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; DCCT/EDIC Research Group

doi:10.1186/s13148-020-00840-6

DNA methylation age calculators reveal association with diabetic neuropathy in type 1 diabetes

Clin Epigenetics. 2020 Apr 5;12(1):52. doi: 10.1186/s13148-020-00840-6.

Authors

Delnaz Roshandel¹, Zhuo Chen², Angelo J Canty³, Shelley B Bull^{4

5}, Rama Natarajan², Andrew D Paterson^{6

7}; DCCT/EDIC Research Group

Collaborators

DCCT/EDIC Research Group:
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 Wood, L 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

Affiliations

¹ Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.
² Department of Diabetes Complications and Metabolism, Beckman Research Institute of City of Hope, Duarte, CA, USA.
³ Department of Mathematics and Statistics, McMaster University, Hamilton, ON, Canada.
⁴ Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada.
⁵ Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada.
⁶ Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON, Canada. Andrew.paterson@sickkids.ca.
⁷ Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada. Andrew.paterson@sickkids.ca.

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.

Keywords: DNA methylation age; Diabetic complications; Type 1 diabetes.

Publication types

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

MeSH terms

Adolescent
Adult
Albumins / metabolism
CpG Islands
DNA Methylation*
Diabetes Mellitus, Type 1 / complications*
Diabetes Mellitus, Type 1 / genetics
Diabetes Mellitus, Type 1 / metabolism
Diabetic Neuropathies / genetics*
Diabetic Neuropathies / metabolism
Epigenesis, Genetic
Female
Genome-Wide Association Study / methods*
Humans
Male
Oligonucleotide Array Sequence Analysis
Young Adult

Substances

Albumins

Abstract

Publication types

MeSH terms

Substances

Grants and funding