Metabolomics reveals a link between homocysteine and lipid metabolism and leukocyte telomere length: the ENGAGE consortium

Ashley van der Spek; Linda Broer; Harmen H M Draisma; René Pool; Eva Albrecht; Marian Beekman; Massimo Mangino; Mait Raag; Dale R Nyholt; Harish K Dharuri; Veryan Codd; Najaf Amin; Eco J C de Geus; Joris Deelen; Ayse Demirkan; Idil Yet; Krista Fischer; Toomas Haller; Anjali K Henders; Aaron Isaacs; Sarah E Medland; Grant W Montgomery; Simon P Mooijaart; Konstantin Strauch; H Eka D Suchiman; Anika A M Vaarhorst; Diana van Heemst; Rui Wang-Sattler; John B Whitfield; Gonneke Willemsen; Margaret J Wright; Nicholas G Martin; Nilesh J Samani; Andres Metspalu; P Eline Slagboom; Tim D Spector; D.I. Boomsma; Cornelia M van Duijn; Christian Gieger

doi:10.1038/s41598-019-47282-6

Metabolomics reveals a link between homocysteine and lipid metabolism and leukocyte telomere length: the ENGAGE consortium

Ashley van der Spek
, Linda Broer
, Harmen H M Draisma
, René Pool
, Eva Albrecht
, Marian Beekman
, Massimo Mangino
, Mait Raag
, Dale R Nyholt
, Harish K Dharuri
, Veryan Codd
, Najaf Amin
, Eco J C de Geus
, Joris Deelen
, Ayse Demirkan
, Idil Yet
, Krista Fischer
, Toomas Haller
, Anjali K Henders
, Aaron Isaacs

Sarah E Medland, Grant W Montgomery, Simon P Mooijaart, Konstantin Strauch, H Eka D Suchiman, Anika A M Vaarhorst, Diana van Heemst, Rui Wang-Sattler, John B Whitfield, Gonneke Willemsen, Margaret J Wright, Nicholas G Martin, Nilesh J Samani, Andres Metspalu, P Eline Slagboom, Tim D Spector, D.I. Boomsma, Cornelia M van Duijn, Christian Gieger

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

Abstract

Telomere shortening has been associated with multiple age-related diseases such as cardiovascular disease, diabetes, and dementia. However, the biological mechanisms responsible for these associations remain largely unknown. In order to gain insight into the metabolic processes driving the association of leukocyte telomere length (LTL) with age-related diseases, we investigated the association between LTL and serum metabolite levels in 7,853 individuals from seven independent cohorts. LTL was determined by quantitative polymerase chain reaction and the levels of 131 serum metabolites were measured with mass spectrometry in biological samples from the same blood draw. With partial correlation analysis, we identified six metabolites that were significantly associated with LTL after adjustment for multiple testing: lysophosphatidylcholine acyl C17:0 (lysoPC a C17:0, p-value = 7.1 × 10-6), methionine (p-value = 9.2 × 10-5), tyrosine (p-value = 2.1 × 10-4), phosphatidylcholine diacyl C32:1 (PC aa C32:1, p-value = 2.4 × 10-4), hydroxypropionylcarnitine (C3-OH, p-value = 2.6 × 10-4), and phosphatidylcholine acyl-alkyl C38:4 (PC ae C38:4, p-value = 9.0 × 10-4). Pathway analysis showed that the three phosphatidylcholines and methionine are involved in homocysteine metabolism and we found supporting evidence for an association of lipid metabolism with LTL. In conclusion, we found longer LTL associated with higher levels of lysoPC a C17:0 and PC ae C38:4, and with lower levels of methionine, tyrosine, PC aa C32:1, and C3-OH. These metabolites have been implicated in inflammation, oxidative stress, homocysteine metabolism, and in cardiovascular disease and diabetes, two major drivers of morbidity and mortality.

Original language	English
Article number	11623
Pages (from-to)	11623
Journal	Scientific Reports
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41598-019-47282-6
Publication status	Published - 12 Aug 2019

Funding

ERF: The ERF study has received funding from the Centre for Medical Systems Biology (CMSB) and Netherlands Consortium for Systems Biology (NCSB), both within the framework of the Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO). ERF study is also a part of EUROSPAN (European Special Populations Research Network) (FP6 STRP grant number 018947 (LSHG-CT-2006-01947)); European Network of Genomic and Genetic Epidemiology (ENGAGE) from the European Community’s Seventh Framework Programme (FP7/2007-2013)/grant agreement HEALTH-F4-2007-201413; “Quality of Life and Management of the Living Resources” of 5th Framework Programme (no. QLG2-CT-2002-01254); FP7 project EUROHEADPAIN (nr 602633), the Internationale Stichting Alzheimer Onderzoek (ISAO); the Hersenstichting Nederland (HSN); and the JNPD under the project PERADES (grant number 733051021, Defining Genetic, Polygenic and Environmental Risk for Alzheimer’s Disease using multiple powerful cohorts, focused Epigenetics and Stem cell metabolomics). A first version of the manuscript has been published in the PhD thesis of Linda Broer “(Genetic) Epidemiology of Aging”112. We are grateful to all general practitioners for their contributions, to P. Veraart for her help in genealogy, J. Vergeer for the supervision of the laboratory work and P. Snijders for his help in data collection. NTR: We thank all participants in the Netherlands Twin Register. Research was funded by the Netherlands Organization for Scientific Research (NWO: MagW/ZonMW grants 904-61-090, 985-10-002,904-61-193,480-04-004, 400-05-717, Addiction-31160008 Middelgroot-911-09-032, Spinozapremie 56-464-14192), Center for Medical Systems Biology (CSMB, NWO Genomics), NBIC/BioAssist/RK(2008.024), Biobanking and Biomolecular Resources Research Infrastructure (BBMRI –NL, 184.021.007), the VU University’s Institute for Health and Care Research (EMGO+), the European Community’s Seventh Framework Program (FP7/2007-2013), ENGAGE (HEALTH-F4-2007-201413) and the European Science Council (ERC - 230374 and ERC-284167). Harmen H.M. Draisma is funded by the Wellcome Trust (WT205915). KORA: KORA was financed by the Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany and supported by grants from the German Federal Ministry of Education and Research (BMBF). Part of this work was financed by the German National Genome Research Network (NGFN; NGFNPlus, project number 01GS0834) and supported within the Munich Center of Health Sciences (MC Health) as part of LMUinnovativ. Telomere assays were funded by the ENGAGE consortium. TwinsUK: The study was funded by the Wellcome Trust; European Community’s Seventh Framework Programme (FP7/2007–2013), ENGAGE project grant agreement (HEALTH-F4-2007-201413). The study also receives support from the Dept of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy’s & St Thomas’ NHS Foundation Trust in partnership with King’s College London. TDS is an NIHR senior Investigator and is holder of an ERC Advanced Principal Investigator award. Genotyping was performed by The Wellcome Trust Sanger Institute, support of the National Eye Institute via an NIH/CIDR genotyping project. EGCUT: EGCUT was supported by Estonian Research Council [IUT20-60, IUT24-6 and PUT1665 to K.F.]; European Union Horizon 2020 [692145 and European Union through the European Regional Development Fund [2014-2020.4.01.15-0012 GENTRANSMED]. We also thank all participants of the Estonian Biobank cohort. EGCUT studies were financed by University of Tartu (grant “Center of Translational Genomics”), by Estonian Goverment (grant #SF0180142s08, grant #ETF9353) and by European Commission through the European Regional Development Fund in the frame of grant “Centre of Excellence in Genomics” and Estonian Research Infrastructure’s Roadmap and through FP7 grant #313010. LLS: We thank all participants of the Leiden Longevity Study. The research leading to these results has received funding from the European Union’s Seventh Framework Programme (FP7/2007–2011) under grant agreement n° 259679. This study was supported by a grant from the Innovation-Oriented Research Program on Genomics (SenterNovem IGE05007), the Centre for Medical Systems Biology, Biobanking and Biomolecular Resources Research Infrastructure, (BBMRI-NL, 184.021.007) and the Netherlands Consortium for Healthy Ageing (grant 050-060-810), all in the framework of the Netherlands Genomics Initiative, Netherlands Organization for Scientific Research (NWO), and by Unilever Colworth. J. Deelen was financially supported by the Alexander von Humboldt Foundation. QIMR: We thank Marlene Grace and Ann Eldridge for twin recruitment and data collection, Lisa Bardsley for preparation of DNA samples, David Smyth for IT/database support, and the twins and their families for their participation. Data collection was supported by grants to NGM and MJW from the Australian Research Council and Australian National Health and Medical Research Council (NHMRC). Telomere length assessment was co-funded by the European Community’s Seventh Framework Programme (FP7/2007–2013), ENGAGE project, grant agreement HEALTH-F4-2007-201413 and NHMRC-European Union Collaborative Research Grant 496739. GWM and DRN were supported by the NHMRC Fellowship (619667) and ARC Future Fellowship (FT0991022) schemes, respectively.

Funders	Funder number
Hersenstichting
Centre for Medical Systems Biology
VU University’s Institute for Health and Care Research
Münchner Zentrum für Gesundheitswissenschaften, Ludwig-Maximilians-Universität München
Biobanking and Biomolecular Resources Research Infrastructure
Internationale Stichting Alzheimer Onderzoek
National Institute for Health Research
Bundesministerium für Bildung und Forschung
European Special Populations Research Network
Tartu Ülikool
European Commission
Deutsches Forschungszentrum für Gesundheit und Umwelt, Helmholtz Zentrum München
Dept of Health
Netherlands Consortium for Systems Biology
National Eye Institute
German National Genome Research Network
Unilever Colworth
BBMRI
Wellcome Trust Sanger Institute
NIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer Research
Alexander von Humboldt-Stiftung
Horizon 2020
BBMRI-NL	184.021.007
Nederlandse Organisatie voor Wetenschappelijk Onderzoek	985-10-002,904-61-193,480-04-004, 904-61-090, 400-05-717
Seventh Framework Programme	FP7/2007-2013, 619667, HEALTH-F4-2007-201413
European Science Council	ERC - 230374, ERC-284167
Quality of Life and Management of the Living Resources” of 5th Framework Programme	QLG2-CT-2002-01254
Spinozapremie	56-464-14192
Wellcome Trust	WT205915, 205915
Horizon 2020 Framework Programme	692145, 259679, 230374, 313010, 284167, 201413, 602633
ENGAGE	HEALTH-F4-2007-201413
NBIC/BioAssist/RK	2008.024
JNPD	733051021
Netherlands Consortium for Healthy Ageing	050-060-810
FP6 STRP	018947, LSHG-CT-2006-01947
NGFN	01GS0834
Australian Research Council	FT0991022
Eesti Teadusagentuur	IUT20-60, PUT1665, IUT24-6
Estonian Goverment	0180142s08, #ETF9353
Innovation-Oriented Research Program on Genomics	IGE05007
European Regional Development Fund	2014-2020.4.01.15-0012 GENTRANSMED
National Health and Medical Research Council	496739

UN SDGs

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

SDG 3 Good Health and Well-being

Cohort Studies

Netherlands Twin Register (NTR)

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10.1038/s41598-019-47282-6

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Cite this

van der Spek, A., Broer, L., Draisma, H. H. M., Pool, R., Albrecht, E., Beekman, M., Mangino, M., Raag, M., Nyholt, D. R., Dharuri, H. K., Codd, V., Amin, N., de Geus, E. J. C., Deelen, J., Demirkan, A., Yet, I., Fischer, K., Haller, T., Henders, A. K., ... Gieger, C. (2019). Metabolomics reveals a link between homocysteine and lipid metabolism and leukocyte telomere length: the ENGAGE consortium. Scientific Reports, 9(1), 11623. Article 11623. https://doi.org/10.1038/s41598-019-47282-6

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title = "Metabolomics reveals a link between homocysteine and lipid metabolism and leukocyte telomere length: the ENGAGE consortium",

abstract = "Telomere shortening has been associated with multiple age-related diseases such as cardiovascular disease, diabetes, and dementia. However, the biological mechanisms responsible for these associations remain largely unknown. In order to gain insight into the metabolic processes driving the association of leukocyte telomere length (LTL) with age-related diseases, we investigated the association between LTL and serum metabolite levels in 7,853 individuals from seven independent cohorts. LTL was determined by quantitative polymerase chain reaction and the levels of 131 serum metabolites were measured with mass spectrometry in biological samples from the same blood draw. With partial correlation analysis, we identified six metabolites that were significantly associated with LTL after adjustment for multiple testing: lysophosphatidylcholine acyl C17:0 (lysoPC a C17:0, p-value = 7.1 × 10-6), methionine (p-value = 9.2 × 10-5), tyrosine (p-value = 2.1 × 10-4), phosphatidylcholine diacyl C32:1 (PC aa C32:1, p-value = 2.4 × 10-4), hydroxypropionylcarnitine (C3-OH, p-value = 2.6 × 10-4), and phosphatidylcholine acyl-alkyl C38:4 (PC ae C38:4, p-value = 9.0 × 10-4). Pathway analysis showed that the three phosphatidylcholines and methionine are involved in homocysteine metabolism and we found supporting evidence for an association of lipid metabolism with LTL. In conclusion, we found longer LTL associated with higher levels of lysoPC a C17:0 and PC ae C38:4, and with lower levels of methionine, tyrosine, PC aa C32:1, and C3-OH. These metabolites have been implicated in inflammation, oxidative stress, homocysteine metabolism, and in cardiovascular disease and diabetes, two major drivers of morbidity and mortality.",

author = "\{van der Spek\}, Ashley and Linda Broer and Draisma, \{Harmen H M\} and Ren{\'e} Pool and Eva Albrecht and Marian Beekman and Massimo Mangino and Mait Raag and Nyholt, \{Dale R\} and Dharuri, \{Harish K\} and Veryan Codd and Najaf Amin and \{de Geus\}, \{Eco J C\} and Joris Deelen and Ayse Demirkan and Idil Yet and Krista Fischer and Toomas Haller and Henders, \{Anjali K\} and Aaron Isaacs and Medland, \{Sarah E\} and Montgomery, \{Grant W\} and Mooijaart, \{Simon P\} and Konstantin Strauch and Suchiman, \{H Eka D\} and Vaarhorst, \{Anika A M\} and \{van Heemst\}, Diana and Rui Wang-Sattler and Whitfield, \{John B\} and Gonneke Willemsen and Wright, \{Margaret J\} and Martin, \{Nicholas G\} and Samani, \{Nilesh J\} and Andres Metspalu and \{Eline Slagboom\}, P and Spector, \{Tim D\} and D.I. Boomsma and \{van Duijn\}, \{Cornelia M\} and Christian Gieger",

year = "2019",

month = aug,

day = "12",

doi = "10.1038/s41598-019-47282-6",

language = "English",

volume = "9",

pages = "11623",

journal = "Scientific Reports",

issn = "2045-2322",

publisher = "Nature Research",

number = "1",

}

van der Spek, A, Broer, L, Draisma, HHM, Pool, R, Albrecht, E, Beekman, M, Mangino, M, Raag, M, Nyholt, DR, Dharuri, HK, Codd, V, Amin, N, de Geus, EJC, Deelen, J, Demirkan, A, Yet, I, Fischer, K, Haller, T, Henders, AK, Isaacs, A, Medland, SE, Montgomery, GW, Mooijaart, SP, Strauch, K, Suchiman, HED, Vaarhorst, AAM, van Heemst, D, Wang-Sattler, R, Whitfield, JB, Willemsen, G, Wright, MJ, Martin, NG, Samani, NJ, Metspalu, A, Eline Slagboom, P, Spector, TD, Boomsma, DI, van Duijn, CM & Gieger, C 2019, 'Metabolomics reveals a link between homocysteine and lipid metabolism and leukocyte telomere length: the ENGAGE consortium', Scientific Reports, vol. 9, no. 1, 11623, pp. 11623. https://doi.org/10.1038/s41598-019-47282-6

TY - JOUR

T1 - Metabolomics reveals a link between homocysteine and lipid metabolism and leukocyte telomere length

T2 - the ENGAGE consortium

AU - van der Spek, Ashley

AU - Broer, Linda

AU - Draisma, Harmen H M

AU - Pool, René

AU - Albrecht, Eva

AU - Beekman, Marian

AU - Mangino, Massimo

AU - Raag, Mait

AU - Nyholt, Dale R

AU - Dharuri, Harish K

AU - Codd, Veryan

AU - Amin, Najaf

AU - de Geus, Eco J C

AU - Deelen, Joris

AU - Demirkan, Ayse

AU - Yet, Idil

AU - Fischer, Krista

AU - Haller, Toomas

AU - Henders, Anjali K

AU - Isaacs, Aaron

AU - Medland, Sarah E

AU - Montgomery, Grant W

AU - Mooijaart, Simon P

AU - Strauch, Konstantin

AU - Suchiman, H Eka D

AU - Vaarhorst, Anika A M

AU - van Heemst, Diana

AU - Wang-Sattler, Rui

AU - Whitfield, John B

AU - Willemsen, Gonneke

AU - Wright, Margaret J

AU - Martin, Nicholas G

AU - Samani, Nilesh J

AU - Metspalu, Andres

AU - Eline Slagboom, P

AU - Spector, Tim D

AU - Boomsma, D.I.

AU - van Duijn, Cornelia M

AU - Gieger, Christian

PY - 2019/8/12

Y1 - 2019/8/12

N2 - Telomere shortening has been associated with multiple age-related diseases such as cardiovascular disease, diabetes, and dementia. However, the biological mechanisms responsible for these associations remain largely unknown. In order to gain insight into the metabolic processes driving the association of leukocyte telomere length (LTL) with age-related diseases, we investigated the association between LTL and serum metabolite levels in 7,853 individuals from seven independent cohorts. LTL was determined by quantitative polymerase chain reaction and the levels of 131 serum metabolites were measured with mass spectrometry in biological samples from the same blood draw. With partial correlation analysis, we identified six metabolites that were significantly associated with LTL after adjustment for multiple testing: lysophosphatidylcholine acyl C17:0 (lysoPC a C17:0, p-value = 7.1 × 10-6), methionine (p-value = 9.2 × 10-5), tyrosine (p-value = 2.1 × 10-4), phosphatidylcholine diacyl C32:1 (PC aa C32:1, p-value = 2.4 × 10-4), hydroxypropionylcarnitine (C3-OH, p-value = 2.6 × 10-4), and phosphatidylcholine acyl-alkyl C38:4 (PC ae C38:4, p-value = 9.0 × 10-4). Pathway analysis showed that the three phosphatidylcholines and methionine are involved in homocysteine metabolism and we found supporting evidence for an association of lipid metabolism with LTL. In conclusion, we found longer LTL associated with higher levels of lysoPC a C17:0 and PC ae C38:4, and with lower levels of methionine, tyrosine, PC aa C32:1, and C3-OH. These metabolites have been implicated in inflammation, oxidative stress, homocysteine metabolism, and in cardiovascular disease and diabetes, two major drivers of morbidity and mortality.

AB - Telomere shortening has been associated with multiple age-related diseases such as cardiovascular disease, diabetes, and dementia. However, the biological mechanisms responsible for these associations remain largely unknown. In order to gain insight into the metabolic processes driving the association of leukocyte telomere length (LTL) with age-related diseases, we investigated the association between LTL and serum metabolite levels in 7,853 individuals from seven independent cohorts. LTL was determined by quantitative polymerase chain reaction and the levels of 131 serum metabolites were measured with mass spectrometry in biological samples from the same blood draw. With partial correlation analysis, we identified six metabolites that were significantly associated with LTL after adjustment for multiple testing: lysophosphatidylcholine acyl C17:0 (lysoPC a C17:0, p-value = 7.1 × 10-6), methionine (p-value = 9.2 × 10-5), tyrosine (p-value = 2.1 × 10-4), phosphatidylcholine diacyl C32:1 (PC aa C32:1, p-value = 2.4 × 10-4), hydroxypropionylcarnitine (C3-OH, p-value = 2.6 × 10-4), and phosphatidylcholine acyl-alkyl C38:4 (PC ae C38:4, p-value = 9.0 × 10-4). Pathway analysis showed that the three phosphatidylcholines and methionine are involved in homocysteine metabolism and we found supporting evidence for an association of lipid metabolism with LTL. In conclusion, we found longer LTL associated with higher levels of lysoPC a C17:0 and PC ae C38:4, and with lower levels of methionine, tyrosine, PC aa C32:1, and C3-OH. These metabolites have been implicated in inflammation, oxidative stress, homocysteine metabolism, and in cardiovascular disease and diabetes, two major drivers of morbidity and mortality.

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UR - https://www.scopus.com/pages/publications/85070891738#tab=citedBy

U2 - 10.1038/s41598-019-47282-6

DO - 10.1038/s41598-019-47282-6

M3 - Article

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VL - 9

SP - 11623

JO - Scientific Reports

JF - Scientific Reports

IS - 1

M1 - 11623

ER -

Metabolomics reveals a link between homocysteine and lipid metabolism and leukocyte telomere length: the ENGAGE consortium

Abstract

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UN SDGs

Cohort Studies

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