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.
Bibliographical noteFunding Information:
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.
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