Jason D Roberts1,2, Eric Vittinghoff3, Ake T Lu4, Alvaro Alonso5, Biqi Wang6,7, Colleen M Sitlani8,9, Pedrum Mohammadi-Shemirani1,10,11, Myriam Fornage12, Jelena Kornej6,13, Jennifer A Brody8,9, Dan E Arking14, Honghuang Lin6,15, Susan R Heckbert8,16, Ivana Prokic17, Mohsen Ghanbari17, Allan C Skanes2, Traci M Bartz8,18,9, Marco V Perez19, Kent D Taylor20, Steven A Lubitz21,22,23, Patrick T Ellinor21,22,23, Kathryn L Lunetta7, James S Pankow24, Guillaume Paré1,25,11, Nona Sotoodehnia8,26,16,9, Emelia J Benjamin6,27,13, Steve Horvath28, Gregory M Marcus29. 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.
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.
Authors: Jonathan P Piccini; Bradley G Hammill; Moritz F Sinner; Paul N Jensen; Adrian F Hernandez; Susan R Heckbert; Emelia J Benjamin; Lesley H Curtis Journal: Circ Cardiovasc Qual Outcomes Date: 2012-01-10
Authors: Jordana T Bell; Pei-Chien Tsai; Tsun-Po Yang; Ruth Pidsley; James Nisbet; Daniel Glass; Massimo Mangino; Guangju Zhai; Feng Zhang; Ana Valdes; So-Youn Shin; Emma L Dempster; Robin M Murray; Elin Grundberg; Asa K Hedman; Alexandra Nica; Kerrin S Small; Emmanouil T Dermitzakis; Mark I McCarthy; Jonathan Mill; Tim D Spector; Panos Deloukas Journal: PLoS Genet Date: 2012-04-19 Impact factor: 5.917
Authors: Carolina Roselli; Mark D Chaffin; Lu-Chen Weng; Stefanie Aeschbacher; Gustav Ahlberg; Christine M Albert; Peter Almgren; Alvaro Alonso; Christopher D Anderson; Krishna G Aragam; Dan E Arking; John Barnard; Traci M Bartz; Emelia J Benjamin; Nathan A Bihlmeyer; Joshua C Bis; Heather L Bloom; Eric Boerwinkle; Erwin B Bottinger; Jennifer A Brody; Hugh Calkins; Archie Campbell; Thomas P Cappola; John Carlquist; Daniel I Chasman; Lin Y Chen; Yii-Der Ida Chen; Eue-Keun Choi; Seung Hoan Choi; Ingrid E Christophersen; Mina K Chung; John W Cole; David Conen; James Cook; Harry J Crijns; Michael J Cutler; Scott M Damrauer; Brian R Daniels; Dawood Darbar; Graciela Delgado; Joshua C Denny; Martin Dichgans; Marcus Dörr; Elton A Dudink; Samuel C Dudley; Nada Esa; Tonu Esko; Markku Eskola; Diane Fatkin; Stephan B Felix; Ian Ford; Oscar H Franco; Bastiaan Geelhoed; Raji P Grewal; Vilmundur Gudnason; Xiuqing Guo; Namrata Gupta; Stefan Gustafsson; Rebecca Gutmann; Anders Hamsten; Tamara B Harris; Caroline Hayward; Susan R Heckbert; Jussi Hernesniemi; Lynne J Hocking; Albert Hofman; Andrea R V R Horimoto; Jie Huang; Paul L Huang; Jennifer Huffman; Erik Ingelsson; Esra Gucuk Ipek; Kaoru Ito; Jordi Jimenez-Conde; Renee Johnson; J Wouter Jukema; Stefan Kääb; Mika Kähönen; Yoichiro Kamatani; John P Kane; Adnan Kastrati; Sekar Kathiresan; Petra Katschnig-Winter; Maryam Kavousi; Thorsten Kessler; Bas L Kietselaer; Paulus Kirchhof; Marcus E Kleber; Stacey Knight; Jose E Krieger; Michiaki Kubo; Lenore J Launer; Jari Laurikka; Terho Lehtimäki; Kirsten Leineweber; Rozenn N Lemaitre; Man Li; Hong Euy Lim; Henry J Lin; Honghuang Lin; Lars Lind; Cecilia M Lindgren; Marja-Liisa Lokki; Barry London; Ruth J F Loos; Siew-Kee Low; Yingchang Lu; Leo-Pekka Lyytikäinen; Peter W Macfarlane; Patrik K Magnusson; Anubha Mahajan; Rainer Malik; Alfredo J Mansur; Gregory M Marcus; Lauren Margolin; Kenneth B Margulies; Winfried März; David D McManus; Olle Melander; Sanghamitra Mohanty; Jay A Montgomery; Michael P Morley; Andrew P Morris; Martina Müller-Nurasyid; Andrea Natale; Saman Nazarian; Benjamin Neumann; Christopher Newton-Cheh; Maartje N Niemeijer; Kjell Nikus; Peter Nilsson; Raymond Noordam; Heidi Oellers; Morten S Olesen; Marju Orho-Melander; Sandosh Padmanabhan; Hui-Nam Pak; Guillaume Paré; Nancy L Pedersen; Joanna Pera; Alexandre Pereira; David Porteous; Bruce M Psaty; Sara L Pulit; Clive R Pullinger; Daniel J Rader; Lena Refsgaard; Marta Ribasés; Paul M Ridker; Michiel Rienstra; Lorenz Risch; Dan M Roden; Jonathan Rosand; Michael A Rosenberg; Natalia Rost; Jerome I Rotter; Samir Saba; Roopinder K Sandhu; Renate B Schnabel; Katharina Schramm; Heribert Schunkert; Claudia Schurman; Stuart A Scott; Ilkka Seppälä; Christian Shaffer; Svati Shah; Alaa A Shalaby; Jaemin Shim; M Benjamin Shoemaker; Joylene E Siland; Juha Sinisalo; Moritz F Sinner; Agnieszka Slowik; Albert V Smith; Blair H Smith; J Gustav Smith; Jonathan D Smith; Nicholas L Smith; Elsayed Z Soliman; Nona Sotoodehnia; Bruno H Stricker; Albert Sun; Han Sun; Jesper H Svendsen; Toshihiro Tanaka; Kahraman Tanriverdi; Kent D Taylor; Maris Teder-Laving; Alexander Teumer; Sébastien Thériault; Stella Trompet; Nathan R Tucker; Arnljot Tveit; Andre G Uitterlinden; Pim Van Der Harst; Isabelle C Van Gelder; David R Van Wagoner; Niek Verweij; Efthymia Vlachopoulou; Uwe Völker; Biqi Wang; Peter E Weeke; Bob Weijs; Raul Weiss; Stefan Weiss; Quinn S Wells; Kerri L Wiggins; Jorge A Wong; Daniel Woo; Bradford B Worrall; Pil-Sung Yang; Jie Yao; Zachary T Yoneda; Tanja Zeller; Lingyao Zeng; Steven A Lubitz; Kathryn L Lunetta; Patrick T Ellinor Journal: Nat Genet Date: 2018-06-11 Impact factor: 38.330
Authors: Ake T Lu; Austin Quach; James G Wilson; Alex P Reiner; Abraham Aviv; Kenneth Raj; Lifang Hou; Andrea A Baccarelli; Yun Li; James D Stewart; Eric A Whitsel; Themistocles L Assimes; Luigi Ferrucci; Steve Horvath Journal: Aging (Albany NY) Date: 2019-01-21 Impact factor: 5.682