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, S. Scherer, F. Miao, L. Zhang, J. Brown-Friday, J. Crandall, H. Engel, S. Engel, H. Martinez, M. Phillips, M. Reid, H. Shamoon, J. Sheindlin, R. Gubitosi-Klug, J. WoodL. Mayer, D. Miller, A. Nayate, M. Novak, S. Pendegast, L. Singerman, D. Weiss, H. Zegarra, E. Brown, P. Crawford, S. Genuth, M. Palmert, P. Pugsley, J. Quin, S. Smith-Brewer, W. Dahms, J. McConnell, C. Beck, K. Farrell, P. Gaston, R. Trail, V. Monnier, D. Sell, C. Strauch, N. S. Gregory, R. Hanna, R. Chan, S. Kiss, A. Orlin, M. Rubin, S. Barron, B. Bosco, D. Brillon, S. Chang, A. Dwoskin, M. Heinemann, L. Jovanovic, M. E. Lackaye, T. Lee, B. Levy, V. Reppucci, M. Richardson, R. Campbell, A. Bhan, J. K. Jones, D. Kruger, P. A. Edwards, H. Remtema, E. Angus, A. Galprin, M. McLellan, A. Thomas, J. D. Carey, F. Whitehouse, R. Bergenstal, S. Dunnigan, K. Gunyou, M. Johnson, A. Carlson, L. Thomas, R. Birk, P. Callahan, G. Castle, R. Cuddihy, M. Franz, D. Freking, L. Gill, J. Gott, P. Hollander, D. Kendall, J. Laechelt, S. List, W. Mestrezat, J. Nelson, B. Olson, N. Rude, M. Spencer, D. Etzwiler, K. Morgan, L. P. Aiello, E. Golden, P. Arrigg, R. Beaser, L. Bestourous, J. Cavallerano, R. Cavicchi, O. Ganda, O. Hamdy, T. Murtha, D. Schlossman, S. Shah, G. Sharuk, P. Silva, P. Silver, M. Stockman, J. Sun, E. Weimann, L. M. Aiello, V. Asuquo, A. Jacobson, R. Kirby, L. Rand, J. Rosenzwieg, H. Wolpert, D. M. Nathan, M. E. Larkin, M. Cayford, A. De Manbey, L. Gurry, J. Heier, A. Joseph, F. Leandre, K. Martin, C. Shah, C. Stevens, N. Thangthaeng, E. Anderson, H. Bode, S. Brink, M. Christofi, C. Cornish, D. Cros, S. Crowell, L. Delahanty, K. Folino, S. Fritz, C. Gauthier-Kelly, J. Godine, C. Haggan, K. Hansen, P. Lou, J. Lynch, C. McKitrick, D. Moore, D. Norman, M. Ong, E. Ryan, C. Taylor, D. Zimbler, A. Vella, G. Ziegler, A. Barkmeier, B. French, M. Haymond, J. Mortenson, J. Pach, R. Rizza, L. Schmidt, W. F. Schwenk, F. J. Service, R. Woodwick, R. Colligan, A. Lucas, B. Zimmerman, K. Nickander, P. Low, C. Sommer, M. Lopes-Virella, L. Luttrell, L. Spillers, J. Fernandes, K. Hermayer, S. Kwon, K. Lee, T. Lyons, M. Nutaitis, A. Blevins, M. Bracey, S. Caulder, J. Colwell, S. Elsing, A. Farr, D. Lee, P. Lindsey, R. Mayfield, J. Parker, N. Patel, C. Pittman, J. Selby, J. Soule, M. Szpiech, T. Thompson, D. Wood, S. Yacoub-Wasef, A. Jenkins, R. Klein, G. Virella, A. Jaffa, R. Carter, J. Stoner, W. T. Garvey, D. Lackland, M. Brabham, D. McGee, D. Zheng, R. K. Mayfield, M. Molitch, A. Wallia, D. Adelman, M. Hartmuller, S. Ajroud-Driss, P. Astelford, A. Degillio, M. Gill, L. Jampol, C. Johnson, L. Kaminski, N. Leloudes, A. Lyon, R. Mirza, D. Ryan, E. Simjanoski, Z. Strugula, S. Colson, B. Schaefer, O. Kolterman, S. Mudaliar, G. Lorenzi, M. Goldbaum, T. Clark, M. Giotta, I. Grant, K. Jones, R. Lyon, M. Prince, R. Reed, M. Swenson, G. Friedenberg, W. I. Sivitz, B. Vittetoe, J. Kramer, M. Bayless, C. Fountain, R. Hoffman, J. MacIndoe, N. Olson, H. Schrott, L. Snetselaar, T. Weingeist, R. Zeitler, R. Miller, S. Johnsonbaugh, M. Carney, D. Counts, T. Donner, J. Gordon, M. Hebdon, R. Hemady, B. Jones, A. Kowarski, R. Liss, S. Mendley, D. Ostrowski, M. Patronas, P. Salemi, S. Steidl, W. H. Herman, C. L. Martin, P. Lee, J. W. Albers, R. Pop-Busui, E. L. Feldman, D. A. Greene, M. J. Stevens, N. Burkhart, T. Sandford, J. Floyd, A. Sarma, R. Dunn, T. Speigelberg, J. Bantle, N. Flaherty, D. Koozekanani, S. Montezuma, J. Terry, F. Goetz, C. Kwong, L. McKenzie, M. Mech, J. Olson, B. Rogness, T. Strand, R. Warhol, N. Wimmergren, M. Steffes, A. Karger, J. Seegmiller, V. Arends, J. Bucksa, B. Chavers, A. Killeen, M. Nowicki, A. Saenger, R. Crow, B. Gloeb, C. O'Donnell, S. Thomas, D. Goldstein, D. Hainsworth, S. Hitt, J. Giangiacomo, D. S. Schade, J. L. Canady, R. B. Avery, M. R. Burge, J. E. Chapin, A. Das, L. H. Ketai, D. Hornbeck, C. Johannes, J. Rich, M. L. Schluter, M. Schutta, P. A. Bourne, A. Brucker, S. Braunstein, B. J. Maschak-Carey, S. Schwartz, L. Baker, T. Orchard, L. Cimino, D. Rubinstein, D. Becker, B. Doft, D. Finegold, K. Kelly, L. Lobes, N. Silvers, T. Songer, D. Steinberg, L. Steranchak, J. Wesche, A. Drash, C. Ryan, B. Burzuk, E. Cupelli, M. Geckle, D. Sandstrom, F. Thoma, T. Williams, T. Woodfill, J. I. Malone, A. Morrison, M. L. Bernal, P. R. Pavan, L. Babbione, T. J. Declue, N. Grove, D. McMillan, H. Solc, E. A. Tanaka, J. Vaccaro-Kish, S. Dagogo-Jack, C. Wigley, S. Huddleston, A. Patel, M. Bryer-Ash, E. Chaum, A. Iannacone, H. Lambeth, D. Meyer, S. Moser, M. B. Murphy, H. Ricks, S. Schussler, S. Yoser, A. Kitabchi, P. Raskin, S. Strowig, Y. G. He, E. Mendelson, R. L. Ufret-Vincenty, M. Basco, S. Cercone, L. Sun, A. Boright, B. A. Perkins, B. Zinman, A. Barnie, N. Bakshi, M. Brent, R. Devenyi, K. Koushan, M. Mandelcorn, F. Perdikaris, L. Tuason, D. Daneman, R. Ehrlich, S. Ferguson, A. Gordon, K. Perlman, S. Rogers, J. Palmer, R. Fahlstrom, I. H. De Boer, L. Olmos De Koo, L. Van Ottingham, S. Catton, J. Ginsberg, J. Kinyoun, J. Brunzell, J. Purnell, H. Wessells, S. Holt, J. Hotaling, C. Kim, Q. Clemens, J. Brown, C. McDonald, M. Driscoll, J. Bylsma, T. Sheidow, W. Brown, C. Canny, P. Colby, S. Debrabandere, J. Dupre, J. Harth, I. Hramiak, M. Jenner, J. Mahon, D. Nicolle, N. W. Rodger, T. Smith, O. Crofford, M. May, J. Lipps Hagan, R. Ramker, T. Adkins, A. Agarwal, C. Lovell, S. Feman, R. Lorenz, L. Survant, N. H. White, L. Levandoski, I. Boniuk, J. Santiago, W. Tamborlane, P. Gatcomb, K. Stoessel, J. Ahern, K. Fong, P. Ossorio, P. Ramos, J. Lachin, I. Bebu, B. Braffett, J. Backlund, L. Diminick, X. Gao, D. Kenny, K. Klumpp, M. Lin, V. Trapani, K. Anderson, K. Chan, P. Cleary, A. Determan, L. Dews, W. Hsu, P. McGee, H. Pan, B. Petty, D. Rosenberg, B. Rutledge, W. Sun, S. Villavicencio, N. Younes, C. Williams, C. Cowie, C. Siebert, A. Harrington, D. O'Leary, J. Polak, L. Funk, E. Z. Soliman, M. Barr, C. Campbell, S. Hensley, J. Hu, L. Keasler, Y. Li, T. Taylor, Z. M. Zhang, R. Prineas, B. Blodi, R. Danis, D. Lawrence, H. Wabers, M. Burger, M. Davis, J. Dingledine, V. Gama, S. Gangaputra, L. Hubbard, S. Neill, R. Sussman, K. Cruickshanks, D. Dalton, K. Bainbridge, M. Budoff, S. Darabian, P. Rezaeian, R. Detrano, M. Fox, L. Kim, R. Oudiz, N. Wong, J. Lima, D. Bluemke, E. Turkbey, H. Chahal, A. Jain, R. Jarboe, C. Liu, A. Malayeri, C. Miao, R. J. Van Der Geest, S. Hazen, A. Pratt, W. Tang, J. Maynard, J. Farquhar, M. Moran, M. Pfiefer, M. Schumer, K. McVary

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Background: 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. Results: 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. Conclusions: 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.

Original languageEnglish (US)
Article number52
JournalClinical epigenetics
Volume12
Issue number1
DOIs
StatePublished - Apr 5 2020

Bibliographical note

Funding Information:
Industry contributors have had no role in the DCCT/EDIC study but have provided free or discounted supplies or equipment to support participants’ adherence to the study: Abbott Diabetes Care (Alameda, CA, USA), Animas (Westchester, PA, USA), Bayer Diabetes Care (Tarrytown, NY, USA), Becton Dickinson (Franklin Lakes, NJ, USA), Eli Lilly (Indianapolis, IN, USA), Extend Nutrition (St Louis, MO, USA), Insulet Corporation (Bedford, MA, USA), LifeScan (Milpitas, CA, USA), Medtronic Diabetes (Minneapolis, MN, USA), Nipro Home Diagnostics (Ft Lauderdale, FL, USA), Nova Diabetes Care (Billerica, MA, USA), Omron (Shelton, CT, USA), Perrigo Diabetes Care (Allegan, MI, USA), Roche Diabetes Care (Indianapolis, IN, USA), and Sanofi (Bridgewater, NJ, USA). The DCCT/EDIC has been supported by cooperative agreement grants (1982–1993 and 2012–2017) and contracts (1982–2012) with the Division of Diabetes Endocrinology and Metabolic Diseases of the NIDKK (current grant nos. U01-DK-094176 and U01-DK-094157) and through support by the National Eye Institute, the National Institute of Neurologic Disorders and Stroke, the General Clinical Research Centers Program (1993– 2007), and the Clinical Translational Science Center Program (2006–present), Bethesda, MD, USA. Funding for genotyping by Illumina HumanCoreExome was provided by JDRF grant 17-2013-9. The study sponsor was not involved in the design of the study; the collection, analysis, and interpretation of data; writing the report; or the decision to submit the report for publication. Methylation study is supported by grants from the National Institutes of Health (NIH): DP3 DK106917-01 and R01 DK065073 (to R.N) and the Wanek family project at the City of Hope (to R.N). Research reported in this publication included work performed in the Integrative Genomics Core at the City of Hope (supported by the National Cancer Institute of the NIH under award number P30CA33572) and the Genomics Core at the University of S. California (Dr. Dan Weisenberger, Director).

Keywords

  • DNA methylation age
  • Diabetic complications
  • Type 1 diabetes

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

Fingerprint Dive into the research topics of 'DNA methylation age calculators reveal association with diabetic neuropathy in type 1 diabetes'. Together they form a unique fingerprint.

Cite this