DNAm-based signatures of accelerated aging and mortality in blood are associated with low renal function
Creators: name: Matías-García, Pamela R.
name: Ward-Caviness, Cavin K.
name: Raffield, Laura M.
name: Gao, Xu
name: Zhang, Yan
name: Wilson, Rory
name: Gào, Xīn
name: Nano, Jana
name: Bostom, Andrew
name: Colicino, Elena
name: Correa, Adolfo
name: Coull, Brent
name: Eaton, Charles
name: Hou, Lifang
name: Just, Allan C.
name: Kunze, Sonja
name: Lange, Leslie
name: Lange, Ethan
name: Lin, Xihong
name: Liu, Simin
name: Nwanaji-Enwerem, Jamaji C.
name: Reiner, Alex
name: Shen, Jincheng
name: Schöttker, Ben
name: Vokonas, Pantel
name: Zheng, Yinan
name: Young, Bessie
name: Schwartz, Joel
name: Horvath, Steve
name: Lu, Ake
name: Whitsel, Eric A.
name: Koenig, Wolfgang
name: Adamski, Jerzy
name: Winkelmann, Juliane
name: Brenner, Hermann
name: Baccarelli, Andrea A.
name: Gieger, Christian
name: Peters, Annette
name: Franceschini, Nora
name: Waldenberger, Melanie
Publisher: name: Universität Ulm
Year: 2021
Subjects: subject: Kidney function
subject: Epigenetic age acceleration
subject: DNAm age
subject: UACR
subject: Serum urate
subject: DDC 570 / Life sciences
subject: DDC 610 / Medicine &amp; health
subject: Aging
subject: Kidney function tests
subject: Glomerular filtration rate
subject: Altern
subject: Nierenfunktionsdiagnostik

description: 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 &lt; 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.