Genome-wide DNA methylation patterns for indicators of liver steatosis: a longitudinal multiomic study - UTU Research Portal

A1 Refereed original research article in a scientific journal

Genome-wide DNA methylation patterns for indicators of liver steatosis: a longitudinal multiomic study

Authors: Ciantar, Jo; Rajić, Sonja; Kostiniuk, Daria; Raulamo, Ella; Kartiosuo, Noora; Lai, Liye; Mishra, Pashupati P.; Lyytikäinen, Leo-Pekka; Kleber, Marcus E.; Rovio, Suvi; Mykkänen, Juha; Pahkala, Katja; Peters, Annette; Winkelmann, Juliane; März, Winfried; Kähönen, Mika; Raitakari, Olli; Lehtimäki, Terho; Waldenberger, Melanie; Marttila, Saara; Raitoharju, Emma

Publisher: Springer Nature

Publication year: 2026

Journal: Clinical Epigenetics

Article number: 22

Volume: 18

Issue: 1

ISSN: 1868-7075

eISSN: 1868-7083

DOI: https://doi.org/10.1186/s13148-025-02037-1

Publication's open availability at the time of reporting: Open Access

Publication channel's open availability : Open Access publication channel

Web address : https://doi.org/10.1186/s13148-025-02037-1

Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/508457291

Self-archived copy's licence: CC BY

Self-archived copy's version: Publisher`s PDF

Abstract

Background

To identify blood DNA methylation profiles related to liver steatosis, we performed an EWAS on the presence of ultrasonically-identified liver steatosis in the Young Finns Study (YFS) participants (n = 1529, 33–50y.), and on liver enzyme levels and fatty liver index (FLI) across three discovery cohorts: YFS, LURIC (n = 2371, 17–92y.) and KORA FF4 (n = 1872, 39–88y.). We further investigated the discovered associations across the longitudinal subset of YFS (n = 255), encompassing three follow-ups over 32 years, and the three-generational YFS-3G follow-up in 2018–2020. Finally, we examined the associations of the discovered CpGs with nearby genetic variation and whole blood expression of nearby genes.

Results

In YFS, the methylation levels of cg06690548 (SLC7A11) were lower in individuals with liver steatosis (Δbeta = − 0.011, FDR = 0.004). Methylation of 9 CpGs associated with GGT and 23 CpGs with FLI in at least two of the discovery cohorts. Methylation at cg06690548 (SLC7A11) and the majority of the CpGs associating with GGT or FLI had the strongest association in the two oldest generations of YFS-3G follow-up (ages 43–59y. and 59–93y.), with minor or non-significant association in the youngest generation (ages 6–36y.). Discovered meQTLs for the CpGs did not modulate the association between the methylation levels and GGT or FLI. The expression of the nearby genes mediated only the association between cg06500161 (ABCG1) and cg20544516 (SREBF1) and FLI.

Conclusions

Our findings highlight the association between the methylation levels of cg06690548 (SLC7A11) and liver steatosis, describe the dynamic relationship between whole blood DNA methylation and MASLD, and contribute to a deeper understanding of the pathophysiology of liver diseases.

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Funding information in the publication:
Open access funding provided by Tampere University (including Tampere University Hospital). The Young Finns Study has been financially supported by the Academy of Finland: grants 356405, 322098, 286284, 134309 (Eye), 126925, 121584, 124282, 129378 (Salve), 117797 (Gendi), and 141071 (Skidi); the Social Insurance Institution of Finland; Competitive State Research Financing of the Expert Responsibility area of Kuopio, Tampere and Turku University Hospitals (grant X51001); Juho Vainio Foundation; Paavo Nurmi Foundation; Finnish Foundation for Cardiovascular Research; Finnish Cultural Foundation; The Sigrid Juselius Foundation; Tampere Tuberculosis Foundation; Emil Aaltonen Foundation; Yrjö Jahnsson Foundation; Signe and Ane Gyllenberg Foundation; Diabetes Research Foundation of Finnish Diabetes Association; EU Horizon 2020 (grant 755320 for TAXINOMISIS and grant 848146 for To Aition); European Research Council (grant 742927 for MULTIEPIGEN project); Tampere University Hospital Supporting Foundation; Finnish Society of Clinical Chemistry; the Cancer Foundation Finland; pBETTER4U_EU (Preventing obesity through Biologically and bEhaviorally Tailored inTERventions for you; project number: 101080117); CVDLink (EU grant nro. 101137278) and the Jane and Aatos Erkko Foundation. Pashupati P. Mishra was supported by the Academy of Finland (Grant number: 349708) and Emma Raitoharju (grants: 330809, 338395). The DNA methylation measurement in the LURIC Study has been financially supported by the 7th Framework Program RiskyCAD (grant agreement no. 305739) of the European Union and the Competence Cluster of Nutrition and Cardiovascular Health (nutriCARD), which is funded by the German Federal Ministry of Education and Research (grant numbers 01EA1411A and 01EA1808A). LURIC has also received funding from the H2020 Programs TO_AITION (grant agreement number 848146) and TIMELY (grant agreement number 101017424) of the European Union. 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. Data collection in the KORA study is done in cooperation with the University Hospital of Augsburg. Furthermore, KORA research was supported within the Munich Center of Health Sciences (MC Health), Ludwig-Maximilians-Universität, as part of LMUinnovativ. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.