DNA methylation age is associated with an altered hemostatic profile in a multiethnic meta-analysis

Cavin K. Ward-Caviness; Jennifer E. Huffman; Karl Everett; Marine Germain; Jenny Van Dongen; W. David Hill; Min A. Jhun; Jennifer A. Brody; Mohsen Ghanbari; Lei Du; Nicholas S. Roetker; Paul S. De Vries; Melanie Waldenberger; Christian Gieger; Petra Wolf; Holger Prokisch; Wolfgang Koenig; Christopher J. O’Donnell; Daniel Levy; Chunyu Liu; Vinh Truong; Philip S. Wells; David Alexandre Trégouët; Weihong Tang; Alanna C. Morrison; Eric Boerwinkle; Kerri L. Wiggins; Barbara McKnight; Xiuqing Guo; Bruce M. Psaty; Nona Sotoodenia; Dorret I. Boomsma; Gonneke Willemsen; Lannie Ligthart; Ian J. Deary; Wei Zhao; Erin B. Ware; Sharon L.R. Kardia; Joyce B.J. Van Meurs; Andre G. Uitterlinden; Oscar H. Franco; Per Eriksson; Anders Franco-Cereceda; James S. Pankow; Andrew D. Johnson; France Gagnon; Pierre Emmanuel Morange; Eco J.C. De Geus; John M. Starr; Jennifer A. Smith; Abbas Dehghan; Hanna M. Björck; Nicholas L. Smith; Annette Peters

doi:10.1182/blood-2018-02-831347

DNA methylation age is associated with an altered hemostatic profile in a multiethnic meta-analysis

Cavin K. Ward-Caviness^*, Jennifer E. Huffman, Karl Everett, Marine Germain, Jenny Van Dongen, W. David Hill, Min A. Jhun, Jennifer A. Brody, Mohsen Ghanbari, Lei Du, Nicholas S. Roetker, Paul S. De Vries, Melanie Waldenberger, Christian Gieger, Petra Wolf, Holger Prokisch, Wolfgang Koenig, Christopher J. O’Donnell, Daniel Levy, Chunyu LiuVinh Truong, Philip S. Wells, David Alexandre Trégouët, Weihong Tang, Alanna C. Morrison, Eric Boerwinkle, Kerri L. Wiggins, Barbara McKnight, Xiuqing Guo, Bruce M. Psaty, Nona Sotoodenia, Dorret I. Boomsma, Gonneke Willemsen, Lannie Ligthart, Ian J. Deary, Wei Zhao, Erin B. Ware, Sharon L.R. Kardia, Joyce B.J. Van Meurs, Andre G. Uitterlinden, Oscar H. Franco, Per Eriksson, Anders Franco-Cereceda, James S. Pankow, Andrew D. Johnson, France Gagnon, Pierre Emmanuel Morange, Eco J.C. De Geus, John M. Starr, Jennifer A. Smith, Abbas Dehghan, Hanna M. Björck, Nicholas L. Smith, Annette Peters

^*Corresponding author for this work

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

81 Downloads (Pure)

Abstract

Many hemostatic factors are associated with age and age-related diseases; however, much remains unknown about the biological mechanisms linking aging and hemostatic factors. DNA methylation is a novel means by which to assess epigenetic aging, which is a measure of age and the aging processes as determined by altered epigenetic states. We used a meta-analysis approach to examine the association between measures of epigenetic aging and hemostatic factors, as well as a clotting time measure. For fibrinogen, we performed European and African ancestry–specific meta-analyses which were then combined via a random effects meta-analysis. For all other measures we could not estimate ancestry-specific effects and used a single fixed effects meta-analysis. We found that 1-year higher extrinsic epigenetic age as compared with chronological age was associated with higher fibrinogen (0.004 g/L/y; 95% confidence interval, 0.001-0.007; P 5 .01) and plasminogen activator inhibitor 1 (PAI-1; 0.13 U/mL/y; 95% confidence interval, 0.07-0.20; P 5 6.6 3 102⁵) concentrations, as well as lower activated partial thromboplastin time, a measure of clotting time. We replicated PAI-1 associations using an independent cohort. To further elucidate potential functional mechanisms, we associated epigenetic aging with expression levels of the PAI-1 protein encoding gene (SERPINE1) and the 3 fibrinogen subunit-encoding genes (FGA, FGG, and FGB) in both peripheral blood and aorta intima-media samples. We observed associations between accelerated epigenetic aging and transcription of FGG in both tissues. Collectively, our results indicate that accelerated epigenetic aging is associated with a procoagulation hemostatic profile, and that epigenetic aging may regulate hemostasis in part via gene transcription.

Original language	English
Pages (from-to)	1842-1850
Number of pages	9
Journal	Blood
Volume	132
Issue number	17
Early online date	24 Jul 2018
DOIs	https://doi.org/10.1182/blood-2018-02-831347
Publication status	Published - 25 Oct 2018

Funding

The work was supported by the Swedish Research Council (12660), the Swedish Heart-Lung Foundation (201202729), the Leducq Foundation (MIBAVA, 12CVD03), FundacióLa Maratóde TV3 (20151332), and a donation by Fredrik Lundberg. Infrastructure for the CHARGE Consortium is supported in part by National Institutes of Health (NIH), National Heart, Lung, and Blood Institute (NHLBI) grant R01HL105756. The CHS research was supported by NIH, NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, and N01HC85086, and NHLBI grants U01HL080295, U01HL130114, K08HL116640, R01HL087652, R01HL092111, R01HL103612, R01HL105756, R01HL103612, R01HL111089, R01HL116747, and R01HL120393 with additional contribution from the NIH, National Institute of Neurological Disorders and Stroke. Additional support was provided through R01AG023629 from the NIH, National Institute on Aging, Merck Foundation/Society of Epidemiologic Research, Laughlin Family, Alpha Phi Foundation, and Locke Charitable Foundation. The provision of genotyping data were supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR001881, and the NIH, National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The Framingham Heart Study is funded by National Institutes of Health contract N01-HC-25195. The laboratory work for this investigation was funded by the Division of Intramural Research, NHLBI, NIH, Bethesda, MD. The analytical component of this project was funded by the Division of Intramural Research, NHLBI, and the Center for Information Technology, NIH, Bethesda, MD. A portion of this research used the Linux Cluster for Genetic Analysis, funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. Support for the Genetic Epidemiology Network of Arteriopathy was provided by the NIH, NHLBI (HL054464, HL054457, HL054481, HL100185, HL119443, and HL133221). The KORA study was initiated and financed by the Helmholtz Zentrum München-German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research and by the State of Bavaria. Furthermore, KORA research was supported within the Munich Center of Health Sciences, Ludwig-Maximilians-Universität, as part of LMUinnovativ. This work was undertaken in the University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, supported by the cross-council Lifelong Health and Wellbeing initiative (MR/ K026992/1). Funding from the Biotechnology and Biological Sciences Research Council, the Medical Research Council (MRC), and the University of Edinburgh is gratefully acknowledged. University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology funding supports I.J.D. W.D.H. is supported by a grant from Age UK (Disconnected Mind Project). The MARTHA project was supported by a grant from the Program Hos-pitalier de Recherche Clinique and the ICAN Institute for Cardiometabolism and Nutrition (ANR-10-IAHU-05). The Human450Methylation epityping was funded by the Canadian Institutes of Health Research (grant MOP 86466) and by the Heart and Stroke Foundation of Canada (grant T6484). The NTR received funding from the BBRMI-NL-financed BIOS Consortium (NWO 184.021.007), and the Netherlands Organization for Scientific Research (genotype/phenotype database for behavior genetic and genetic epidemiological studies; ZonMwMiddelgroot 911–09–032). J.v.D. is supported by ACTION. ACTION receives funding from the European Union Seventh Framework Program (FP7/2007-2013) under grant agreement no 602768. The Rotterdam Study is supported by Erasmus MC (Erasmus Medical Center Rotterdam), the Erasmus University Rotterdam, the Netherlands Organization for Scientific Research, the Netherlands Organization for Health Research and Development, the Research Institute for Diseases in the Elderly, the Ministry of Education, Culture and Science, and the Ministry of Health, Welfare and Sports.

Funders	Funder number
ACTION
Erasmus Medical Center Rotterdam
FundacióLa Maratóde TV3	20151332
ICAN Institute for Cardiometabolism and Nutrition	ANR-10-IAHU-05
Laughlin Family
Locke Charitable Foundation
MIBAVA	12CVD03
Program Hos-pitalier de Recherche Clinique
Robert Dawson Evans Endowment	HL054457, HL119443, HL133221, HL100185, HL054481, HL054464
Society of Epidemiologic Research
Southern California Diabetes Endocrinology Research Center	N01-HC-25195
University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology
cross-council Lifelong Health and Wellbeing initiative	MR/ K026992/1
National Institutes of Health
National Institute on Aging
National Heart, Lung, and Blood Institute	R01HL111089, K08HL116640, HHSN268200800007C, R01HL116747, R01HL092111, N01HC55222, N01HC85081, U01HL080295, N01HC85082, R01HL085083, R01HL105756, N01HC85080, HHSN268201200036C, N01HC85086, N01HC85083, R01HL120393, N01HC85079, R01HL103612, R01HL087652, U01HL130114
National Institute of Diabetes and Digestive and Kidney Diseases	DK063491
National Institute of Neurological Disorders and Stroke	R01AG023629
Center for Information Technology
Merck Company Foundation
Alpha Phi Foundation
National Center for Advancing Translational Sciences	UL1TR001881
Division of Intramural Research, National Institute of Allergy and Infectious Diseases
Indiana Clinical and Translational Sciences Institute
Seventh Framework Programme	602768
Canadian Institutes of Health Research	MOP 86466
Heart and Stroke Foundation of Canada	T6484
Medical Research Council
Biotechnology and Biological Sciences Research Council
Age UK
University of Edinburgh
Fondation Leducq
ZonMw
Erasmus Universiteit Rotterdam
Bundesministerium für Bildung und Forschung
Ministerie van Volksgezondheid, Welzijn en Sport
Erasmus Medisch Centrum
Ministerie van Onderwijs, Cultuur en Wetenschap
Nederlandse Organisatie voor Wetenschappelijk Onderzoek	911–09–032, 184.021.007
Hjärt-Lungfonden	201202729
Vetenskapsrådet	12660
Seventh Framework Programme
Deutsches Forschungszentrum für Gesundheit und Umwelt, Helmholtz Zentrum München

Cohort Studies

Netherlands Twin Register (NTR)

UN SDGs

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

Access to Document

10.1182/blood-2018-02-831347

DNA methylation age is associated with an altered hemostatic profile in a multiethnic metaanalysisFinal published version, 882 KBLicence: Article 25fa Dutch Copyright Act

Persistent URL (handle)

Persistent link

Cite this

Ward-Caviness, C. K., Huffman, J. E., Everett, K., Germain, M., Van Dongen, J., Hill, W. D., Jhun, M. A., Brody, J. A., Ghanbari, M., Du, L., Roetker, N. S., De Vries, P. S., Waldenberger, M., Gieger, C., Wolf, P., Prokisch, H., Koenig, W., O’Donnell, C. J., Levy, D., ... Peters, A. (2018). DNA methylation age is associated with an altered hemostatic profile in a multiethnic meta-analysis. Blood, 132(17), 1842-1850. https://doi.org/10.1182/blood-2018-02-831347

@article{5127e7d5741143a394b412e7ada33fbc,

title = "DNA methylation age is associated with an altered hemostatic profile in a multiethnic meta-analysis",

abstract = "Many hemostatic factors are associated with age and age-related diseases; however, much remains unknown about the biological mechanisms linking aging and hemostatic factors. DNA methylation is a novel means by which to assess epigenetic aging, which is a measure of age and the aging processes as determined by altered epigenetic states. We used a meta-analysis approach to examine the association between measures of epigenetic aging and hemostatic factors, as well as a clotting time measure. For fibrinogen, we performed European and African ancestry–specific meta-analyses which were then combined via a random effects meta-analysis. For all other measures we could not estimate ancestry-specific effects and used a single fixed effects meta-analysis. We found that 1-year higher extrinsic epigenetic age as compared with chronological age was associated with higher fibrinogen (0.004 g/L/y; 95% confidence interval, 0.001-0.007; P 5 .01) and plasminogen activator inhibitor 1 (PAI-1; 0.13 U/mL/y; 95% confidence interval, 0.07-0.20; P 5 6.6 3 1025) concentrations, as well as lower activated partial thromboplastin time, a measure of clotting time. We replicated PAI-1 associations using an independent cohort. To further elucidate potential functional mechanisms, we associated epigenetic aging with expression levels of the PAI-1 protein encoding gene (SERPINE1) and the 3 fibrinogen subunit-encoding genes (FGA, FGG, and FGB) in both peripheral blood and aorta intima-media samples. We observed associations between accelerated epigenetic aging and transcription of FGG in both tissues. Collectively, our results indicate that accelerated epigenetic aging is associated with a procoagulation hemostatic profile, and that epigenetic aging may regulate hemostasis in part via gene transcription.",

author = "Ward-Caviness, {Cavin K.} and Huffman, {Jennifer E.} and Karl Everett and Marine Germain and {Van Dongen}, Jenny and Hill, {W. David} and Jhun, {Min A.} and Brody, {Jennifer A.} and Mohsen Ghanbari and Lei Du and Roetker, {Nicholas S.} and {De Vries}, {Paul S.} and Melanie Waldenberger and Christian Gieger and Petra Wolf and Holger Prokisch and Wolfgang Koenig and O{\textquoteright}Donnell, {Christopher J.} and Daniel Levy and Chunyu Liu and Vinh Truong and Wells, {Philip S.} and Tr{\'e}gou{\"e}t, {David Alexandre} and Weihong Tang and Morrison, {Alanna C.} and Eric Boerwinkle and Wiggins, {Kerri L.} and Barbara McKnight and Xiuqing Guo and Psaty, {Bruce M.} and Nona Sotoodenia and Boomsma, {Dorret I.} and Gonneke Willemsen and Lannie Ligthart and Deary, {Ian J.} and Wei Zhao and Ware, {Erin B.} and Kardia, {Sharon L.R.} and {Van Meurs}, {Joyce B.J.} and Uitterlinden, {Andre G.} and Franco, {Oscar H.} and Per Eriksson and Anders Franco-Cereceda and Pankow, {James S.} and Johnson, {Andrew D.} and France Gagnon and Morange, {Pierre Emmanuel} and {De Geus}, {Eco J.C.} and Starr, {John M.} and Smith, {Jennifer A.} and Abbas Dehghan and Bj{\"o}rck, {Hanna M.} and Smith, {Nicholas L.} and Annette Peters",

note = "Copyright {\textcopyright} 2018 American Society of Hematology.",

year = "2018",

month = oct,

day = "25",

doi = "10.1182/blood-2018-02-831347",

language = "English",

volume = "132",

pages = "1842--1850",

journal = "Blood",

issn = "0006-4971",

publisher = "Elsevier B.V.",

number = "17",

}

Ward-Caviness, CK, Huffman, JE, Everett, K, Germain, M, Van Dongen, J, Hill, WD, Jhun, MA, Brody, JA, Ghanbari, M, Du, L, Roetker, NS, De Vries, PS, Waldenberger, M, Gieger, C, Wolf, P, Prokisch, H, Koenig, W, O’Donnell, CJ, Levy, D, Liu, C, Truong, V, Wells, PS, Trégouët, DA, Tang, W, Morrison, AC, Boerwinkle, E, Wiggins, KL, McKnight, B, Guo, X, Psaty, BM, Sotoodenia, N, Boomsma, DI, Willemsen, G, Ligthart, L, Deary, IJ, Zhao, W, Ware, EB, Kardia, SLR, Van Meurs, JBJ, Uitterlinden, AG, Franco, OH, Eriksson, P, Franco-Cereceda, A, Pankow, JS, Johnson, AD, Gagnon, F, Morange, PE, De Geus, EJC, Starr, JM, Smith, JA, Dehghan, A, Björck, HM, Smith, NL & Peters, A 2018, 'DNA methylation age is associated with an altered hemostatic profile in a multiethnic meta-analysis', Blood, vol. 132, no. 17, pp. 1842-1850. https://doi.org/10.1182/blood-2018-02-831347

TY - JOUR

T1 - DNA methylation age is associated with an altered hemostatic profile in a multiethnic meta-analysis

AU - Ward-Caviness, Cavin K.

AU - Huffman, Jennifer E.

AU - Everett, Karl

AU - Germain, Marine

AU - Van Dongen, Jenny

AU - Hill, W. David

AU - Jhun, Min A.

AU - Brody, Jennifer A.

AU - Ghanbari, Mohsen

AU - Du, Lei

AU - Roetker, Nicholas S.

AU - De Vries, Paul S.

AU - Waldenberger, Melanie

AU - Gieger, Christian

AU - Wolf, Petra

AU - Prokisch, Holger

AU - Koenig, Wolfgang

AU - O’Donnell, Christopher J.

AU - Levy, Daniel

AU - Liu, Chunyu

AU - Truong, Vinh

AU - Wells, Philip S.

AU - Trégouët, David Alexandre

AU - Tang, Weihong

AU - Morrison, Alanna C.

AU - Boerwinkle, Eric

AU - Wiggins, Kerri L.

AU - McKnight, Barbara

AU - Guo, Xiuqing

AU - Psaty, Bruce M.

AU - Sotoodenia, Nona

AU - Boomsma, Dorret I.

AU - Willemsen, Gonneke

AU - Ligthart, Lannie

AU - Deary, Ian J.

AU - Zhao, Wei

AU - Ware, Erin B.

AU - Kardia, Sharon L.R.

AU - Van Meurs, Joyce B.J.

AU - Uitterlinden, Andre G.

AU - Franco, Oscar H.

AU - Eriksson, Per

AU - Franco-Cereceda, Anders

AU - Pankow, James S.

AU - Johnson, Andrew D.

AU - Gagnon, France

AU - Morange, Pierre Emmanuel

AU - De Geus, Eco J.C.

AU - Starr, John M.

AU - Smith, Jennifer A.

AU - Dehghan, Abbas

AU - Björck, Hanna M.

AU - Smith, Nicholas L.

AU - Peters, Annette

PY - 2018/10/25

Y1 - 2018/10/25

N2 - Many hemostatic factors are associated with age and age-related diseases; however, much remains unknown about the biological mechanisms linking aging and hemostatic factors. DNA methylation is a novel means by which to assess epigenetic aging, which is a measure of age and the aging processes as determined by altered epigenetic states. We used a meta-analysis approach to examine the association between measures of epigenetic aging and hemostatic factors, as well as a clotting time measure. For fibrinogen, we performed European and African ancestry–specific meta-analyses which were then combined via a random effects meta-analysis. For all other measures we could not estimate ancestry-specific effects and used a single fixed effects meta-analysis. We found that 1-year higher extrinsic epigenetic age as compared with chronological age was associated with higher fibrinogen (0.004 g/L/y; 95% confidence interval, 0.001-0.007; P 5 .01) and plasminogen activator inhibitor 1 (PAI-1; 0.13 U/mL/y; 95% confidence interval, 0.07-0.20; P 5 6.6 3 1025) concentrations, as well as lower activated partial thromboplastin time, a measure of clotting time. We replicated PAI-1 associations using an independent cohort. To further elucidate potential functional mechanisms, we associated epigenetic aging with expression levels of the PAI-1 protein encoding gene (SERPINE1) and the 3 fibrinogen subunit-encoding genes (FGA, FGG, and FGB) in both peripheral blood and aorta intima-media samples. We observed associations between accelerated epigenetic aging and transcription of FGG in both tissues. Collectively, our results indicate that accelerated epigenetic aging is associated with a procoagulation hemostatic profile, and that epigenetic aging may regulate hemostasis in part via gene transcription.

AB - Many hemostatic factors are associated with age and age-related diseases; however, much remains unknown about the biological mechanisms linking aging and hemostatic factors. DNA methylation is a novel means by which to assess epigenetic aging, which is a measure of age and the aging processes as determined by altered epigenetic states. We used a meta-analysis approach to examine the association between measures of epigenetic aging and hemostatic factors, as well as a clotting time measure. For fibrinogen, we performed European and African ancestry–specific meta-analyses which were then combined via a random effects meta-analysis. For all other measures we could not estimate ancestry-specific effects and used a single fixed effects meta-analysis. We found that 1-year higher extrinsic epigenetic age as compared with chronological age was associated with higher fibrinogen (0.004 g/L/y; 95% confidence interval, 0.001-0.007; P 5 .01) and plasminogen activator inhibitor 1 (PAI-1; 0.13 U/mL/y; 95% confidence interval, 0.07-0.20; P 5 6.6 3 1025) concentrations, as well as lower activated partial thromboplastin time, a measure of clotting time. We replicated PAI-1 associations using an independent cohort. To further elucidate potential functional mechanisms, we associated epigenetic aging with expression levels of the PAI-1 protein encoding gene (SERPINE1) and the 3 fibrinogen subunit-encoding genes (FGA, FGG, and FGB) in both peripheral blood and aorta intima-media samples. We observed associations between accelerated epigenetic aging and transcription of FGG in both tissues. Collectively, our results indicate that accelerated epigenetic aging is associated with a procoagulation hemostatic profile, and that epigenetic aging may regulate hemostasis in part via gene transcription.

UR - http://www.scopus.com/inward/record.url?scp=85055588295&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85055588295&partnerID=8YFLogxK

U2 - 10.1182/blood-2018-02-831347

DO - 10.1182/blood-2018-02-831347

M3 - Article

C2 - 30042098

SN - 0006-4971

VL - 132

SP - 1842

EP - 1850

JO - Blood

JF - Blood

IS - 17

ER -

DNA methylation age is associated with an altered hemostatic profile in a multiethnic meta-analysis

Abstract

Funding

Cohort Studies

UN SDGs

Access to Document

Persistent URL (handle)

Other files and links

Fingerprint

Cite this