Integration of epidemiologic, pharmacologic, genetic and gut microbiome data in a drug–metabolite atlas,Nature Medicine

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Integration of epidemiologic, pharmacologic, genetic and gut microbiome data in a drug–metabolite atlas
Nature Medicine ( IF 58.7 ) Pub Date : 2020-01-13 , DOI: 10.1038/s41591-019-0722-x
Jun Liu _{1,

2} , Lies Lahousse _{1,

3} , Michel G Nivard _{4,

5} , Mariska Bot _{4,

5} , Lianmin Chen _{6,

7} , Jan Bert van Klinken _{8,

9,

10} , Carisha S Thesing _{4,

5} , Marian Beekman ₁₁ , Erik Ben van den Akker _{11,

12,

13} , Roderick C Slieker _{5,

14,

15} , Eveline Waterham ₁₆ , Carla J H van der Kallen _{17,

18} , Irene de Boer ₁₉ , Ruifang Li-Gao ₂₀ , Dina Vojinovic ₁ , Najaf Amin ₁ , Djawad Radjabzadeh ₂₁ , Robert Kraaij ₂₁ , Louise J M Alferink ₂₂ , Sarwa Darwish Murad ₂₂ , André G Uitterlinden _{1,

21} , Gonneke Willemsen _{4,

5} , Rene Pool _{4,

5} , Yuri Milaneschi _{4,

5} , Diana van Heemst ₂₃ , H Eka D Suchiman ₁₁ , Femke Rutters _{5,

14} , Petra J M Elders _{5,

24} , Joline W J Beulens _{5,

14} , Amber A W A van der Heijden _{5,

24} , Marleen M J van Greevenbroek _{17,

18} , Ilja C W Arts _{18,

25,

26} , Gerrit L J Onderwater ₁₉ , Arn M J M van den Maagdenberg _{8,

19} , Dennis O Mook-Kanamori _{20,

27} , Thomas Hankemeier _{28,

29} , Gisela M Terwindt ₁₉ , Coen D A Stehouwer _{17,

18} , Johanna M Geleijnse ₁₆ , Leen M 't Hart _{5,

11,

14,

15} , P Eline Slagboom ₁₁ , Ko Willems van Dijk _{8,

9,

30} , Alexandra Zhernakova ₆ , Jingyuan Fu _{6,

7} , Brenda W J H Penninx _{4,

5} , Dorret I Boomsma _{4,

5} , Ayşe Demirkan _{1,

6,

31} , Bruno H C Stricker _{1,

21,

32} , Cornelia M van Duijn _{1,

2,

28}

Affiliation

Department of Epidemiology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands.
Nuffield Department of Population Health, University of Oxford, Oxford, UK.
Department of Bioanalysis, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium.
Department of Biological Psychology, Amsterdam University Medical Center, Vrije Universiteit, Amsterdam, the Netherlands.
Amsterdam Public Health Research Institute, Amsterdam, the Netherlands.
Department of Genetics, University Medical Center Groningen, Groningen, the Netherlands.
Department of Pediatrics, University Medical Center Groningen, Groningen, the Netherlands.
Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands.
Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands.
Department of Clinical Chemistry, Laboratory Genetic Metabolic Disease, Amsterdam University Medical Center, Amsterdam, the Netherlands.
Department of Biomedical Data Sciences, section of Molecular Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.
Department of Pattern Recognition and Bioinformatics, Delft University of Technology, Delft, the Netherlands.
Leiden Computational Biology Center, Leiden University Medical Center, Leiden, the Netherlands.
Department of Epidemiology and Biostatistics, Amsterdam University Medical Center, Vrije Universiteit, Amsterdam, the Netherlands.
Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands.
Division of Human Nutrition and Health, Wageningen University, Wageningen, the Netherlands.
Department of Internal Medicine, Maastricht University, Maastricht, the Netherlands.
School for Cardiovascular Diseases, Maastricht University, Maastricht, the Netherlands.
Department of Neurology, Leiden University Medical Center, Leiden, the Netherlands.
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.
Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, the Netherlands.
Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands.
Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.
Department of General Practice and Elderly Care Medicine, Amsterdam University Medical Center, Vrije Universiteit, Amsterdam, the Netherlands.
Department of Epidemiology, Maastricht University, Maastricht, the Netherlands.
Maastricht Center for Systems Biology, Maastricht University, Maastricht, the Netherlands.
Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, the Netherlands.
Leiden Academic Center for Drug Research, Leiden University, Leiden, the Netherlands.
Netherlands Metabolomics Center, Leiden, the Netherlands.
Department of Internal Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, the Netherlands.
Section of Statistical Multi-omics, Department of Clinical and Experimental Medicine, University of Surrey, Guildford, UK.
Inspectorate of Healthcare, The Hague, the Netherlands.

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/).

中文翻译：

在药物代谢物图谱中整合流行病学、药理学、遗传和肠道微生物组数据

高通量代谢分析的进展为深入了解药物对人体代谢的影响提供了前所未有的机会。荷兰的 Biobanking BioMolecular Research Infrastructure 为 87 种常用处方药和 150 种通过质子核磁共振评估的临床相关血浆代谢物构建了药物代谢物关联图谱。该地图集包括对 10 个队列（18,873 人）的荟萃分析，并在评估包括联合治疗在内的混杂因素后发现了 1,071 个药物-代谢物关联。我们表明，来自横断面研究的他汀类药物对代谢物的影响估计与干预和遗传观察研究的估计相当。进一步的数据整合将质子泵抑制剂与循环代谢物、肝功能、肝脏脂肪变性和肠道微生物群。我们的图谱为有针对性的实验药物研究和临床试验提供了一个工具，以提高药物疗效、安全性和再利用。我们为地图集的可视化提供了一个基于网络的资源 (http://bbmri.researchlumc.nl/atlas/)。

更新日期：2020-01-13

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