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Ward-Caviness, C.K. ; Huffman, J.E.* ; Evertt, 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.* ; Liu, C.* ; Truong, V.* ; Wells, P.S.* ; Trégouët, D.A.* ; Tang, W.* ; Morrison, A.C.* ; Boerwinkle, E.* ; Wiggins, K.L.* ; McKnight, B.* ; Guo, X.* ; Psaty, B.M.* ; Sotoodehnia, N.* ; Boomsa, D.I.* ; Willemsen, G.* ; Ligthart, L.* ; Deary, I.J.* ; Zhao, W.* ; Ware, E.B.* ; Kardia, S.L.R.* ; van Meurs, J.B.J.* ; Uitterlinden, A.G.* ; Franco, O.H.* ; Eriksson, P.* ; Franco-Cereceda, A.* ; Pankow, J.S.* ; Johnson, A.D.* ; Gagnon, F.* ; Morange, P.E.* ; de Geus, E.J.C.* ; Starr, J.M.* ; Smith, J.A.* ; Dehghan, A.* ; Björck, H.M.* ; Smith, N.L.* ; Peters, A.

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

Blood 132, 1842-1850 (2018)

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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 = .01) and plasminogen activator inhibitor 1 (PAI-1; 0.13 U/mL/y; 95% confidence interval, 0.07-0.20; P = 6.6 x 10(-5)) 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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