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
N1 - Publisher Copyright:
© 2021, The Author(s).
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
UR - http://www.scopus.com/inward/record.url?scp=85107224684&partnerID=8YFLogxK
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 -