Record W2367975225 · doi:10.1073/pnas.1603712113

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

2016· article· en· W2367975225 on OpenAlexaff

Zhuo Chen, 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, 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, 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, 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, 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, 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, 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, Cynthia A Beck, Paul Gaston, R. R. Trail, Patricia A. Cleary, Jye‐Yu C. Backlund, Ionut Bebu, 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, M. Geckle, Elisa Cupelli, Floyd Thoma, B. Burzuk, T. Woodfill, 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, Vincent M. Monnier, David R. Sell, Christopher Strauch, Stanley L. Hazen, Arthur G. Pratt, Wan‐Yee Tang, John D. Brunzell, Jonathan Q. Purnell, L. Zhang, Zhuo Chen, Andrew P. Boright, Shelley B. Bull, Lianqin Sun, Stephen W. Scherer, 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, John Maynard, Hunter Wessells, Aruna V. Sarma, R. Dunn, Sarah K. Holt, Jim Hotaling, C. Kim, Quentin Clemens, Kevin T. McVary

Bibliographic record

VenueProceedings of the National Academy of Sciences · 2016

Typearticle

Languageen

FieldBiochemistry, Genetics and Molecular Biology

TopicEpigenetics and DNA Methylation

Canadian institutionsHospital for Sick Children

FundersNational Institute of Diabetes and Digestive and Kidney DiseasesNational Cancer InstituteNational Heart, Lung, and Blood InstituteNational Institutes of HealthJuvenile Diabetes Research Foundation International

KeywordsEpigeneticsDNA methylationEpigenomicsCohortDiabetes mellitusBioinformaticsType 2 diabetesMedicinePersistence (discontinuity)Type 2 Diabetes MellitusPopulationMethylationBiologyInternal medicineEndocrinologyGeneticsDNAGene

DOI10.1073/pnas.1603712113

Abstract

fetched live from OpenAlex

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.

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.

How this classification was reachedexpand

Full frame distilled prediction

Teacher imitation

Not calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.

metaresearch head score (Codex)0.004

metaresearch head score (Gemma)0.001

Version: codex-gemma-dda1882f352aValidation status: machine_predicted_unvalidated

Candidate categoriesnone

Consensus categoriesnone

DomainCandidate signal: none · Consensus signal: none

Study designCandidate signal: Bench or experimental · Consensus signal: Bench or experimental

GenreCandidate signal: Empirical · Consensus signal: Empirical

Teacher disagreement score0.102

Threshold uncertainty score0.138

Codex and Gemma teacher scores by category

Category	Codex	Gemma
Metaresearch	0.004	0.001
Meta-epidemiology (narrow)	0.000	0.000
Meta-epidemiology (broad)	0.000	0.000
Bibliometrics	0.000	0.000
Science and technology studies	0.000	0.000
Scholarly communication	0.000	0.000
Open science	0.000	0.000
Research integrity	0.000	0.000
Insufficient payload (model declined to judge)	0.000	0.000

Machine scores (provisional)

The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.

Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.

Opus teacher head0.037

GPT teacher head0.296

Teacher spread0.259 · how far apart the two teachers sit on this one work

Validation statusscore_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it

Classification

machine, unvalidated

Machine predicted; a candidate call from one teacher head, not a consensus.

The models applied no category: nothing in the taxonomy fit this work.

Study designBench or experimental

Domainnot available

GenreEmpirical

How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".

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Citations240

Published2016

Admission routes1

Has abstractyes

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