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 & 34 others 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, Jim 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

Research output: Contribution to journalArticle

3 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)1842-1850
Number of pages9
JournalBlood
Volume132
Issue number17
DOIs
StatePublished - Oct 25 2018

Fingerprint

Hemostatics
DNA Methylation
Epigenomics
Meta-Analysis
Aging of materials
Plasminogen Activator Inhibitor 1
Fibrinogen
Gene encoding
Transcription
Confidence Intervals
Partial Thromboplastin Time
Thromboplastin
Hemostasis
Genes
Aorta
Blood
Tissue

Cite this

Ward-Caviness, C. K., Huffman, J. E., Everett, K., Germain, M., Van Dongen, J., Hill, W. 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

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

In: Blood, Vol. 132, No. 17, 25.10.2018, p. 1842-1850.

Research output: Contribution to journalArticle

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, J, 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
Ward-Caviness CK, Huffman JE, Everett K, Germain M, Van Dongen J, Hill WD et al. DNA methylation age is associated with an altered hemostatic profile in a multiethnic meta-analysis. Blood. 2018 Oct 25;132(17):1842-1850. https://doi.org/10.1182/blood-2018-02-831347
Ward-Caviness, Cavin K. ; Huffman, Jennifer E. ; Everett, Karl ; Germain, Marine ; Van Dongen, Jenny ; Hill, W. David ; Jhun, Min A. ; Brody, Jennifer A. ; Ghanbari, Mohsen ; Du, Lei ; Roetker, Nicholas S. ; De Vries, Paul S. ; Waldenberger, Melanie ; Gieger, Christian ; Wolf, Petra ; Prokisch, Holger ; Koenig, Wolfgang ; O’Donnell, Christopher J. ; Levy, Daniel ; Liu, Chunyu ; Truong, Vinh ; Wells, Philip S. ; Trégouët, David Alexandre ; Tang, Weihong ; Morrison, Alanna C. ; Boerwinkle, Eric ; Wiggins, Kerri L. ; McKnight, Barbara ; Guo, Xiuqing ; Psaty, Bruce M. ; Sotoodenia, Nona ; Boomsma, Dorret I. ; Willemsen, Gonneke ; Ligthart, Lannie ; Deary, Ian J. ; Zhao, Wei ; Ware, Erin B. ; Kardia, Sharon L.R. ; Van Meurs, Joyce B.J. ; Uitterlinden, Andre G. ; Franco, Oscar H. ; Eriksson, Per ; Franco-Cereceda, Anders ; Pankow, Jim ; Johnson, Andrew D. ; Gagnon, France ; Morange, Pierre Emmanuel ; De Geus, Eco J.C. ; Starr, John M. ; Smith, Jennifer A. ; Dehghan, Abbas ; Björck, Hanna M. ; Smith, Nicholas L. ; Peters, Annette. / DNA methylation age is associated with an altered hemostatic profile in a multiethnic meta-analysis. In: Blood. 2018 ; Vol. 132, No. 17. pp. 1842-1850.
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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.",
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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, Jim

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.

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