO and the Russian Foundation for Basic Research (NWO-RFBR no. 047.017.043). High-throughput metabolomics measurements in the ERF study were supported by BBMRI-NL. Rotterdam Study: we thank the study subjects, the staff from Rotterdam Study and the participating pharmacists and general practitioners. The Rotterdam Study is supported by Erasmus MC and Erasmus University Rotterdam; by NWO, the Netherlands Organisation for Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Netherlands Genomics Initiative (NGI), the Ministry of Education, Culture and Science, the Ministry of HealthWelfare and Sports, the European Commission (DG XII) and the Municipality of Rotterdam. L.L. reports expert consultation from Boehringer Ingelheim and Novartis, and unrestricted grants from AstraZeneca and Chiesi. We are also grateful to nurse ultrasonographist, Mrs. van Wijngaarden for performing abdominal ultrasonography and liver stiffness measurements. The generation and management of stool microbiome data for Rotterdam Study (Rotterdam Study III-2) were executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, Rotterdam. We thank N. El Faquir and J. Verkroost-Van Heemst for their help in sample collection and registration, and P. van der Wal, K. Arabe, H. Razawy and K. Singh Asra for their help in DNA isolation and sequencing. Furthermore, we thank J. Raes and J. Wang (KU Leuven, Belgium) for their guidance in 16S rRNA profiling and dataset generation. NTR: we are grateful to all twins and their relatives for their continued participation. Funding was obtained from NWO and MagW/ZonMW (grant nos. 904-61-090, 985-10-002, 904-61-193,480-04-004, 400-05-717, Addiction-31160008, Middelgroot-911-09-032 and Spinozapremie 56-464-14192); BBMRI-NL (no. 184.021.007); VU University{\textquoteright}s Institute for Health and Care Research (no. EMGO1); Neuroscience Campus Amsterdam (NCA); the European Community{\textquoteright}s Seventh Framework Program (no. FP7/2007-2013); ENGAGE (no. HEALTH-F4-2007-201413); and the European Science Council (ERCAdvanced, no. 230374). M.G.N. is supported by the ZonMw grant, {\textquoteleft}Genetics as a research tool: a natural experiment to elucidate the causal effects of social mobility on health{\textquoteright} (pnr:531003014), ZonMw project: {\textquoteleft}Can sex-and gender-specific gene expression and epigenetics explain sex-differences in disease prevalence and etiology?{\textquoteright} (pnr:849200011) and grant no. R01AG05462802S. NESDA: the infrastructure for the NESDA study (www.nesda.nl) was funded through the Geestkracht program of ZonMw (grant no. 10-000-1002) and through financial contributions of participating universities and mental health care organizations (VU University Medical Center, GGZ inGeest, Leiden University Medical Center, Leiden University, GGZ Rivierduinen, University Medical Center Groningen, University of Groningen, Lentis, GGZ Friesland, GGZ Drenthe and Rob Giel Onderzoekscentrum). LLS: we thank all participants. This study was supported by a grant from the Innovation-Oriented Research Program on Genomics (SenterNovem, no. IGE05007), the Centre for Medical Systems Biology and the Netherlands Consortium for Healthy Ageing (grant no. 050-060-810), all within the framework of NWO by the BBMRI Metabolomics Consortium funded by BBMRI-NL (NWO, grant nos. 184.021.007 and 184033111). LifeLines DEEP: we thank participants and staff of the LifeLines DEEP cohort for their collaboration. We thank J. Dekens, M. Platteel, A. Maatman and J. Arends for management and technical support. This project was funded by the Netherlands Heart Foundation (IN-CONTROL CVON, grant no. 2012-03 to A.Z. and J.F.; by NWO (nos. NWO-VIDI 864.13.013 to J.F. and NWO-VIDI 016.178.056 to A.Z.; and by the European Research Council Starting Grant no. 715772 to A.Z., who also holds a Rosalind Franklin Fellowship from the University of Groningen. Hoorn DCS: we thank participants of this study and research staff of the Diabetes Care System West-Friesland. High-throughput metabolomics measurements in the DCS study were supported by BBMRI-NL and the Parelsnoer Initiative which is part of, and is funded by, the Dutch Federation of University Medical Centres and, from 2007 to 2011, received initial funding from the Dutch Government. To perform additional research (in subsamples of the DCS cohort), funding was received from several sources including the Dutch Federation of University Medical Centres, health insurers, NWO, ZonMw, the Dutch Diabetes Foundation, the European Foundation for the Study of Diabetes, International Diabetes Federation, the European Innovative Medicine Initiative and the European Union. Alpha Omega Cohort: the Alpha Omega Cohort is registered with ClinicalTrials.gov. (identifier: NCT03192410). It was funded by the Netherlands Heart Foundation (grant no. 200T401) and the National Institutes of Health (NIH, grant no. R01HL076200). J.M.G. received funding from Unilever for analyses of dietary and circulating fatty acids in the Alpha Omega Cohort. High-throughput metabolomics measurements for the Alpha Omega Cohort were supported by BBMRI-NL. TMS: this study was supported by the European Regional Development Fund via OP-Zuid, the Province of Limburg, the Dutch Ministry of Economic Affairs (grant no. 31O.041), Stichting De Weijerhorst (Maastricht, the Netherlands), the Pearl String Initiative Diabetes (Amsterdam, the Netherlands), CARIM School for Cardiovascular Diseases (Maastricht, the Netherlands), Stichting Annadal (Maastricht, the Netherlands), Health Foundation Limburg (Maastricht, the Netherlands) and by unrestricted grants from Janssen-Cilag B.V. (Tilburg, the Netherlands), Novo Nordisk Farma B.V. (Alphen aan den Rijn, the Netherlands) and Sanofi-Aventis Netherlands B.V. (Gouda, the Netherlands). LUMINA: the LUMINA study is funded by grants obtained from ZonMw (no. 90700217) and VIDI (ZonMw, no. 91711319) (to G.M.T.); by NCSB and the Centre for Medical System Biology (CMSB), Funding Information: 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 G{\'e}notypage (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). Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2020",

month = jan,

day = "1",

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

language = "English",

volume = "26",

pages = "110--117",

journal = "Nature Medicine",

issn = "1078-8956",

publisher = "Nature Research",

number = "1",

}

Liu, J, Lahousse, L, Nivard, MG, Bot, M, Chen, LM, van Klinken, JB, Thesing, CS, Beekman, M, van den Akker, EB, Slieker, RC, Waterham, E, van der Kallen, CJH, de Boer, I, Li-Gao, RF, 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, JY, 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

TY - JOUR

T1 - Integration of epidemiologic, pharmacologic, genetic and gut microbiome data in a drug-metabolite atlas

AU - Liu, J.

AU - Lahousse, L.

AU - Nivard, M.G.

AU - Bot, M.

AU - Chen, L.M.

AU - van Klinken, J.B.

AU - Thesing, C.S.

AU - Beekman, M.

AU - van den Akker, E.B.

AU - Slieker, R.C.

AU - Waterham, E.

AU - van der Kallen, C.J.H.

AU - de Boer, I.

AU - Li-Gao, R.F.

AU - Vojinovic, D.

AU - Amin, N.

AU - Radjabzadeh, D.

AU - Kraaij, R.

AU - Alferink, L.J.M.

AU - Murad, S.D.

AU - Uitterlinden, A.G.

AU - Willemsen, G.

AU - Pool, R.

AU - Milaneschi, Y.

AU - van Heemst, D.

AU - Suchiman, H.E.D.

AU - Rutters, F.

AU - Elders, P.J.M.

AU - Beulens, J.W.J.

AU - van der Heijden, A.A.W.A.

AU - van Greevenbroek, M.M.J.

AU - Arts, I.C.W.

AU - Onderwater, G.L.J.

AU - van den Maagdenberg, A.M.J.M.

AU - Mook-Kanamori, D.O.

AU - Hankemeier, T.

AU - Terwindt, G.M.

AU - Stehouwer, C.D.A.

AU - Geleijnse, J.M.

AU - 't Hart, L.M.

AU - Slagboom, P.E.

AU - van Dijk, K.W.

AU - Zhernakova, A.

AU - Fu, J.Y.

AU - Penninx, B.W.J.H.

AU - Boomsma, D.I.

AU - Demirkan, A.

AU - Stricker, B.H.C.

AU - van Duijn, C.M.

N1 - Funding Information: We acknowledge all participants included in the cohorts. We also acknowledge the BBMRI Metabolomics Consortium (see Supplementary Information, http://www.bbmri. nl/omics-metabolomics/) funded by BBMRI-NL, a research infrastructure financed by the Dutch government through the Netherlands Organisation for Scientific Research (NWO) (grant nos. 184.021.007 and 184033111). This work is part of the CardioVasculair Onderzoek Nederland (CVON 2012-03), the Common mechanisms and pathways in Stroke and Alzheimer’s disease (CoSTREAM) project (www.costream.eu, grant agreement no. 667375), the Memorabel program (project no. 733050814), Netherlands X-omics Research Infrastructure and U01-AG061359 NIA. The full list of funding information for each cohort can be found in the cohort acknowledgements below. J.L., C.M.v.D. and A.D. benefitted from exchange grants from the Personalized pREvention of Chronic DIseases consortium (no. H2020-MSCA-RISE-2014). A.D. is supported by the Dutch Science Organization (ZonMW-VENI, grant no. 2015). L.C. is supported by a joint PhD fellowship from China Scholarship Council (no. 201708320268) and University of Groningen. M.G.N. is supported by Royal Netherlands Academy of Science Professor Award (no. PAH/6635) to D.I.B. D.O.M.-K. is supported by the ZonMW-VENI (grant no. 916.14.023). B.H.C.S. received a grant from TransQST (no. 116030-2; IMI2). D.R. is funded by an Erasmus MC mRACE grant (Profiling of the human gut microbiome). Cohort acknowledgements, ERF: we are grateful to all study participants and their relatives, general practitioners and neurologists for their contributions and to P. Veraart for her help in genealogy, J. Vergeer for supervision of the laboratory work and P. Snijders for his help in data collection. ERF was supported by the Consortium for Systems Biology (NCSB), both within the framework of the Netherlands Genomics Initiative (NGI)/NWO). The ERF study as a part of European Special Populations Research Network (EUROSPAN) was supported by European Commission FP6 STRP, grant no. 018947 (LSHG-CT-2006-01947) and also received funding from the European Community’s Seventh Framework Programme (FP7/2007-2013)/grant agreement no. HEALTH-F4-2007-201413 by the European Commission under the program ‘Quality of Life and Management of the Living Resources’ of the 5th Framework Programme (no. QLG2-CT-2002-01254), as well as the FP7 project EUROHEADPAIN (no. 602633). High-throughput analysis of ERF data was supported by a joint grant from NWO and the Russian Foundation for Basic Research (NWO-RFBR no. 047.017.043). High-throughput metabolomics measurements in the ERF study were supported by BBMRI-NL. Rotterdam Study: we thank the study subjects, the staff from Rotterdam Study and the participating pharmacists and general practitioners. The Rotterdam Study is supported by Erasmus MC and Erasmus University Rotterdam; by NWO, the Netherlands Organisation for Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Netherlands Genomics Initiative (NGI), the Ministry of Education, Culture and Science, the Ministry of HealthWelfare and Sports, the European Commission (DG XII) and the Municipality of Rotterdam. L.L. reports expert consultation from Boehringer Ingelheim and Novartis, and unrestricted grants from AstraZeneca and Chiesi. We are also grateful to nurse ultrasonographist, Mrs. van Wijngaarden for performing abdominal ultrasonography and liver stiffness measurements. The generation and management of stool microbiome data for Rotterdam Study (Rotterdam Study III-2) were executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, Rotterdam. We thank N. El Faquir and J. Verkroost-Van Heemst for their help in sample collection and registration, and P. van der Wal, K. Arabe, H. Razawy and K. Singh Asra for their help in DNA isolation and sequencing. Furthermore, we thank J. Raes and J. Wang (KU Leuven, Belgium) for their guidance in 16S rRNA profiling and dataset generation. NTR: we are grateful to all twins and their relatives for their continued participation. Funding was obtained from NWO and MagW/ZonMW (grant nos. 904-61-090, 985-10-002, 904-61-193,480-04-004, 400-05-717, Addiction-31160008, Middelgroot-911-09-032 and Spinozapremie 56-464-14192); BBMRI-NL (no. 184.021.007); VU University’s Institute for Health and Care Research (no. EMGO1); Neuroscience Campus Amsterdam (NCA); the European Community’s Seventh Framework Program (no. FP7/2007-2013); ENGAGE (no. HEALTH-F4-2007-201413); and the European Science Council (ERCAdvanced, no. 230374). M.G.N. is supported by the ZonMw grant, ‘Genetics as a research tool: a natural experiment to elucidate the causal effects of social mobility on health’ (pnr:531003014), ZonMw project: ‘Can sex-and gender-specific gene expression and epigenetics explain sex-differences in disease prevalence and etiology?’ (pnr:849200011) and grant no. R01AG05462802S. NESDA: the infrastructure for the NESDA study (www.nesda.nl) was funded through the Geestkracht program of ZonMw (grant no. 10-000-1002) and through financial contributions of participating universities and mental health care organizations (VU University Medical Center, GGZ inGeest, Leiden University Medical Center, Leiden University, GGZ Rivierduinen, University Medical Center Groningen, University of Groningen, Lentis, GGZ Friesland, GGZ Drenthe and Rob Giel Onderzoekscentrum). LLS: we thank all participants. This study was supported by a grant from the Innovation-Oriented Research Program on Genomics (SenterNovem, no. IGE05007), the Centre for Medical Systems Biology and the Netherlands Consortium for Healthy Ageing (grant no. 050-060-810), all within the framework of NWO by the BBMRI Metabolomics Consortium funded by BBMRI-NL (NWO, grant nos. 184.021.007 and 184033111). LifeLines DEEP: we thank participants and staff of the LifeLines DEEP cohort for their collaboration. We thank J. Dekens, M. Platteel, A. Maatman and J. Arends for management and technical support. This project was funded by the Netherlands Heart Foundation (IN-CONTROL CVON, grant no. 2012-03 to A.Z. and J.F.; by NWO (nos. NWO-VIDI 864.13.013 to J.F. and NWO-VIDI 016.178.056 to A.Z.; and by the European Research Council Starting Grant no. 715772 to A.Z., who also holds a Rosalind Franklin Fellowship from the University of Groningen. Hoorn DCS: we thank participants of this study and research staff of the Diabetes Care System West-Friesland. High-throughput metabolomics measurements in the DCS study were supported by BBMRI-NL and the Parelsnoer Initiative which is part of, and is funded by, the Dutch Federation of University Medical Centres and, from 2007 to 2011, received initial funding from the Dutch Government. To perform additional research (in subsamples of the DCS cohort), funding was received from several sources including the Dutch Federation of University Medical Centres, health insurers, NWO, ZonMw, the Dutch Diabetes Foundation, the European Foundation for the Study of Diabetes, International Diabetes Federation, the European Innovative Medicine Initiative and the European Union. Alpha Omega Cohort: the Alpha Omega Cohort is registered with ClinicalTrials.gov. (identifier: NCT03192410). It was funded by the Netherlands Heart Foundation (grant no. 200T401) and the National Institutes of Health (NIH, grant no. R01HL076200). J.M.G. received funding from Unilever for analyses of dietary and circulating fatty acids in the Alpha Omega Cohort. High-throughput metabolomics measurements for the Alpha Omega Cohort were supported by BBMRI-NL. TMS: this study was supported by the European Regional Development Fund via OP-Zuid, the Province of Limburg, the Dutch Ministry of Economic Affairs (grant no. 31O.041), Stichting De Weijerhorst (Maastricht, the Netherlands), the Pearl String Initiative Diabetes (Amsterdam, the Netherlands), CARIM School for Cardiovascular Diseases (Maastricht, the Netherlands), Stichting Annadal (Maastricht, the Netherlands), Health Foundation Limburg (Maastricht, the Netherlands) and by unrestricted grants from Janssen-Cilag B.V. (Tilburg, the Netherlands), Novo Nordisk Farma B.V. (Alphen aan den Rijn, the Netherlands) and Sanofi-Aventis Netherlands B.V. (Gouda, the Netherlands). LUMINA: the LUMINA study is funded by grants obtained from ZonMw (no. 90700217) and VIDI (ZonMw, no. 91711319) (to G.M.T.); by NCSB and the Centre for Medical System Biology (CMSB), Funding Information: 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). Publisher Copyright: © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.

PY - 2020/1/1

Y1 - 2020/1/1

N2 - 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/).

AB - 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/).

KW - circulating metabolites

KW - design

KW - diabetes-mellitus

KW - magnetic-resonance metabolomics

KW - mendelian randomization

KW - obesity

KW - population

KW - profiles

KW - risk

KW - serum metabolome

KW - POPULATION

KW - PROFILES

KW - DESIGN

KW - SERUM METABOLOME

KW - RISK

KW - MENDELIAN RANDOMIZATION

KW - CIRCULATING METABOLITES

KW - DIABETES-MELLITUS

KW - MAGNETIC-RESONANCE METABOLOMICS

KW - OBESITY

U2 - 10.1038/s41591-019-0722-x

DO - 10.1038/s41591-019-0722-x

M3 - Article

C2 - 31932804

SN - 1078-8956

VL - 26

SP - 110

EP - 117

JO - Nature Medicine

JF - Nature Medicine

IS - 1

ER -

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

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