DNAm-based signatures of accelerated aging and mortality in blood are associated with low renal function

Pamela R. Matías-García; Cavin K. Ward-Caviness; Laura M. Raffield; Xu Gao; Yan Zhang; Rory Wilson; Xīn Gào; Jana Nano; Andrew Bostom; Elena Colicino; Adolfo Correa; Brent Coull; Charles Eaton; Lifang Hou; Allan C. Just; Sonja Kunze; Leslie Lange; Ethan Lange; Xihong Lin; Simin Liu; Jamaji C. Nwanaji-Enwerem; Alex Reiner; Jincheng Shen; Ben Schöttker; Pantel Vokonas; Yinan Zheng; Bessie Young; Joel Schwartz; Steve Horvath; Ake Lu; Eric A. Whitsel; Wolfgang Koenig; Jerzy Adamski; Juliane Winkelmann; Hermann Brenner; Andrea A. Baccarelli; Christian Gieger; Annette Peters; Nora Franceschini; Melanie Waldenberger

doi:10.1186/s13148-021-01082-w

DNAm-based signatures of accelerated aging and mortality in blood are associated with low renal function

Pamela R. Matías-García^*, Cavin K. Ward-Caviness, Laura M. Raffield, Xu Gao, Yan Zhang, Rory Wilson, Xīn Gào, Jana Nano, Andrew Bostom, Elena Colicino, Adolfo Correa, Brent Coull, Charles Eaton, Lifang Hou, Allan C. Just, Sonja Kunze, Leslie Lange, Ethan Lange, Xihong Lin, Simin LiuJamaji C. Nwanaji-Enwerem, Alex Reiner, Jincheng Shen, Ben Schöttker, Pantel Vokonas, Yinan Zheng, Bessie Young, Joel Schwartz, Steve Horvath, Ake Lu, Eric A. Whitsel, Wolfgang Koenig, Jerzy Adamski, Juliane Winkelmann, Hermann Brenner, Andrea A. Baccarelli, Christian Gieger, Annette Peters, Nora Franceschini, Melanie Waldenberger^*

^*Corresponding author for this work

Preventive Medicine

Research output: Contribution to journal › Article › peer-review

20 Scopus citations

Abstract

Background: The difference between an individual's chronological and DNA methylation predicted age (DNAmAge), termed DNAmAge acceleration (DNAmAA), can capture life-long environmental exposures and age-related physiological changes reflected in methylation status. Several studies have linked DNAmAA to morbidity and mortality, yet its relationship with kidney function has not been assessed. We evaluated the associations between seven DNAm aging and lifespan predictors (as well as GrimAge components) and five kidney traits (estimated glomerular filtration rate [eGFR], urine albumin-to-creatinine ratio [uACR], serum urate, microalbuminuria and chronic kidney disease [CKD]) in up to 9688 European, African American and Hispanic/Latino individuals from seven population-based studies. Results: We identified 23 significant associations in our large trans-ethnic meta-analysis (p < 1.43E−03 and consistent direction of effect across studies). Age acceleration measured by the Extrinsic and PhenoAge estimators, as well as Zhang’s 10-CpG epigenetic mortality risk score (MRS), were associated with all parameters of poor kidney health (lower eGFR, prevalent CKD, higher uACR, microalbuminuria and higher serum urate). Six of these associations were independently observed in European and African American populations. MRS in particular was consistently associated with eGFR (β = − 0.12, 95% CI = [− 0.16, − 0.08] change in log-transformed eGFR per unit increase in MRS, p = 4.39E−08), prevalent CKD (odds ratio (OR) = 1.78 [1.47, 2.16], p = 2.71E-09) and higher serum urate levels (β = 0.12 [0.07, 0.16], p = 2.08E−06). The “first-generation” clocks (Hannum, Horvath) and GrimAge showed different patterns of association with the kidney traits. Three of the DNAm-estimated components of GrimAge, namely adrenomedullin, plasminogen-activation inhibition 1 and pack years, were positively associated with higher uACR, serum urate and microalbuminuria. Conclusion: DNAmAge acceleration and DNAm mortality predictors estimated in whole blood were associated with multiple kidney traits, including eGFR and CKD, in this multi-ethnic study. Epigenetic biomarkers which reflect the systemic effects of age-related mechanisms such as immunosenescence, inflammaging and oxidative stress may have important mechanistic or prognostic roles in kidney disease. Our study highlights new findings linking kidney disease to biological aging, and opportunities warranting future investigation into DNA methylation biomarkers for prognostic or risk stratification in kidney disease.

Original language	English (US)
Article number	121
Journal	Clinical Epigenetics
Volume	13
Issue number	1
DOIs	https://doi.org/10.1186/s13148-021-01082-w
State	Published - Dec 2021

Funding

The KORA study was initiated and financed by the Helmholtz Zentrum München–German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Furthermore, KORA research has been supported within the Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universität, as part of LMUinnovativ. The ESTHER study was supported by the Baden-Württemberg State Ministry of Science, Research and Arts (Stuttgart, Germany), the Federal Ministry of Education and Research (Berlin, Germany), and the Federal Ministry of Family Affairs, Senior Citizens, Women and Youth (Berlin, Germany). The sponsors had no role in the study design, in the collection, analysis, and interpretation of data and preparation, review, or approval of the manuscript. The Normative Aging Study is supported by the National Institute of Environmental Health Sciences (grants P30ES009089, R01ES021733, R01ES025225, and R01ES027747). The VA Normative Aging Study is supported by the Cooperative Studies Program/Epidemiology Research and Information Center of the U.S. Department of Veterans Affairs and is a component of the Massachusetts Veterans Epidemiology Research and Information Center, Boston, Massachusetts. The WHI program is funded by the National Heart, Lung and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C and HHSN268201600004C. The authors thank the WHI investigators and staff for their dedication, and the study participants for making the program possible. A full listing of WHI investigators can be found at: http://www.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI%20Investigator%20Long%20List.pdf . This study was supported by the National Institutes of Health R01- MD012765, R01-DK117445 and R21-HL140385 to NF; by NIH/NIEHS R01-ES020836 to LH, AB and EAW; and by NIH/NHLBI contract 60442456 BAA23 to SH. The Jackson Heart Study (JHS) is supported and conducted in collaboration with Jackson State University (HHSN268201800013I), Tougaloo College (HHSN268201800014I), the Mississippi State Department of Health (HHSN268201800015I) and the University of Mississippi Medical Center (HHSN268201800010I, HHSN268201800011I and HHSN268201800012I) contracts from the National Heart, Lung and Blood Institute (NHLBI) and the National Institute on Minority Health and Health Disparities (NIMHD). The authors also wish to thank the staffs and participants of the JHS. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung and Blood Institute; the National Institutes of Health; or the US Department of Health and Human Services. The funders had no role in the design and conduct of the study, in the collection, analysis and interpretation of the data, and in the preparation, review or approval of the manuscript. The project described was supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant KL2TR002490 (LMR). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. LMR was also funded by T32 HL129982 and R21-HL140385.

Keywords

Aging
DNAm age
Epigenetic age acceleration
Glomerular filtration rate
Kidney function
Serum urate
UACR

ASJC Scopus subject areas

Molecular Biology
Genetics
Developmental Biology
Genetics(clinical)

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10.1186/s13148-021-01082-w

Cite this

Matías-García, P. R., Ward-Caviness, C. K., Raffield, L. M., Gao, X., Zhang, Y., Wilson, R., Gào, X., Nano, J., Bostom, A., Colicino, E., Correa, A., Coull, B., Eaton, C., Hou, L., Just, A. C., Kunze, S., Lange, L., Lange, E., Lin, X., ... Waldenberger, M. (2021). DNAm-based signatures of accelerated aging and mortality in blood are associated with low renal function. Clinical Epigenetics, 13(1), Article 121. https://doi.org/10.1186/s13148-021-01082-w

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title = "DNAm-based signatures of accelerated aging and mortality in blood are associated with low renal function",

abstract = "Background: The difference between an individual's chronological and DNA methylation predicted age (DNAmAge), termed DNAmAge acceleration (DNAmAA), can capture life-long environmental exposures and age-related physiological changes reflected in methylation status. Several studies have linked DNAmAA to morbidity and mortality, yet its relationship with kidney function has not been assessed. We evaluated the associations between seven DNAm aging and lifespan predictors (as well as GrimAge components) and five kidney traits (estimated glomerular filtration rate [eGFR], urine albumin-to-creatinine ratio [uACR], serum urate, microalbuminuria and chronic kidney disease [CKD]) in up to 9688 European, African American and Hispanic/Latino individuals from seven population-based studies. Results: We identified 23 significant associations in our large trans-ethnic meta-analysis (p < 1.43E−03 and consistent direction of effect across studies). Age acceleration measured by the Extrinsic and PhenoAge estimators, as well as Zhang{\textquoteright}s 10-CpG epigenetic mortality risk score (MRS), were associated with all parameters of poor kidney health (lower eGFR, prevalent CKD, higher uACR, microalbuminuria and higher serum urate). Six of these associations were independently observed in European and African American populations. MRS in particular was consistently associated with eGFR (β = − 0.12, 95% CI = [− 0.16, − 0.08] change in log-transformed eGFR per unit increase in MRS, p = 4.39E−08), prevalent CKD (odds ratio (OR) = 1.78 [1.47, 2.16], p = 2.71E-09) and higher serum urate levels (β = 0.12 [0.07, 0.16], p = 2.08E−06). The “first-generation” clocks (Hannum, Horvath) and GrimAge showed different patterns of association with the kidney traits. Three of the DNAm-estimated components of GrimAge, namely adrenomedullin, plasminogen-activation inhibition 1 and pack years, were positively associated with higher uACR, serum urate and microalbuminuria. Conclusion: DNAmAge acceleration and DNAm mortality predictors estimated in whole blood were associated with multiple kidney traits, including eGFR and CKD, in this multi-ethnic study. Epigenetic biomarkers which reflect the systemic effects of age-related mechanisms such as immunosenescence, inflammaging and oxidative stress may have important mechanistic or prognostic roles in kidney disease. Our study highlights new findings linking kidney disease to biological aging, and opportunities warranting future investigation into DNA methylation biomarkers for prognostic or risk stratification in kidney disease.",

keywords = "Aging, DNAm age, Epigenetic age acceleration, Glomerular filtration rate, Kidney function, Serum urate, UACR",

author = "Mat{\'i}as-Garc{\'i}a, {Pamela R.} and Ward-Caviness, {Cavin K.} and Raffield, {Laura M.} and Xu Gao and Yan Zhang and Rory Wilson and Xīn G{\`a}o and Jana Nano and Andrew Bostom and Elena Colicino and Adolfo Correa and Brent Coull and Charles Eaton and Lifang Hou and Just, {Allan C.} and Sonja Kunze and Leslie Lange and Ethan Lange and Xihong Lin and Simin Liu and Nwanaji-Enwerem, {Jamaji C.} and Alex Reiner and Jincheng Shen and Ben Sch{\"o}ttker and Pantel Vokonas and Yinan Zheng and Bessie Young and Joel Schwartz and Steve Horvath and Ake Lu and Whitsel, {Eric A.} and Wolfgang Koenig and Jerzy Adamski and Juliane Winkelmann and Hermann Brenner and Baccarelli, {Andrea A.} and Christian Gieger and Annette Peters and Nora Franceschini and Melanie Waldenberger",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = dec,

doi = "10.1186/s13148-021-01082-w",

language = "English (US)",

volume = "13",

journal = "Clinical Epigenetics",

issn = "1868-7075",

publisher = "BioMed Central",

number = "1",

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Matías-García, PR, Ward-Caviness, CK, Raffield, LM, Gao, X, Zhang, Y, Wilson, R, Gào, X, Nano, J, Bostom, A, Colicino, E, Correa, A, Coull, B, Eaton, C, Hou, L, Just, AC, Kunze, S, Lange, L, Lange, E, Lin, X, Liu, S, Nwanaji-Enwerem, JC, Reiner, A, Shen, J, Schöttker, B, Vokonas, P, Zheng, Y, Young, B, Schwartz, J, Horvath, S, Lu, A, Whitsel, EA, Koenig, W, Adamski, J, Winkelmann, J, Brenner, H, Baccarelli, AA, Gieger, C, Peters, A, Franceschini, N & Waldenberger, M 2021, 'DNAm-based signatures of accelerated aging and mortality in blood are associated with low renal function', Clinical Epigenetics, vol. 13, no. 1, 121. https://doi.org/10.1186/s13148-021-01082-w

TY - JOUR

T1 - DNAm-based signatures of accelerated aging and mortality in blood are associated with low renal function

AU - Matías-García, Pamela R.

AU - Ward-Caviness, Cavin K.

AU - Raffield, Laura M.

AU - Gao, Xu

AU - Zhang, Yan

AU - Wilson, Rory

AU - Gào, Xīn

AU - Nano, Jana

AU - Bostom, Andrew

AU - Colicino, Elena

AU - Correa, Adolfo

AU - Coull, Brent

AU - Eaton, Charles

AU - Hou, Lifang

AU - Just, Allan C.

AU - Kunze, Sonja

AU - Lange, Leslie

AU - Lange, Ethan

AU - Lin, Xihong

AU - Liu, Simin

AU - Nwanaji-Enwerem, Jamaji C.

AU - Reiner, Alex

AU - Shen, Jincheng

AU - Schöttker, Ben

AU - Vokonas, Pantel

AU - Zheng, Yinan

AU - Young, Bessie

AU - Schwartz, Joel

AU - Horvath, Steve

AU - Lu, Ake

AU - Whitsel, Eric A.

AU - Koenig, Wolfgang

AU - Adamski, Jerzy

AU - Winkelmann, Juliane

AU - Brenner, Hermann

AU - Baccarelli, Andrea A.

AU - Gieger, Christian

AU - Peters, Annette

AU - Franceschini, Nora

AU - Waldenberger, Melanie

PY - 2021/12

Y1 - 2021/12

N2 - Background: The difference between an individual's chronological and DNA methylation predicted age (DNAmAge), termed DNAmAge acceleration (DNAmAA), can capture life-long environmental exposures and age-related physiological changes reflected in methylation status. Several studies have linked DNAmAA to morbidity and mortality, yet its relationship with kidney function has not been assessed. We evaluated the associations between seven DNAm aging and lifespan predictors (as well as GrimAge components) and five kidney traits (estimated glomerular filtration rate [eGFR], urine albumin-to-creatinine ratio [uACR], serum urate, microalbuminuria and chronic kidney disease [CKD]) in up to 9688 European, African American and Hispanic/Latino individuals from seven population-based studies. Results: We identified 23 significant associations in our large trans-ethnic meta-analysis (p < 1.43E−03 and consistent direction of effect across studies). Age acceleration measured by the Extrinsic and PhenoAge estimators, as well as Zhang’s 10-CpG epigenetic mortality risk score (MRS), were associated with all parameters of poor kidney health (lower eGFR, prevalent CKD, higher uACR, microalbuminuria and higher serum urate). Six of these associations were independently observed in European and African American populations. MRS in particular was consistently associated with eGFR (β = − 0.12, 95% CI = [− 0.16, − 0.08] change in log-transformed eGFR per unit increase in MRS, p = 4.39E−08), prevalent CKD (odds ratio (OR) = 1.78 [1.47, 2.16], p = 2.71E-09) and higher serum urate levels (β = 0.12 [0.07, 0.16], p = 2.08E−06). The “first-generation” clocks (Hannum, Horvath) and GrimAge showed different patterns of association with the kidney traits. Three of the DNAm-estimated components of GrimAge, namely adrenomedullin, plasminogen-activation inhibition 1 and pack years, were positively associated with higher uACR, serum urate and microalbuminuria. Conclusion: DNAmAge acceleration and DNAm mortality predictors estimated in whole blood were associated with multiple kidney traits, including eGFR and CKD, in this multi-ethnic study. Epigenetic biomarkers which reflect the systemic effects of age-related mechanisms such as immunosenescence, inflammaging and oxidative stress may have important mechanistic or prognostic roles in kidney disease. Our study highlights new findings linking kidney disease to biological aging, and opportunities warranting future investigation into DNA methylation biomarkers for prognostic or risk stratification in kidney disease.

AB - Background: The difference between an individual's chronological and DNA methylation predicted age (DNAmAge), termed DNAmAge acceleration (DNAmAA), can capture life-long environmental exposures and age-related physiological changes reflected in methylation status. Several studies have linked DNAmAA to morbidity and mortality, yet its relationship with kidney function has not been assessed. We evaluated the associations between seven DNAm aging and lifespan predictors (as well as GrimAge components) and five kidney traits (estimated glomerular filtration rate [eGFR], urine albumin-to-creatinine ratio [uACR], serum urate, microalbuminuria and chronic kidney disease [CKD]) in up to 9688 European, African American and Hispanic/Latino individuals from seven population-based studies. Results: We identified 23 significant associations in our large trans-ethnic meta-analysis (p < 1.43E−03 and consistent direction of effect across studies). Age acceleration measured by the Extrinsic and PhenoAge estimators, as well as Zhang’s 10-CpG epigenetic mortality risk score (MRS), were associated with all parameters of poor kidney health (lower eGFR, prevalent CKD, higher uACR, microalbuminuria and higher serum urate). Six of these associations were independently observed in European and African American populations. MRS in particular was consistently associated with eGFR (β = − 0.12, 95% CI = [− 0.16, − 0.08] change in log-transformed eGFR per unit increase in MRS, p = 4.39E−08), prevalent CKD (odds ratio (OR) = 1.78 [1.47, 2.16], p = 2.71E-09) and higher serum urate levels (β = 0.12 [0.07, 0.16], p = 2.08E−06). The “first-generation” clocks (Hannum, Horvath) and GrimAge showed different patterns of association with the kidney traits. Three of the DNAm-estimated components of GrimAge, namely adrenomedullin, plasminogen-activation inhibition 1 and pack years, were positively associated with higher uACR, serum urate and microalbuminuria. Conclusion: DNAmAge acceleration and DNAm mortality predictors estimated in whole blood were associated with multiple kidney traits, including eGFR and CKD, in this multi-ethnic study. Epigenetic biomarkers which reflect the systemic effects of age-related mechanisms such as immunosenescence, inflammaging and oxidative stress may have important mechanistic or prognostic roles in kidney disease. Our study highlights new findings linking kidney disease to biological aging, and opportunities warranting future investigation into DNA methylation biomarkers for prognostic or risk stratification in kidney disease.

KW - Aging

KW - DNAm age

KW - Epigenetic age acceleration

KW - Glomerular filtration rate

KW - Kidney function

KW - Serum urate

KW - UACR

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U2 - 10.1186/s13148-021-01082-w

DO - 10.1186/s13148-021-01082-w

M3 - Article

C2 - 34078457

AN - SCOPUS:85107224684

SN - 1868-7075

VL - 13

JO - Clinical Epigenetics

JF - Clinical Epigenetics

IS - 1

M1 - 121

ER -

DNAm-based signatures of accelerated aging and mortality in blood are associated with low renal function

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