DNA methylation age calculators reveal association with diabetic neuropathy in type 1 diabetes.
Delnaz Roshandel,Zhuo Chen,Angelo J. Canty,Shelley B. Bull,Rama Natarajan,Andrew D. Paterson,Stephen W. Scherer,F. Miao,L. Zhang,J. Brown-Friday,Jill P. Crandall,H. Engel,Samuel S. Engel,H. Martinez,M. Phillips,M. Reid,H. Shamoon,J. Sheindlin,Rose A. Gubitosi-Klug,Jamie R. Wood,L. Mayer,David G. Miller,A. Nayate,M. Novak,S. Pendegast,Lawrence J. Singerman,D. Weiss,H. Zegarra,E. Brown,P. Crawford,Saul M. Genuth,Mark R. Palmert,P. Pugsley,J. Quin,Sheila Smith-Brewer,William Dahms,J. McConnell,C. Beck,Kaleigh Farrell,P. Gaston,R. Trail,Vincent M. Monnier,David R. Sell,C. Strauch,N. S. Gregory,R. Hanna,R. Chan,Szilard Kiss,Anton Orlin,Michael Rubin,S. Barron,B. Bosco,David J. Brillon,S. Chang,A. Dwoskin,Murk-Hein Heinemann,L. Jovanovic,M. E. Lackaye,Tae Sup Lee,B. Levy,V. Reppucci,M. Richardson,R. G. Campbell,A. Bhan,J. K. Jones,Davida F. Kruger,Paul A. Edwards,H. Remtema,E. Angus,A. Galprin,M. McLellan,Abraham Thomas,J. D. Carey,Fred W. Whitehouse,Richard M. Bergenstal,S. Dunnigan,K. Gunyou,Mark W. Johnson,A. Carlson,Lorraine Thomas,R. Birk,P. Callahan,G. Castle,R. Cuddihy,M. Franz,D. Freking,L. Gill,J. Gott,P. Hollander,David M. Kendall,J. Laechelt,S. List,W. Mestrezat,Julie A. Nelson,B. Olson,N. Rude,M. Spencer,D. Etzwiler,Katherine A. Morgan,Lloyd Paul Aiello,E. Golden,Paul G. Arrigg,R. Beaser,L. Bestourous,Jerry D. Cavallerano,Robert W. Cavicchi,Om P. Ganda,Osama Hamdy,Timothy J. Murtha,Deborah K. Schlossman,Suresh D. Shah,George S. Sharuk,Paolo S. Silva,Pamela A. Silver,Margaret E. Stockman,Jong Mu Sun,E. Weimann,L. M. Aiello,V. Asuquo,Alan M. Jacobson,R. Kirby,Larry Rand,J. Rosenzwieg,Howard Wolpert,David M. Nathan,Mary E. Larkin,M. Cayford,A. De Manbey,L. Gurry,J. Heier,A. Joseph,F. Leandre,K. Martin,C. Shah,Cladd E. Stevens,N. Thangthaeng,Ellen J. Anderson,H. Bode,S. Brink,M. Christofi,C. Cornish,D. Cros,S. Crowell,L. Delahanty,K. Folino,Stefan Fritz,C. Gauthier-Kelly,John E. Godine,C. Haggan,K. Hansen,P. Lou,Jane L. Lynch,Charles McKitrick,David D. Moore,D. Norman,M. Ong,E. Ryan,Cormac T. Taylor,D. Zimbler,A. Vella,G. Ziegler,Andrew J. Barkmeier,B. French,Morey W. Haymond,J. Mortenson,John M. Pach,Robert A. Rizza,Lois E. Schmidt,W. F. Schwenk,R. Woodwick,Robert C. Colligan,A. Lucas,B. Zimmerman,K. Nickander,Philip A. Low,C. Sommer,Maria F. Lopes-Virella,Louis M. Luttrell,L. Spillers,Jyotika K. Fernandes,Kathie L. Hermayer,S. Kwon,K. Lee,Timothy J. Lyons,M. Nutaitis,A. Blevins,M. Bracey,S. Caulder,John A. Colwell,S. Elsing,A. Farr,David A. Lee,P. Lindsey,Ronald K. Mayfield,J. Parker,Nikhil D. Patel,C. Pittman,J. Selby,J. Soule,M. Szpiech,T. Thompson,D. Wood,S. Yacoub-Wasef,Alicia J. Jenkins,Ronald Klein,Gabriel Virella,Ayad A. Jaffa,Rickey E. Carter,Julie A. Stoner,W. T. Garvey,Daniel T. Lackland,M. Brabham,Daniel L. McGee,D. Zheng,R. K. Mayfield,Mark E. Molitch,Amisha Wallia,D. Adelman,M. Hartmuller,Senda Ajroud-Driss,P. Astelford,A. Degillio,Manjot K. Gill,Lee M. Jampol,C. Johnson,L. Kaminski,N. Leloudes,Alexander R. Lyon,Rukhsana G. Mirza,Dawn M. Ryan,Evica Simjanoski,Z. Strugula,S. Colson,B. Schaefer,Orville G. Kolterman,Sunder Mudaliar,Gayle M. Lorenzi,Michael H. Goldbaum,Tom Clark,M. Giotta,Igor Grant,Karen L. Jones,R. Lyon,M. Prince,R. Reed,M. Swenson,G. Friedenberg,William I. Sivitz,B. Vittetoe,John Kramer,Margaret L. Bayless,Connie Fountain,Richard M. Hoffman,J. MacIndoe,N. Olson,H. Schrott,Linda Snetselaar,Thomas A. Weingeist,R. Zeitler,Rachel G. Miller,S. Johnsonbaugh,M. Carney,D. Counts,Thomas Donner,J. Gordon,M. Hebdon,Ramzi K. Hemady,Bradley D. Jones,A. Kowarski,R. Liss,S. Mendley,D. Ostrowski,M. Patronas,P. Salemi,Scott M. Steidl,William H. Herman,Catherine L. Martin,P. Lee,James W. Albers,Rodica Pop-Busui,Eva L. Feldman,Douglas A. Greene,Martin J. Stevens,N. Burkhart,T. Sandford,James S. Floyd,Aruna V. Sarma,R. Dunn,T. Speigelberg,John P. Bantle,N. Flaherty,Dara D. Koozekanani,Sandra R. Montezuma,Joseph M. Terry,F. Goetz,C. Kwong,L. McKenzie,M. Mech,Janet E. Olson,B. Rogness,T. Strand,R. Warhol,N. Wimmergren,Michael W. Steffes,Amy B. Karger,J. Seegmiller,Valerie L. Arends,Jean M. Bucksa,Blanche M. Chavers,A. Killeen,Maren Nowicki,Amy K. Saenger,Richard S. Crow,B. Gloeb,Christopher J. O'Donnell,Shyam M. Thomas,David E. Goldstein,Dean P. Hainsworth,Susan M. Hitt,J. Giangiacomo,David S. Schade,J. L. Canady,R. B. Avery,Mark R. Burge,John E. Chapin,Arup Das,L. H. Ketai,D. Hornbeck,C. Johannes,J. Rich,M. L. Schluter,Mark H. Schutta,P. A. Bourne,Alexander J. Brucker,S. Braunstein,Barbara J. Maschak-Carey,Sharon B. Schwartz,L. Baker,Trevor J. Orchard,L. Cimino,D. Rubinstein,D. J. Becker,Bernard H. Doft,D. Finegold,K. Kelly,Louis A. Lobes,N. Silvers,Thomas J. Songer,D. Steinberg,L. Steranchak,J. Wesche,Allan L. Drash,Chris Ryan,B. Burzuk,E. Cupelli,M. Geckle,D. Sandstrom,F. Thoma,T. Williams,T. Woodfill,John I. Malone,Alanna C. Morrison,M. L. Bernal,Peter R. Pavan,L. Babbione,T. J. Declue,N. Grove,D. McMillan,H. Solc,E. A. Tanaka,J. Vaccaro-Kish,Samuel Dagogo-Jack,C. Wigley,S. Huddleston,Anushka Patel,Michael Bryer-Ash,Edward Chaum,A. Iannacone,Helen Lambeth,D. Meyer,S. Moser,M. B. Murphy,H. Ricks,S. Schussler,S. Yoser,Abbas E. Kitabchi,Philip Raskin,Suzanne M. Strowig,Y. G. He,E. Mendelson,R. L. Ufret-Vincenty,M. Basco,S. Cercone,L. Sun,Andrew P. Boright,Bruce A. Perkins,B. Zinman,Annette Barnie,N. Bakshi,Michael H. Brent,Robert G. Devenyi,K. Koushan,Mark S. Mandelcorn,F. Perdikaris,L. Tuason,Denis Daneman,R. Ehrlich,S. Ferguson,Allan Gordon,Kusiel Perlman,Sophie Rogers,Jerry P. Palmer,R. Fahlstrom,I. H. de Boer,L. Olmos De Koo,L. Van Ottingham,S. Catton,J. Ginsberg,James L. Kinyoun,John D. Brunzell,Jonathan Q. Purnell,Hunter Wessells,S. Holt,J. Hotaling,C. Kim,Q. Clemens,J. Brown,C. McDonald,M. Driscoll,J. Bylsma,Tom G. Sheidow,W. Brown,C. Canny,P. Colby,S. Debrabandere,John Dupre,J. Harth,Irene Hramiak,M. Jenner,Jeffrey L. Mahon,David A. Nicolle,N. W. Rodger,T. Smith,Oscar B. Crofford,M. May,J. Lipps Hagan,R. Ramker,T. Adkins,Anita Agarwal,C. Lovell,Stephen S. Feman,Rodney A. Lorenz,L. Survant,Neil H. White,Lucy A. Levandoski,Isaac Boniuk,Julio V. Santiago,William V. Tamborlane,Patricia Gatcomb,K. Stoessel,J. Ahern,Kelvin C. Fong,Pamela Ossorio,P. Ramos,John M. Lachin,Ionut Bebu,Barbara H. Braffett,Jye-Yu C. Backlund,Lisa Diminick,Xiaoyu Gao,D. Kenny,K. Klumpp,M. Lin,Victoria R. Trapani,Karen L. Anderson,K. Chan,Patricia A. Cleary,A. Determan,L. Dews,W. Hsu,Paula McGee,H. Pan,B. Petty,D. Rosenberg,Brandy N. Rutledge,Wanjie Sun,Stephan Villavicencio,Naji Younes,C. Williams,Catherine C. Cowie,C. Siebert,Anita Harrington,Daniel H. O'Leary,Joseph F. Polak,L. Funk,Elsayed Z. Soliman,M. Barr,Charles Campbell,S. Hensley,J. Hu,L. Keasler,Y. Li,T. Taylor,Z. M. Zhang,Ronald J. Prineas,B. Blodi,Ronald P. Danis,D. Lawrence,Hugh D. Wabers,M. Burger,Matthew D. Davis,J. Dingledine,V. Gama,Sapna Gangaputra,Larry D. Hubbard,S. Neill,R. Sussman,Karen J. Cruickshanks,D. Dalton,Kathleen E. Bainbridge,Matthew J. Budoff,S. Darabian,P. Rezaeian,Robert Detrano,M. Fox,L. Kim,Ronald J. Oudiz,N. Wong,Joao A. Lima,David A. Bluemke,Evrim B. Turkbey,Harjit Chahal,Alka Jain,R. Jarboe,Cyndi F. Liu,A. Malayeri,C. Miao,R. J. van der Geest,Stanley L. Hazen,A. Pratt,W. Tang,John D. Maynard,J. Farquhar,M. Moran,M. Pfiefer,M. Schumer,K. McVary +546 more
TLDR
Pan-tissue and GrimAge were higher whereas Skin & Blood and PhenoAge were lower than chronological age and DNAm age was not associated with the risk of CVD or retinopathy over 18–20 years after DNAm measurement.Abstract:
Many CpGs become hyper or hypo-methylated with age. Multiple methods have been developed by Horvath et al. to estimate DNA methylation (DNAm) age including Pan-tissue, Skin & Blood, PhenoAge, and GrimAge. Pan-tissue and Skin & Blood try to estimate chronological age in the normal population whereas PhenoAge and GrimAge use surrogate markers associated with mortality to estimate biological age and its departure from chronological age. Here, we applied Horvath’s four methods to calculate and compare DNAm age in 499 subjects with type 1 diabetes (T1D) from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study using DNAm data measured by Illumina EPIC array in the whole blood. Association of the four DNAm ages with development of diabetic complications including cardiovascular diseases (CVD), nephropathy, retinopathy, and neuropathy, and their risk factors were investigated. Pan-tissue and GrimAge were higher whereas Skin & Blood and PhenoAge were lower than chronological age (p < 0.0001). DNAm age was not associated with the risk of CVD or retinopathy over 18–20 years after DNAm measurement. However, higher PhenoAge (β = 0.023, p = 0.007) and GrimAge (β = 0.029, p = 0.002) were associated with higher albumin excretion rate (AER), an indicator of diabetic renal disease, measured over time. GrimAge was also associated with development of both diabetic peripheral neuropathy (OR = 1.07, p = 9.24E−3) and cardiovascular autonomic neuropathy (OR = 1.06, p = 0.011). Both HbA1c (β = 0.38, p = 0.026) and T1D duration (β = 0.01, p = 0.043) were associated with higher PhenoAge. Employment (β = − 1.99, p = 0.045) and leisure time (β = − 0.81, p = 0.022) physical activity were associated with lower Pan-tissue and Skin & Blood, respectively. BMI (β = 0.09, p = 0.048) and current smoking (β = 7.13, p = 9.03E−50) were positively associated with Skin & Blood and GrimAge, respectively. Blood pressure, lipid levels, pulse rate, and alcohol consumption were not associated with DNAm age regardless of the method used. Various methods of measuring DNAm age are sub-optimal in detecting people at higher risk of developing diabetic complications although some work better than the others.read more
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