Epigenetic Age and the Risk of Incident Atrial Fibrillation-Reference-Cited by-同舟云学术

Epigenetic Age and the Risk of Incident Atrial Fibrillation

Published:2021-12-14 Issue:24 Volume:144 Page:1899-1911
ISSN:0009-7322
Container-title:Circulation
language:en
Short-container-title:Circulation

Author:

Roberts Jason D.¹²^ORCID,Vittinghoff Eric³^ORCID,Lu Ake T.⁴^ORCID,Alonso Alvaro⁵^ORCID,Wang Biqi⁶⁷,Sitlani Colleen M.⁸⁹^ORCID,Mohammadi-Shemirani Pedrum¹¹⁰¹¹,Fornage Myriam¹²^ORCID,Kornej Jelena⁶¹³^ORCID,Brody Jennifer A.⁸⁹^ORCID,Arking Dan E.¹⁴^ORCID,Lin Honghuang⁶¹⁵^ORCID,Heckbert Susan R.⁸¹⁶^ORCID,Prokic Ivana¹⁷^ORCID,Ghanbari Mohsen¹⁷^ORCID,Skanes Allan C.²,Bartz Traci M.⁸¹⁸⁹,Perez Marco V.¹⁹^ORCID,Taylor Kent D.²⁰^ORCID,Lubitz Steven A.²¹²²²³^ORCID,Ellinor Patrick T.²¹²²²³^ORCID,Lunetta Kathryn L.⁷^ORCID,Pankow James S.²⁴^ORCID,Paré Guillaume¹²⁵¹¹^ORCID,Sotoodehnia Nona⁸²⁶¹⁶⁹,Benjamin Emelia J.⁶²⁷¹³^ORCID,Horvath Steve²⁸,Marcus Gregory M.²⁹^ORCID

Affiliation:

1. Population Health Research Institute (J.D.R., P.M-S., G.P.);

2. Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, Western University, London, ON, Canada (J.D.R., A.C.S.).

3. Department of Epidemiology and Biostatistics (E.V.) University of California, San Francisco.

4. Department of Human Genetics, David Geffen School of Medicine (A.T.L., S.H.); University of California, Los Angeles.

5. Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA (A.A.).

6. Framingham Heart Study, Framingham, MA (B.W., J.K., H.L., E.J.B.).

7. Departments of Biostatistics (B.W., K.L.L.), School of Public Health;

8. Cardiovascular Health Research Unit (C.M.S., J.A.B., S.R.H., T.M.B., N.S.);

9. Medicine (C.M.S., J.A.B., T.M.B., N.S.); University of Washington, Seattle.

10. Departments of Medical Sciences (P.M-S.), McMaster University, Hamilton, ON, Canada.

11. Thrombosis and Atherosclerosis Research Institute, Department of Medicine, David Braley Cardiac, Vascular, and Stroke Research Institute (P.M-S., G.P.); McMaster University, Hamilton, ON, Canada.

12. Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston (M.F.).

13. Sections of Cardiovascular Medicine (J.K., E.J.B.), Department of Medicine, School of Medicine; Boston University, MA.

14. McKusick-Nathans Institute, Department of Genetic Medicine, Baltimore, MD (D.E.A.).

15. Computational Biomedicine (H.L.), Department of Medicine, School of Medicine; Boston University, MA.

16. Departments of Epidemiology (S.R.H., N.S.), University of Washington, Seattle.

17. Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands (I.P., M.G.).

18. Biostatistics (T.M.B.), University of Washington, Seattle.

19. Division of Cardiovascular Medicine, Stanford University School of Medicine, CA (M.V.P.).

20. Institute for Translational Genomics, The Lundquist Institute at Harbour–University of California, Los Angeles Medical Center, Torrance, CA (K.D.T.).

21. Cardiovascular Research Center (S.A.L., P.T.E.); Massachusetts General Hospital, Boston.

22. Cardiac Arrhythmia Service (S.A.L., P.T.E.), Massachusetts General Hospital, Boston.

23. Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge (S.A.L., P.T.E.).

24. Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis (J.S.P.).

25. Pathology and Molecular Medicine (G.P.); McMaster University, Hamilton, ON, Canada.

26. Division of Cardiology (N.S.);

27. Epidemiology (E.J.B.), School of Public Health;

28. Department of Biostatistics, School of Public Health (S.H.); University of California, Los Angeles.

29. Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine (G.M.M.); University of California, San Francisco.

Abstract

Background: The most prominent risk factor for atrial fibrillation (AF) is chronological age; however, underlying mechanisms are unexplained. Algorithms using epigenetic modifications to the human genome effectively predict chronological age. Chronological and epigenetic predicted ages may diverge in a phenomenon referred to as epigenetic age acceleration (EAA), which may reflect accelerated biological aging. We sought to evaluate for associations between epigenetic age measures and incident AF. Methods: Measures for 4 epigenetic clocks (Horvath, Hannum, DNA methylation [DNAm] PhenoAge, and DNAm GrimAge) and an epigenetic predictor of PAI-1 (plasminogen activator inhibitor-1) levels (ie, DNAm PAI-1) were determined for study participants from 3 population-based cohort studies. Cox models evaluated for associations with incident AF and results were combined via random-effects meta-analyses. Two-sample summary-level Mendelian randomization analyses evaluated for associations between genetic instruments of the EAA measures and AF. Results: Among 5600 participants (mean age, 65.5 years; female, 60.1%; Black, 50.7%), there were 905 incident AF cases during a mean follow-up of 12.9 years. Unadjusted analyses revealed all 4 epigenetic clocks and the DNAm PAI-1 predictor were associated with statistically significant higher hazards of incident AF, though the magnitudes of their point estimates were smaller relative to the associations observed for chronological age. The pooled EAA estimates for each epigenetic measure, with the exception of Horvath EAA, were associated with incident AF in models adjusted for chronological age, race, sex, and smoking variables. After multivariable adjustment for additional known AF risk factors that could also potentially function as mediators, pooled EAA measures for 2 clocks remained statistically significant. Five-year increases in EAA measures for DNAm GrimAge and DNAm PhenoAge were associated with 19% (adjusted hazard ratio [HR], 1.19 [95% CI, 1.09–1.31]; P <0.01) and 15% (adjusted HR, 1.15 [95% CI, 1.05–1.25]; P <0.01) higher hazards of incident AF, respectively. Mendelian randomization analyses for the 5 EAA measures did not reveal statistically significant associations with AF. Conclusions: Our study identified adjusted associations between EAA measures and incident AF, suggesting that biological aging plays an important role independent of chronological age, though a potential underlying causal relationship remains unclear. These aging processes may be modifiable and not constrained by the immutable factor of time.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Physiology (medical),Cardiology and Cardiovascular Medicine

Link

https://www.ahajournals.org/doi/pdf/10.1161/CIRCULATIONAHA.121.056456

Reference43 articles.

1. Translational Challenges in Atrial Fibrillation

2. Atrial Fibrillation

3. Biological Versus Chronological Aging

4. Interventions to Slow Aging in Humans: Are We Ready?

5. DNA methylation-based biomarkers and the epigenetic clock theory of ageing

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