Epigenetic Age and the Risk of Incident Atrial Fibrillation

• Type of Material: Article
• Authors: Jason D Roberts, McMaster University; Eric Vittinghoff, University of California San Francisco; Ake T Lu, University of California Los Angeles; Alvaro Alonso, Emory University; Biqi Wang, Framingham Heart Dis Epidemiol Study; Colleen M Sitlani, University of Washington; Pedrum Mohammadi-Shemirani, McMaster University; Myriam Fornage, University of Texas Health Science Center at Houston; Jelena Kornej, Framingham Heart Study; Jennifer A Brody, University of Washington; Dan E Arking, McKusick-Nathans Institute; Honghuang Lin, Framingham Heart Dis Epidemiol Study; Susan R Heckbert, University of Washington; Ivana Prokic, Erasmus MC; Mohsen Ghanbari, Erasmus MC; Allan C Skanes, Western University, London; Traci M Bartz, University of Washington; Marco Perez, Stanford University; Kent D Taylor, Harbour-UCLA Medical Center; Steven A Lubitz, Massachusetts General Hospital; Patrick T Ellinor, Massachusetts General Hospital; Kathryn L Lunetta, Boston University; James S Pankow, University of Minnesota; Guillaume Pare, McMaster University; Nona Sotoodehnia, University of Washington; Emeilia J Benjamin, Framingham Heart Dis Epidemiol Study; Steve Horvath, University of California Los Angeles; Gregory M Marcus, University of California San Francisco
• Language: English
• Date: 2021-12-14
• Publisher: LIPPINCOTT WILLIAMS & WILKINS
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2021 American Heart Association, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1161/CIRCULATIONAHA.121.056456
• Title of Journal or Parent Work: CIRCULATION
• Volume: 144
• Issue: 24
• Start Page: 1899
• End Page: 1911
• Grant/Funding Information: CHS: Infrastructure for the CHARGE Consortium is supported in part by the National Heart, Lung, and Blood Institute grant R01HL105756. The CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086; and NHLBI grants U01HL080295, U01HL130114, K08HL116640, R01HL087652, R01HL092111, R01HL103612, R01HL105756, R01HL103612, R01HL111089, R01HL116747 and R01HL120393 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 from the National Institute on Aging (NIA), Merck Foundation / Society of Epidemiologic Research as well as Laughlin Family, Alpha Phi Foundation, and Locke Charitable Foundation. A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center.; Dr. Sotoodehnia is supported by R01HL141989 from the NHLBI.; Dr. Lubitz is supported by NIH grant 1R01HL139731 and American Heart Association grant 18SFRN34250007.; The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.; Drs. Lu and Horvath are supported by a National Institute of Health U01 grant, U01AG060908 - 01.; FHS: The Framingham Heart Study is funded by NIH, NHLBI, 75N92019D00031; HHSN268201500001I. Funding also provided by NHLBI: R01HL128914; 2R01 HL092577; American Heart Association, 18SFRN34110082; The laboratory work for this investigation was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, and by a Director’s Challenge Award, National Institutes of Health.; ARIC: The Atherosclerosis Risk in Communities study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services (contract numbers HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I and HHSN268201700005I). Funding was also provided by 5RC2HL102419, R01NS087541, K24HL148521, and American Heart Association grant 16EIA26410001.; Dr. Kornej received funding from the Marie Sklodowska-Curie Actions under the European Union’s Horizon 2020 research and innovation programme (grant agreement No 838259).
• Keywords: DNA METHYLATION; ATHEROSCLEROSIS RISK; DISEASE; Cardiovascular System & Cardiology; Science & Technology; Peripheral Vascular Disease; Life Sciences & Biomedicine; atrial fibrillation; epigenomics; genetics; SURVIVAL; aging; Cardiac & Cardiovascular Systems

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.