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 JournalArticle

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
Pages (from-to)1842-1850
Number of pages9
JournalBlood
Volume132
Issue number17
Early online date24 Jul 2018
DOIs
Publication statusPublished - 25 Oct 2018

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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