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

Research output: Contribution to journal › Article › peer-review

14 Scopus citations

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
DOIs	https://doi.org/10.1182/blood-2018-02-831347
State	Published - 25 Oct 2018
Externally published	Yes

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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{75240ecd35dc4f479c31ea74c9eeff87,

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",

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

U2 - 10.1182/blood-2018-02-831347

DO - 10.1182/blood-2018-02-831347

M3 - Article

C2 - 30042098

AN - SCOPUS:85055588295

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

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