Epigenomic profiling reveals an association between persistence of DNA methylation and metabolic memory in the DCCT/EDIC type 1 diabetes cohort

Authors: Zhuo Chen, Feng Miao, Andrew D. Paterson, John M. Lachin, Lingxiao Zhang, Dustin E. Schones, Xiwei Wu, Jinhui Wang, Joshua D. Tompkins, Saul Genuth, Barbara H. Braffett, Arthur D. Riggs, Rama Natarajan, David M. Nathan, Bernard Zinman, Oscar B. Crofford, Saul Genuth, J. Brown-Friday, Jill P. Crandall, H. Engel, Samuel S. Engel, Helen Martinez, Mark Phillips, M. Reid, Harry Shamoon, J. Sheindlin, Rose Gubitosi‐Klug, Laurel Mayer, S. Pendegast, Hernando Zegarra, David Miller, Lawrence J. Singerman, Sheila Smith-Brewer, M. NOVAK, John Quin, Saul Genuth, Mark R. Palmert, Eric J. Brown, J. McConnell, P. Pugsley, Paul Crawford, William T. Dahms, David J. Brillon, M. E. Lackaye, Szilárd Kiss, R. Chan, Anton Orlin, Mark A. Rubin, V. Reppucci, T. Lee, M. Heinemann, Shu-Lin Chang, Brian Levy, Lois Jovanovič, M. Richardson, B. Bosco, A. Dwoskin, R. Hanna, S. Barron, R. Keith Campbell, Arti Bhan, Davida Kruger, J. K. Jones, Paul Edwards, Arti Bhan, Jason Carey, Elizabeth M. Angus, Abraham Thomas, A. Galprin, Michael D. McLellan, Fred W. Whitehouse, Richard M. Bergenstal, Matthew Johnson, K. Gunyou, L. Thomas, J. Laechelt, Priscilla Hollander, M. Spencer, David M. Kendall, Robert Cuddihy, P. Callahan, S. List, John Parker Gott, Nathalie Rude, Beth A. Olson, M. Franz, G. Castle, Ruby Birk, J. Nelson, D. Freking, L. Gill, W. Mestrezat, Donnell D. Etzwiler, Kari Lock Morgan, Lloyd Paul Aiello, E. Golden, Paul G. Arrigg, V. Asuquo, Richard S. Beaser, L. Bestourous, Jerry D. Cavallerano, Robert W. Cavicchi, Om P. Ganda, Osama Hamdy, R. S. Kirby, T. Murtha, D. Schlossman, Sachin J. Shah, George S. Sharuk, P. Silva, P. Silver, Margaret E. Stockman, Jennifer K. Sun, E. Weimann, Howard Wolpert, Lloyd M. Aiello, A. Jacobson, Lawrence I. Rand, J. Rosenzwieg, David M. Nathan, Mary Larkin, M. Christofi, K. Folino, John E. Godine, Peter Lou, Christine Stevens, Ellen Anderson, H. Bode, Stuart J. Brink, Chad Cornish, David Cros, Linda M. Delahanty, Andrea deManbey, C. Haggan, Jane Lynch, Charles McKitrick, Dennis K. Norman, Dirk F. Moore, Mei‐Sing Ong, Caitlin Taylor, D. Zimbler, Sheila E. Crowell, Stephanie A. Fritz, Kasper D. Hansen, C. Gauthier‐Kelly, F. J. Service, G. Ziegler, Robert C. Colligan, Louise Schmidt, Benjamin French, R. Woodwick, R. A. Rizza, W. F. Schwenk, Morey W. Haymond, John M. Pach, J. Mortenson, B. Zimmerman, Alexander R. Lucas, Louis M. Luttrell, M. Lopes-Virella, Susan Caulder, C. Pittman, Neha Patel, K. Lee, M. Nutaitis, Jyotika K. Fernandes, Kathie L. Hermayer, Soo Bin Kwon, Amy Blevins, Jeremy C. Parker, John A. Colwell, D. Lee, J. Soule, P. Lindsey, M. Bracey, A. Farr, S. Elsing, T. Thompson, J. Bayne Selby, Timothy J. Lyons, S. Yacoub‐Wasef, M. Szpiech, D. Wood, Ronald K. Mayfield, Mark E. Molitch, Daphne T. Adelman, S. Colson, Lee M. Jampol, Alice T. Lyon, Manjot K. Gill, Z. Strugula, L. Kaminski, Rukhsana G. Mirza, Evica Simjanoski, Donna H. Ryan, Cheryl K.H. Johnson, Amisha Wallia, Senda Ajroud‐Driss, P. Astelford, N. Leloudes, Aria Degillio, B. Schaefer, S. Mudaliar, Gayle M. Lorenzi, Michael H. Goldbaum, Kenneth L. Jones, Martin R. Prince, Michael R. Swenson, Igor Grant, Rebecca G. Reed, R. Lyon, Orville Kolterman, M Giotta, Taylor L. Clark, Georgina Friedenberg, William I. Sivitz, B. Vittetoe, Joanna Kramer, M. Bayless, Rodney Zeitler, Helmut G. Schrott, Nels C. Olson, Linda Snetselaar, Robert P. Hoffman, John H. MacIndoe, T. A. Weingeist, C. Fountain, Susan R. Mendley, S. Johnsonbaugh, Marena Patronas, Maureen F. Carney, P. Salemi, R. Liss, M. Hebdon, Debra Counts, Thomas Donner, Jason Gordon, R Hemady, A. Avinoam Kowarski, Daniela Ostrowski, Scott M. Steidl, B.E. Jones, William H. Herman, Catherine L. Martin, Rodica Pop‐Busui, D. A. Greene, M. J. Stevens, N. Burkhart, T. Sandford, J. Floyd, John P. Bantle, N. Wimmergren, James G. Terry, Dara D. Koozekanani, Sandra R. Montezuma, B. Rogness, M. Mech, T. Strand, Janet E. Olson, Laurie J. McKenzie, C. Kwong, F. C. Goetz, R. Warhol, Dean P. Hainsworth, David E. Goldstein, Susan Hitt, Joseph Giangiacomo, David S. Schade, Janene L. Canady, Mark R. Burge, Arup Das, Robert B. Avery, Loren H. Ketai, J. E. Chapin, Michael Schlüter, Jonathan Rich, Carolyn Johannes, D. Hornbeck, Mark H. Schutta, P. A. Bourne, Alexander J. Brucker, Seth Braunstein, Stanley S. Schwartz, B. J. Maschak-Carey, L. Baker, Trevor J. Orchard, L. Cimino, Thomas J. Songer, Bernard H. Doft, Sara H. Olson, Dorothy Becker, Debra Rubinstein, Robert L. Bergren, J. Fruit, Rick Hyre, C. Palmer, N. Silvers, Louis A. Lobes, Pamela Rath, Paula Conrad, S. Yalamanchi, J. Wesche, M. Bratkowksi, S Arslanian, Jeffrey S. Rinkoff, Joseph W. Warnicki, Denis Curtin, Dori Steinberg, G. Vagstad, R. Harris, L. Steranchak, J. Arch, Katherine Kelly, P. Ostrosaka, M. Guiliani, Marion Good, T. Williams, Kenneth M. Olsen, Andrew Campbell, C. Shipe, Robin Conwit, David N. Finegold, M. Zaucha, Allan Drash, Anthony Morrison, John I. Malone, M. L. Bernal, Peter R. Pavan, N. Grove, Eitaro Tanaka, Donald C. McMillan, J. Vaccaro‐Kish, L. Babbione, H. Solc, Terry J. DeClue, Samuel Dagogo‐Jack, Catrin Wigley, Harriet Ricks, A. Kitabchi, Edward Chaum, Maryanne Murphy, S. Moser, Dale R. Meyer, A. Iannacone, S. Yoser, Michael Bryer‐Ash, S. Schüßler, Helen Lambeth, Philip Raskin, Suzanne Strowig, Monica Ramirez Basco, S. Cercone, Bernard Zinman, Annette Barnie, Robert G. Devenyi, Mark S. Mandelcorn, Michael H. Brent, S. Rogers, A. Gordon, N. Bakshi, Bruce A. Perkins, Laurie Tuason, F. Perdikaris, Rodney Ehrlich, Denis Daneman, Kusiel Perlman, Sarah E. Ferguson, Julie R. Palmer, R. Fahlstrom, Ian H. de Boer, James L. Kinyoun, Lois Van Ottingham, S. Catton, J S Ginsberg, Charlotte McDonald, J. Harth, M. Driscoll, Tom Sheidow, J. Mahon, C. Canny, David A. Nicolle, Pamela G. Colby, John Dupré, Irene Hramiak, N. W. Rodger, M. Jenner, Trish Smith, William F. Brown, Michael May, Joseph Hagan, Adhish Agarwal, T. Adkins, Rodney A. Lorenz, Stephen S. Feman, L. Survant, Neil H. White, L. Levandoski, G. Grand, M. Thomas, Dayle Hunt Joseph, Kevin J. Blinder, Ganga Sagar Shah, Dean B. Burgess, Isaac Boniuk, Julio Santiago, William V. Tamborlane, P. Gatcomb, Kathleen Stoessel, P. Ramos, Kelvin C. Fong, Pilar N. Ossorio, J. Ahern, Rose Gubitosi‐Klug, Cynthia A Beck, Saul Genuth, John Quin, Paul Gaston, Mark R. Palmert, R. R. Trail, William T. Dahms, John M. Lachin, Patricia A. Cleary, Jye‐Yu C. Backlund, Ionut Bebu, Barbara H. Braffett, L. Diminick, Xu Gao, Wei‐Chung Hsu, K. Klumpp, Martin J. Larsen, Paula McGee, Wanjie Sun, S. Villavicencio, Kenton L. Anderson, L. Dews, Naji Younes, Brandy Rutledge, K. Chan, D Rosenberg, B. Petty, A. Determan, Danelle Kenny, C. C. Williams, Catherine C. Cowie, Carolyn Siebert, Michael W. Steffes, Valerie Arends, J. Bucksa, M. Nowicki, Blanche M. Chavers, Dena O’Leary, Joseph F. Polak, Anita Harrington, L. Funk, Richard S. Crow, B. Gloeb, Sofia Thomas, Christopher J. O’Donnell, Elsayed Z. Soliman, Z. M. Zhang, Y. Li, C. Campbell, Lisa Keasler, S. Hensley, Jingbo Hu, Margo Barr, T. Taylor, Ronald J. Prineas, Eva L. Feldman, James W. Albers, Phillip A. Low, Christine Sommer, K. Nickander, T. Speigelberg, M. Pfiefer, M. Schumer, María Morán, J. W. Farquhar, Christopher M. Ryan, D. Sandstrom, T. Williams, M. Geckle, Elisa Cupelli, Floyd Thoma, B. Burzuk, T. Woodfill, R. Danis, Barbara Blodi, David Lawrence, Hugh Wabers, Sapna Gangaputra, Sallie Neill, Matthias Burger, J. Dingledine, V. Gama, Rachael D. Sussman, Matthew D. Davis, Larry D. Hubbard, Matthew J. Budoff, Sirous Darabian, Panteha Rezaeian, Nicholas C. Wong, Marie Fox, Ronald J. Oudiz, L. Kim, Robert Detrano, Karen J. Cruickshanks, Dayna S. Dalton, Kathleen E. Bainbridge, J. Lima, David A. Bluemke, Evrim Türkbey, Rob J. van der Geest, C. Liu, Ashkan A. Malayeri, Arun K. Jain, C. Miao, Harjit Chahal, R. Jarboe, David M. Nathan, Vincent M. Monnier, David R. Sell, Christopher Strauch, Stanley L. Hazen, Arthur G. Pratt, Wan‐Yee Tang, John D. Brunzell, Jonathan Q. Purnell, Rama Natarajan, F. Miao, L. Zhang, Zhuo Chen, Andrew D. Paterson, Andrew P. Boright, Shelley B. Bull, Lianqin Sun, Stephen W. Scherer, M. Lopes-Virella, Timothy J. Lyons, Alicia J. Jenkins, Ronald Klein, Gabriel Virella, Ayad A. Jaffa, R. Carter, Julie A. Stoner, W. Timothy Garvey, Daniel T. Lackland, M. Brabham, D L McGee, Dawei Zheng, Ronald K. Mayfield, John Maynard, Hunter Wessells, Aruna V. Sarma, A. Jacobson, R. Dunn, Sarah K. Holt, Jim Hotaling, C. Kim, Quentin Clemens, J. Brown, Kevin T. McVary - Proceedings of the National Academy of Sciences, PNAS 2016 cited by 240

We examined whether persistence of epigenetic DNA methylation (DNA-me) alterations at specific loci over two different time points in people with diabetes are associated with metabolic memory, the prolonged beneficial effects of intensive vs. conventional therapy during the Diabetes Control and Complications Trial (DCCT) on the progression of microvascular outcomes in the long-term follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) Study. We compared DNA-me profiles in genomic DNA of whole blood (WB) isolated at EDIC Study baseline from 32 cases (DCCT conventional therapy group subjects showing retinopathy or albuminuria progression by EDIC Study year 10) vs. 31 controls (DCCT intensive therapy group subjects without complication progression by EDIC year 10). DNA-me was also profiled in blood monocytes (Monos) of the same patients obtained during EDIC Study years 16-17. In WB, 153 loci depicted hypomethylation, and 225 depicted hypermethylation, whereas in Monos, 155 hypomethylated loci and 247 hypermethylated loci were found (fold change ≥1.3; P < 0.005; cases vs. controls). Twelve annotated differentially methylated loci were common in both WB and Monos, including thioredoxin-interacting protein (TXNIP), known to be associated with hyperglycemia and related complications. A set of differentially methylated loci depicted similar trends of associations with prior HbA1c in both WB and Monos. In vitro, high glucose induced similar persistent hypomethylation at TXNIP in cultured THP1 Monos. These results show that DNA-me differences during the DCCT persist at certain loci associated with glycemia for several years during the EDIC Study and support an epigenetic explanation for metabolic memory.