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

Nat Med. 2020 Jan;26(1):110-117. doi: 10.1038/s41591-019-0722-x. Epub 2020 Jan 13.

Authors

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 Beekman¹², Erik Ben van den Akker^{12

13

14}, Roderick C Slieker^{6

15

16}, Eveline Waterham¹⁷, Carla J H van der Kallen^{18

19}, Irene de Boer²⁰, Ruifang Li-Gao²¹, Dina Vojinovic³, Najaf Amin³, Djawad Radjabzadeh²², Robert Kraaij²², Louise J M Alferink²³, Sarwa Darwish Murad²³, André G Uitterlinden^{3

22}, Gonneke Willemsen^{5

6}, Rene Pool^{5

6}, Yuri Milaneschi^{5

6}, Diana van Heemst²⁴, H Eka D Suchiman¹², 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 Onderwater²⁰, Arn M J M van den Maagdenberg^{9

20}, Dennis O Mook-Kanamori^{21

28}, Thomas Hankemeier^{29

30}, Gisela M Terwindt²⁰, Coen D A Stehouwer^{18

19}, Johanna M Geleijnse¹⁷, Leen M 't Hart^{6

12

15

16}, P Eline Slagboom¹², Ko Willems van Dijk^{9

10

31}, Alexandra Zhernakova⁷, 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. jun.liu@ndph.ox.ac.uk.
² Nuffield Department of Population Health, University of Oxford, Oxford, UK. jun.liu@ndph.ox.ac.uk.
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. cornelia.vanduijn@ndph.ox.ac.uk.
³⁵ Nuffield Department of Population Health, University of Oxford, Oxford, UK. cornelia.vanduijn@ndph.ox.ac.uk.
³⁶ Leiden Academic Center for Drug Research, Leiden University, Leiden, the Netherlands. cornelia.vanduijn@ndph.ox.ac.uk.

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/).

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Body Mass Index
Confounding Factors, Epidemiologic
Endophenotypes
Epidemiologic Studies*
Gastrointestinal Microbiome / genetics*
Humans
Liver / metabolism
Metabolome / genetics*
Models, Biological
Pharmaceutical Preparations*
Protein Interaction Maps

Substances

Pharmaceutical Preparations