Epigenome-wide association study of circulating interleukin-6 connects DNA methylation to immunometabolic and inflammatory health

Lucy Sinke; Jenny van Dongen; Thomas Delerue; Rory Wilson; Yujing Xia; Marian Beekman; Gonneke Willemsen; Christian Gieger; Christian Herder; Wolfgang Koenig; Annette Peters; Eco J.C. de Geus; José M. Ordovas; Jordana T. Bell; Melanie Waldenberger; Dorret I. Boomsma; P. Eline Slagboom; Bastiaan T. Heijmans

doi:10.1038/s42003-026-09520-2

Epigenome-wide association study of circulating interleukin-6 connects DNA methylation to immunometabolic and inflammatory health

Lucy Sinke^*
, Jenny van Dongen
, Thomas Delerue
, Rory Wilson
, Yujing Xia
, Marian Beekman
, Gonneke Willemsen
, Christian Gieger
, Christian Herder
, Wolfgang Koenig
, Annette Peters
, Eco J.C. de Geus
, José M. Ordovas
, Jordana T. Bell
, Melanie Waldenberger
, Dorret I. Boomsma
, P. Eline Slagboom
, Bastiaan T. Heijmans^*

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

Interleukin-6 (IL-6) drives metabolic and inflammatory processes central to disease. Current knowledge implicates epigenetic mechanisms in the regulation of these pathways, including through the methylation of CpG sites. This blood-based meta-analysis of three cohorts (n = 4,361) identifies 401 IL-6–associated CpGs enriched in regulatory regions and linked to key immunometabolic genes, including AIM2, MTOR, and IL6R. Three complementary causal inference approaches support most sites as responding to IL-6, with SOCS3 (Suppressor of Cytokine Signalling 3) methylation statistically mediating inflammatory bowel disease risk. Notably, one CpG connected to NFATC2IP (Nuclear Factor of Activated T-cells 2 Interacting Protein) plausibly influences both IL-6 production and multiple immunometabolic conditions, including body mass index and type 2 diabetes. Collectively, our results map the DNA methylation landscape surrounding circulating IL-6 levels and unveil directional effects and distinct functional relationships between epigenetics and inflammation. (Figure presented.)

Original language	English
Article number	242
Journal	Communications biology
Volume	9
Issue number	1
Early online date	4 Feb 2026
DOIs	https://doi.org/10.1038/s42003-026-09520-2
Publication status	E-pub ahead of print - 4 Feb 2026

Bibliographical note

Publisher Copyright:
© The Author(s) 2026.

Funding

The authors thank the staff and participants of all cohorts involved in this study for their contributions. The work of L.S. was supported by the Joint Programming Initiative “a Healthy Diet for a Healthy Life” (JPI-HDHL) DIMENSION project [ZonMW project number: 529051021]. This paper makes use of data generated by the BIOS consortium, and access to this data can be requested from https://ega-archive.org/datasets/EGAD00010000887 . Funding for the BIOS consortium was provided by the Netherlands Organization for Scientific Research (NWO 184.021.007), made available as a Rainbow Project of the Biobanking and Biomolecular Research Infrastructure Netherlands (BBMRI-NL). This paper makes use of data generated by the CHARGE Inflammation Working Group. NTR This research was funded by Genotype/phenotype database for behaviour genetic and genetic epidemiological studies (ZonMW Middelgroot 911-09-032); Netherlands Twin Registry Repository: researching the interplay between genome and environment (NWO-Groot 480-15-001/674); the Avera Institute, Sioux Falls (USA) and the National Institutes of Health (NIH R01 HD042157-01A1, MH081802, Grand Opportunity grants 1RC2 MH089951 and 1RC2 MH089995); NWO, project 184.034.019, and by the BBRMI-NL-financed BIOS Consortium (NWO 184.021.007); epigenetic data were generated at the Human Genomics Facility (HUGE-F) at EUR. J.v.D. is supported by NWO Large Scale infrastructures, X-Omics (184.034.019). DIB acknowledges the Royal Netherlands Academy of Science Professor Award (PAH/6635). KORA F4 The KORA research platform (KORA, Cooperative Health Research in the Region of Augsburg) was initiated and financed by the Helmholtz Munich German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research and by the State of Bavaria. Furthermore, KORA research was supported within the Munich Center of Health Sciences (MC Health), Ludwig-Maximilians-Universität, as part of LMUinnovativ. The work was supported by the German Federal Ministry of Education and Research (BMBF) within the framework of the EU Joint Programming Initiative “A Healthy Diet for a Healthy Life” (DIMENSION; grant number 01EA1902A). The German Diabetes Center is supported by the Ministry of Culture and Science of the state of North Rhine-Westphalia (Düsseldorf, Germany) and the German Federal Ministry of Health (Berlin, Germany). This study was supported in part by a grant from the German Federal Ministry of Education and Research to the German Center for Diabetes Research (DZD). LLS The LLS was supported by a grant from the Innovation-Oriented Research Program on Genomics (SenterNovem IGE01014 and IGE05007), the Centre for Medical Systems Biology, and the National Institute for Healthy Ageing (Grant 05040202 and 05060810), in the framework of the Netherlands Genomics Initiative/Netherlands Organization for Scientific Research. Funders had no say in the study design, collection, analysis, interpretation, writing, or decision to submit this work. DNAm data of whole blood samples was generated for 821 unrelated participants from the offspring-partner generation of the LLS by the Human Genotyping facility (HuGe-F, Erasmus MC, Rotterdam, The Netherlands) within the Biobank-Based Integrative Omics Studies (BIOS) consortium, funded by BBMRI-NL, a research infrastructure financed by the Dutch government (NOW 184.021.007). Genomic DNA (500 ng) was bisulfite converted using the Zymo EZ-96 DNA methylation kit (Zymo Research Corp, Irvine, CA, USA). 4 μl was then hybridized on the Infinium HumanMethylation450 BeadChip array (Illumina Inc., San Diego, CA, USA) according to the manufacturer’s protocol. Data preprocessing and quality control followed the DNAmArray workflow and is described in detail in Supplementary Methods (Cohort Descriptions).

Funders	Funder number
Centre for Medical Systems Biology
CHARGE Inflammation Working Group
Netherlands Organization for Scientific Research
German Federal Ministry of Education and Research
Münchner Zentrum für Gesundheitswissenschaften, Ludwig-Maximilians-Universität München
Now
Helmholtz Munich German Research Center for Environmental Health
National Institutes of Health	1RC2 MH089951, 1RC2 MH089995, 184.034.019, MH081802, R01 HD042157-01A1
Sioux Falls
German Federal Ministry of Health
Helmholtz Zentrum München
JPI-HDHL
Dutch Government
Avera Institute
Ministerium für Kultur und Wissenschaft des Landes Nordrhein-Westfalen
ZonMw	529051021
BMBF
Royal Netherlands Academy of Science
Munich Center of Health Sciences
NWO
Bundesministerium für Gesundheit
Ministry of Culture and Science of the State of North Rhine-Westphalia
Joint Programming Initiative A healthy diet for a healthy life
NWO-Groot	480-15-001/674
BBMRI-NL	911-09-032
Bundesministerium für Forschung, Technologie und Raumfahrt	01EA1902A
Innovation-Oriented Research Program on Genomics	IGE05007, IGE01014
NIH	1RC2 MH089951, 1RC2 MH089995, MH081802, R01 HD042157-01A1
Koninklijke Nederlandse Akademie van Wetenschappen	PAH/6635
Nederlandse Organisatie voor Wetenschappelijk Onderzoek	184.021.007
National Institute for Healthy Ageing	05040202, 05060810

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Sinke, L., van Dongen, J., Delerue, T., Wilson, R., Xia, Y., Beekman, M., Willemsen, G., Gieger, C., Herder, C., Koenig, W., Peters, A., de Geus, E. J. C., Ordovas, J. M., Bell, J. T., Waldenberger, M., Boomsma, D. I., Slagboom, P. E., & Heijmans, B. T. (2026). Epigenome-wide association study of circulating interleukin-6 connects DNA methylation to immunometabolic and inflammatory health. Communications biology, 9(1), Article 242. Advance online publication. https://doi.org/10.1038/s42003-026-09520-2

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abstract = "Interleukin-6 (IL-6) drives metabolic and inflammatory processes central to disease. Current knowledge implicates epigenetic mechanisms in the regulation of these pathways, including through the methylation of CpG sites. This blood-based meta-analysis of three cohorts (n = 4,361) identifies 401 IL-6–associated CpGs enriched in regulatory regions and linked to key immunometabolic genes, including AIM2, MTOR, and IL6R. Three complementary causal inference approaches support most sites as responding to IL-6, with SOCS3 (Suppressor of Cytokine Signalling 3) methylation statistically mediating inflammatory bowel disease risk. Notably, one CpG connected to NFATC2IP (Nuclear Factor of Activated T-cells 2 Interacting Protein) plausibly influences both IL-6 production and multiple immunometabolic conditions, including body mass index and type 2 diabetes. Collectively, our results map the DNA methylation landscape surrounding circulating IL-6 levels and unveil directional effects and distinct functional relationships between epigenetics and inflammation. (Figure presented.)",

author = "Lucy Sinke and \{van Dongen\}, Jenny and Thomas Delerue and Rory Wilson and Yujing Xia and Marian Beekman and Gonneke Willemsen and Christian Gieger and Christian Herder and Wolfgang Koenig and Annette Peters and \{de Geus\}, \{Eco J.C.\} and Ordovas, \{Jos{\'e} M.\} and Bell, \{Jordana T.\} and Melanie Waldenberger and Boomsma, \{Dorret I.\} and Slagboom, \{P. Eline\} and Heijmans, \{Bastiaan T.\}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2026.",

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Sinke, L, van Dongen, J, Delerue, T, Wilson, R, Xia, Y, Beekman, M, Willemsen, G, Gieger, C, Herder, C, Koenig, W, Peters, A, de Geus, EJC, Ordovas, JM, Bell, JT, Waldenberger, M, Boomsma, DI, Slagboom, PE & Heijmans, BT 2026, 'Epigenome-wide association study of circulating interleukin-6 connects DNA methylation to immunometabolic and inflammatory health', Communications biology, vol. 9, no. 1, 242. https://doi.org/10.1038/s42003-026-09520-2

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AU - Beekman, Marian

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AU - de Geus, Eco J.C.

AU - Ordovas, José M.

AU - Bell, Jordana T.

AU - Waldenberger, Melanie

AU - Boomsma, Dorret I.

AU - Slagboom, P. Eline

AU - Heijmans, Bastiaan T.

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Epigenome-wide association study of circulating interleukin-6 connects DNA methylation to immunometabolic and inflammatory health

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